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Evaluation of SPN-812 (Viloxazine Extended-release Capsule) in Preschool-age Children With ADHD
Joseph T Hull, PhD - jhull@supernus.com
NCT04781140
Inclusion Criteria:
• Is male or female 4 years 0 months of age to less than or equal to 5 years 9 months of age at Visit 1 (Screening) and considered medically healthy.
• Subject's parent(s) or legal guardian(s)/representative(s) is (are) willing and able to provide written informed consent before completing any study related procedures.
• Has a primary diagnosis of ADHD according to DSM-IV-TR criteria and confirmed with the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL).
• Has an ADHD-RS-IV-P Total Score of ≥ 28 (males) or ≥ 24 (females) at Visit 1 (Screening) and at Visit 2 (Baseline).
• Has a CGI-S score of ≥ 4 (moderate or worse) at Visit 1 (Screening) and at Visit 2 (Baseline).
• Has undergone an adequate course of non-pharmacologic treatment or is having symptoms severe enough to warrant pharmacologic treatment without prior non-pharmacologic treatment.
• Is participating in a structured group activity (e.g., preschool, kindergarten, sports, Sunday school, summer camp or childcare program) at least 2 days a week during study so as to assess symptoms and impairment in a setting outside the home.
• Has not initiated any behavioral intervention/therapy within 30 days of Visit 1 (Screening) and does not plan to initiate any new or discontinue any ongoing behavioral intervention/therapy during the study (e.g., subject is eligible if behavioral intervention/therapy is initiated 30 or more days prior to Visit 1 \[Screening\] and continues with a similar duration/frequency throughout their study).
• Subjects who are on ADHD medication at Visit 1 (Screening), but whose ADHD symptoms are not well controlled on current ADHD medication (e.g., meets Inclusion Criterion #4), meet all other inclusion/exclusion criteria, and discontinues ADHD medication at least 7 days prior to the day of Visit 2 (Baseline) are eligible to participate.
• Has no current condition in the opinion of the Investigator that could confound efficacy assessments, safety assessments or increase participant risk.
• Has lived with the same parent(s) or legal guardian(s) or has lived under a shared living arrangement (e.g., joint legal custody) for greater than or equal to 6 months prior to Visit 1 (Screening).
• Has a body weight ≥5th percentile for age and sex at Visit 1 (Screening) and Visit 2 (Baseline).
Exclusion Criteria:
• Has a diagnosis at Screening (per K-SADS-PL) of another psychiatric disorder that is considered to be the primary diagnosis rather than ADHD or has a comorbid psychiatric disorder secondary to ADHD that, in the opinion of the investigator (after consulting medical monitor), will likely interfere with study treatment adherence and/or impact study results.
• Has a current diagnosis of a major neurological disorder. The eligibility of those who have seizures, a history of seizure-like events (e.g., syncope, myoclonus, severe muscle spasms), a family history of seizure disorder (immediate family, i.e., sibling, parent), and/or febrile seizures will be assessed on a case-by-case basis after consulting the medical monitor.
• History of Bipolar Disorder diagnosed in a first degree relative.
• Has global development delay or intellectual disability by medical history.
• Has a current diagnosis of a significant (per Investigator's evaluation and/or judgement) systemic disease.
• Has body mass index \> 95th percentile for the subject's age and sex at Visit 1 (Screening) or Visit 2 (Baseline).
• Has a mean resting systolic and diastolic blood pressure\* that are both \>95th percentile for age sex, and height and has a mean resting pulse rate\* that is \>95th percentile for age and sex (males: \>117 bpm; females: \>122 bpm) at Visit 1 (Screening) or Visit 2 (Baseline). \* Note: The mean of three measurements while seated.
• Has a clinically significant electrocardiogram finding(s) at Visit 1 (Screening).
• Is currently taking SPN-812 for ADHD, has previously taken SPN-812 for ADHD, but discontinued due to a lack of efficacy or adverse reactions, or has history of allergic reaction, hypersensitivity or intolerance to viloxazine.
• Has an allergy to or cannot swallow pudding and applesauce and cannot swallow intact capsule whole.
• Has any food allergy, intolerance, restriction or special diet that, in the opinion of the Investigator, could contraindicate the subject's participation in the study.
• Has received any investigational drug within the longer of 30 days or 5 half-lives prior to Visit 2 (e.g., first dose of study medication).
• Has a positive urine drug test at Visit 1 (Screening). A positive test for amphetamines is allowed for subjects receiving a stimulant ADHD medication at Screening. The subject will be required to discontinue the stimulant for the duration of the study, beginning at least 7 days prior to Visit 2 (Baseline).
• Is using of prohibited concomitant medications including known CYP1A2 substrates (e.g., theophylline, melatonin) during the Screening Period or (anticipated) for the duration of the study.
• Any reason that, in the opinion of the Investigator, would prevent the subject from participating in the study.
• Has suicidal ideation ("Yes" indicated on C-SSRS question 4 or 5) or suicidal behavior ("Yes" indicated on C-SSRS for any suicidal behavior) within 6 months prior to or the day of Visit 1 (Screening) or has attempted suicide ("Yes" indicated on C-SSRS for lifetime).
DRUG: 100mg SPN-812, DRUG: Placebo
Attention-Deficit/Hyperactivity Disorder
ADHD
Study of Efficacy and Safety of LNP023 in Participants With Active Lupus Nephritis Class III-IV, +/- V
Novartis Pharmaceuticals - novartis.email@novartis.com
NCT05268289
Inclusion Criteria:
Unequivocally positive ANA test result and/or a positive anti dsDNA at screening Active biopsy-proven lupus nephritis within 3 months of screening demonstrating Class III or IV lupus nephritis with or without co-existing features of Class V lupus nephritis.
Documentation of active renal disease at the time of screening necessitating the commencement of therapy with corticosteroids in combination with MMF/MPS.
eGFR ≥ 30 ml/min/1.73 m2 Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections Vaccination against Haemophilus influenzae infection Supportive care including stable dose regimen of anti-malarials (e.g. hydroxychloroquine) unless contraindicated, ACEi or ARB at either locally approved maximal daily dose or the maximally tolerated dose (per investigators' judgement) at screening, as per the local clinical practice. Doses should remain stable throughout the study.
First presentation or flare of lupus nephritis.
Exclusion Criteria:
Induction treatment with cyclophosphamide within 3 months of planned treatment for this study; treatment with calcineurin inhibitors within the previous 3 months prior to randomization.
Presence of rapidly progressive glomerulonephritis (RPGN) as defined by 50% decline in eGFR within 3 months prior to screening.
Renal biopsy presenting with interstitial fibrosis/tubular atrophy (IF/TA) or glomerulosclerosis of more than 50%, or which in the opinion of the investigator is such that it precludes likely response to immunosuppressive therapy.
Participants being treated with systemic corticosteroids (\>5 mg/day prednisone or equivalent) for indications other than SLE or LN e.g. acute asthma, inflammatory bowel disease.
Participants being treated with systemic corticosteroids for SLE or LN will be excluded if they have taken more than an average of 15 mg/day prednisone (or equivalent) in the previous 4 weeks and more than an average of 30 mg/day in the previous 1 week Receipt of more than a total dose of 1000 mg equivalent i.v. pulse methylprednisolone (cumulative dose) within 2 weeks prior to enrollment (and at enrollment)
Other protocol-defined inclusion/exclusion criteria may apply DRUG: Iptacopan (part 1), DRUG: Iptacopan (part 2), DRUG: Placebo + standard of care, DRUG: Iptacopan + placebo
Lupus Nephritis
LNP023, Iptacopan, Lupus Nephritis, proteinuria, Urine Protein-to-Creatinine Ratio, complete renal response, estimated glomerular filtration rate, renal flares, Systemic Lupus Erythematosus
The Effects of IL-1 Blockade on Inotrope Sensitivity in Patients With Heart Failure (AID-HEART) (AID-HEART)
Benjamin VanTassell - bvantassell@vcu.edu
NCT06062966
Inclusion Criteria:
* Primary diagnosis for the clinic visit is stage D heart failure being on chronic stable dose of inotrope therapy (dobutamine or milrinone for the previous 28 days)
* Prior documentation of impaired left ventricular systolic function (ejection fraction \<50%) at most recent assessment by any imaging modality (within 12 months)
* Stable dose of inotrope treatment without a recent hospitalization within the previous month
* Age ≥21 years and willing/able to provide written informed consent
* The patient is willing and able to comply with the protocol (i.e. self administration of the treatment, and exercise protocol).
* Screening plasma C-reactive protein levels \>2 mg/L
Exclusion Criteria:
* Concomitant clinically significant comorbidities including (but not limited to) acute coronary syndromes, uncontrolled hypertension or orthostatic hypotension, tachy- or brady-arrhythmias, acute or chronic pulmonary disease or neuromuscular disorders affecting respiration that would interfere with the execution, interpretation, or completion of the study
* Recent (previous 3 months) or planned resynchronization therapy (CRT), or valve surgeries
* Previous or planned implantation of left ventricular assist devices or heart transplant within the next 3 months
* Recent (\<14 days) use of immunosuppressive or anti-inflammatory drugs (including oral corticosteroids at a dose of prednisone equivalent of 0.5 mg/kg/day but not including inhaled or low dose oral corticosteroids or non-steroidal anti-inflammatory drugs)
* Chronic inflammatory disorder (including but not limited to rheumatoid arthritis, systemic lupus erythematosus)
* Active infection (of any type), including chronic/recurrent infectious disease (including HBV, HCV, and HIV/AIDS) - but excluding HCV+ with undetectable plasma RNA
* Prior (within the past 5 years) or current malignancy on targeted treatment - excluding carcinoma in situ \[any location\] or localized non-melanoma skin cancer
* Stage V kidney disease or on renal-replacement therapy
* Neutropenia (\<1,500/mm3 or \<1,000/mm3 in African-American patients)
* Pregnancy or breastfeeding
* Angina, hypertension, arrhythmias, electrocardiograph (ECG) changes, or other non-cardiac limitations that limit 6MWD obtained during the baseline testing
* Hypersensitivity to anakinra or to E. coli derived products DRUG: Anakinra
Heart Failure
Inotrope sensitivity, IL-1 Blockade, Subcutaneous (SC), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV, 6 Minute Walk Test (6MWT)
ARTEMIS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack (ARTEMIS)
Novo Nordisk - clinicaltrials@novonordisk.com
NCT06118281
Key inclusion:
* Age 18 years or above at the time of signing the informed consent.
* Hospitalisation for acute myocardial infarction with evidence of type 1 myocardial infarction (MI) by invasive angiography performed at site with percutaneous coronary intervention (PCI) capabilities.
* ST-segment elevation myocardial infarction (STEMI) with all the following: a) Relevant onset of symptoms suggestive of cardiac ischaemia within 12 hours before hospitalisation, at the investigator's discretion.
b) Electrocardiogram (ECG)-changes (in the absence of left ventricular hypertrophy or left bundle branch block): ST-segment elevation at the J point in at least two contiguous leads greater than or equal 0.25 (millivolt) mV in men less than 40 years, greater than or equal 0.2 mV in men greater than or equal 40 years, or greater than or equal 0.15 mV in women in leads V2-V3; and/or greater than or equal 0.1 mV in all other leads.
OR
* Non-ST-segment myocardial infarction with all the following: a) Relevant onset of symptoms suggestive of cardiac ischaemia within 24 hours before hospitalisation, at the investigator's discretion. b) Rise and/or fall in car-diac troponin I or T with at least one value above the 99th percentile upper reference limit.
* Possibility for both randomisation and administration of the loading dose of study intervention as early as possible after invasive procedure, and latest within 36 hours of hospitalisation (time 0) for STEMI, and latest within 72 hours of hospitalisation (time 0) for NSTEMI.
* Presence of at least one of the following criteria confirmed based on the participant's medical records and/or medical history interview: a) Any prior MI. b) Prior coronary revascularisation. c) Diabetes mellitus treated with ongoing glucose-lowering agent(s). d)Known chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) greater than or equal to 15 and less than 60 milliliter per minute per 1.73 square meter (mL/min/1.73 m\^2). e) Prior ischaemic stroke. f) Known carotid disease or peripheral artery disease in the lower extremities. g) Multivessel coronary artery disease (current/prior). h) For STEMI patients only: anterior MI at index acute myocardial infarction (AMI)
Key exclusion:
* Use of fibrinolytic therapy for treatment of the current AMI.
* Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV.
* Ongoing haemodynamic instability defined as any of the following: a) Killip Class III or IV. b) Sustained and/or symptomatic hypotension (systolic blood pressure less than 90 millimeters of mercury (mmHg)).
* Severe kidney impairment defined as any of the following: a) eGFR less than 15 mililitre per minute per 1.73 m\^2. b) Chronic haemodialysis or peritoneal dialysis.
* Known alanine aminotransferase (ALT) greater than 8 x upper limit of normal (reference range) (ULN).
* Severe hepatic disease defined as at least one of the following: a) Previously known or current hepatic encephalopathy (clinical evaluation). b) Previously known or current ascites (clinical eval-uation). c) Jaundice (clinical evaluation). d) Previous oesophageal/gastric variceal bleeding. c) Known hepatic cirrhosis.
* Major cardiac surgical (including but not restricted to coronary artery bypass graft surgery (CABG)), non-cardiac surgical, or major endoscopic procedure (thoracoscopic or laparoscopic) within the past 60 days or any major surgical procedure planned at the time of randomisation or as treatment for the current AMI (CABG). Deferred (staged)percutaneous coronary intervention for a non-culprit vessel identified during the current AMI is allowed.
* Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.
* Known (acute or chronic) hepatitis B or hepatitis C.
* History or evidence of untreated latent tuberculosis (TB) such as (but not limited to): a) History of a positive TB test or chest X-ray compatible with latent TB; and TB treatment initiated less than 28 days prior to randomisation. b) Participants with TB risk factors but unwilling to undergo TB treatment if confirmed positive for latent TB based on central laboratory test at baseline (visit 2).
DRUG: Ziltivekimab, DRUG: Placebo
Cardiovascular Risk, Acute Myocardial Infarction (AMI)
HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants (ESTHI)
Nichol Nunn - nichol.nunn@hsc.utah.edu
NCT04177914
Inclusion Criteria:
• Corrected age \<104 weeks and 0 days, AND
• Child is ≥ 37 weeks post menstrual age, AND
• Child must have symptomatic hydrocephalus, defined as: Ventriculomegaly on MRI (frontal-occipital horn ratio (FOR) \>0.45, which approximates "moderate ventriculomegaly"), and at least one of the following: * Head circumference \>98th percentile for corrected age with either bulging fontanelle or splayed sutures * Upgaze paresis/palsy (sundowning) * CSF leak * Papilledema * Tense pseudomeningocele or tense fluid along a track * Vomiting or irritability, with no other attributable cause * Bradycardias or apneas, with no other attributable cause * Intracranial pressure (ICP) monitoring showing persistent elevation of pressure with or without plateau waves AND
• No prior history of shunt insertion or endoscopic third ventriculostomy (ETV) procedure (previous temporization devices and/or external ventricular drains permissible)
Exclusion Criteria:
• Hydrocephalus due to intraventricular hemorrhage in a child born before 37 weeks gestational age; OR
• Anatomy not suitable for ETV+CPC or anteriorly placed ventriculoperitoneal shunt defined as: * Moderate to severe prepontine adhesions on steady state free precession (SSFP) or T2 weighted fast (turbo) spin echo (FSE/TSE) MRI, which includes the following sequences: FIESTA, FIESTA-C, TrueFISP, CISS, Balanced FFE (bFFE), CUBE, SPACE, VISTA, IsoFSE, and 3D MVOX * Closure of one or both foramina of Monro * Thick floor of third ventricle (≥ 3mm) * Narrow third ventricle (\<5mm) * Presence of scalp, bone, or ventricular lesions that make placement of an anterior shunt impracticable; OR
• Underlying condition with a high chance of mortality within 12 months; OR
• Hydrocephalus with loculated CSF compartments; OR
• Peritoneal cavity not suitable for distal shunt placement; OR
• Active CSF infection; OR
• Hydranencephaly; OR
• Child requires an intraventricular procedure (e.g. endoscopic biopsy) in addition to the initial first-time permanent procedure for the treatment of hydrocephalus.
PROCEDURE: Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization (ETV+CPC), DEVICE: Ventriculoperitoneal Shunt
Hydrocephalus
Hydrocephalus, Infants, Ventriculoperitoneal Shunt, ETV+CPC, endoscopic third ventriculostomy, choroid plexus cauterization
ASSESS ALL ALS Study
ALL ALS Patient Navigator - info@all-als.org
NCT06578195
Inclusion Criteria for ALS participants:
• Age 18 years or older
• Capable of providing informed consent
• Willing to follow study procedures
• Diagnosis of ALS by a physician
• Access to a smartphone, computer or tablet, and internet (need not be in the home - access to a public library or other available computer with internet connection is sufficient) Inclusion Criteria for control participants:
• Age 18 years or older
• Capable of providing informed consent
• Willing to follow study procedures
• No diagnosis of ALS , Progressive Muscular Atrophy (PMA) or Primary Lateral Sclerosis (PLS)
• No history of familial ALS/Frontotemporal Dementia (FTD) in a close family member\*\* unless the participant has previously tested negative for the known causative ALS genes. Participants with a family history of singleton ALS are permitted to enroll. * \*\* Defined by the presence of a known ALS causative gene such as C9orf72 in a family member or a family history suggestive of an inherited ALS/FTD syndrome defined by two family members with a history of ALS and/or FTD.
• Access to a smartphone, computer or tablet, and internet (need not be in the home - access to a public library or other available computer with internet connection is sufficient) Exclusion Criteria for all participants:
• Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, active suicidal ideation, suicide attempt, or untreated major depression \<= 90 days of screening, that would interfere with the study procedure, according to Investigator's judgement.
• Clinically significant unstable medical condition (other than ALS) (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, malignant and potentially progressive cancer) that would render the participant unlikely to be able to complete 12 months of follow-up, according to Investigator's judgment. Exclusion Criteria for participants undergoing optional Lumbar Puncture
• Medically unable to undergo lumbar puncture (LP) as determined by the site investigator (i.e., bleeding disorder, a skin infection at or near the LP site, known or suspected intracranial or intraspinal tumor or other cause of increased intracranial pressure).
• Allergy to Lidocaine or other local anesthetic agents.
• Use of anticoagulant medication or antiplatelet medications (aside from aspirin 81 mg) that cannot be safely withheld prior to lumbar puncture.
• Blood dyscrasia, abnormal bleeding diathesis, or the use of dialysis for renal failure.
• Current pregnancy based on participant self-report
• Clinical judgement of the site investigator that the participant would be unable to undergo multiple lumbar punctures.
• Age 18 years or older
• Capable of providing informed consent
• Willing to follow study procedures
• Diagnosis of ALS by a physician
• Access to a smartphone, computer or tablet, and internet (need not be in the home - access to a public library or other available computer with internet connection is sufficient) Inclusion Criteria for control participants:
• Age 18 years or older
• Capable of providing informed consent
• Willing to follow study procedures
• No diagnosis of ALS , Progressive Muscular Atrophy (PMA) or Primary Lateral Sclerosis (PLS)
• No history of familial ALS/Frontotemporal Dementia (FTD) in a close family member\*\* unless the participant has previously tested negative for the known causative ALS genes. Participants with a family history of singleton ALS are permitted to enroll. * \*\* Defined by the presence of a known ALS causative gene such as C9orf72 in a family member or a family history suggestive of an inherited ALS/FTD syndrome defined by two family members with a history of ALS and/or FTD.
• Access to a smartphone, computer or tablet, and internet (need not be in the home - access to a public library or other available computer with internet connection is sufficient) Exclusion Criteria for all participants:
• Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, active suicidal ideation, suicide attempt, or untreated major depression \<= 90 days of screening, that would interfere with the study procedure, according to Investigator's judgement.
• Clinically significant unstable medical condition (other than ALS) (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, malignant and potentially progressive cancer) that would render the participant unlikely to be able to complete 12 months of follow-up, according to Investigator's judgment. Exclusion Criteria for participants undergoing optional Lumbar Puncture
• Medically unable to undergo lumbar puncture (LP) as determined by the site investigator (i.e., bleeding disorder, a skin infection at or near the LP site, known or suspected intracranial or intraspinal tumor or other cause of increased intracranial pressure).
• Allergy to Lidocaine or other local anesthetic agents.
• Use of anticoagulant medication or antiplatelet medications (aside from aspirin 81 mg) that cannot be safely withheld prior to lumbar puncture.
• Blood dyscrasia, abnormal bleeding diathesis, or the use of dialysis for renal failure.
• Current pregnancy based on participant self-report
• Clinical judgement of the site investigator that the participant would be unable to undergo multiple lumbar punctures.
Amyotrophic Lateral Sclerosis
ALS, Amyotrophic Lateral Sclerosis, biomarker, observational
A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma
Mansoor Raza Mirza, MD - ACR-368-201ClinicalTrial@acrivon.com
NCT05548296
Inclusion Criteria:
General
• Participant must be able to give signed, written informed consent.
• Participant must have histologically documented, high-grade endometrial cancer.
• Treatment History Requirements:
• Subject must have received prior platinum-based chemotherapy
• Subject must have received prior anti-PD-(L)1 therapy
• Participant must have histologically confirmed metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen.
• Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (by local Investigator) in a baseline tumor imaging that has been obtained within 28 days of the treatment start. Participant must have radiographic evidence of disease progression based on RECIST v1.1 criteria following the most recent line of treatment.
• Arm 1 and 2 only: Participant must be willing to provide tissue from a newly obtained tumor biopsy from an accessible tumor lesion not previously irradiated after written informed consent. Newly obtained is defined as a specimen taken after written informed consent is obtained, during the 28-day Screening period.
• Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available.
• Participant must have stabilized or recovered (Grade 1 or baseline) from all prior therapy related toxicities, except as follows:
• Alopecia is accepted.
• Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to need for replacement therapy are accepted (including hypothyroidism, diabetes mellitus, or adrenal insufficiency).
• Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 are accepted.
• Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1.
• Participant must have an estimated life expectancy of longer than 3 months.
• Participant must have adequate organ function at Screening, defined as:
• Absolute neutrophil count \> 1500 cells/µL without growth factor support within 1 week prior to obtaining the hematology values at Screening.
• Hemoglobin ≥ 9.0 g/dL.
• Platelets ≥ 150,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening.
• Calculated creatinine clearance (CrCl) ≥ 50 mL/min as calculated by the Cockcroft-Gault formula.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); ≤ 5 × ULN if liver metastases are present.
• Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome ≤ 3 x ULN is acceptable.
• Serum albumin ≥ 3 g/dL.
• Participant must have adequate coagulation profile as defined below if not on anticoagulation. If subject is receiving anticoagulation therapy, then subject must be on a stable dose of anticoagulation for ≥ 1 month:
• Prothrombin time within 1.5 x ULN.
• Activated partial thromboplastin time within 1.5 x ULN.
Exclusion Criteria:
General
• Participant with known symptomatic brain metastases requiring \> 10 mg/day of prednisolone (or its equivalent). Participants with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of ACR-368 treatment, fulfill the steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ≥ 4 weeks after treatment.
• Participant has mesenchymal tumors of the uterus.
• Participant has a history of clinically meaningful ascites, defined as history of paracentesis or thoracentesis with therapeutic intent, within 4 weeks of Screening. Subjects with planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing are excluded.
• Participant had systemic therapy or radiation therapy within 3 weeks prior to the first dose of study drug.
• Participants has known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is considered uncontrolled based on the criteria included in Appendix 2.
• Participant has a history of clinically meaningful coagulopathy, bleeding diathesis.
• Participant has cardiovascular disease, defined as:
• Uncontrolled hypertension defined as blood pressure \> 160/90 mmHg at Screening confirmed by repeat (medication permitted).
• History of torsades de pointes, significant Screening electrocardiogram (ECG) abnormalities, including ventricular rhythm disturbances, unstable cardiac arrhythmia requiring medication, pathologic symptomatic bradycardia, left bundle branch block, second degree atrioventricular (AV) block type II, third degree AV block, Grade ≥ 2 bradycardia, uncorrected hypokalemia not amenable to correction, congenital long QT syndrome, prolonged QT interval due to medications, corrected QT based on Fridericia's formula (QTcF) \> 450 msec (for men) or \> 470 msec (for women).
• Symptomatic heart failure (per New York Heart Association guidelines; (Caraballo, 2019), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction \< 20%, transient ischemic attack, or cerebrovascular accident within 6 months of Day 1).
• Participant has a history of major surgery within 4 weeks of Screening.
• Participant has experienced bowel obstruction related to the current cancer within the last 6 months or signs or symptoms of intestinal obstruction, which include nausea, vomiting, or objective radiologic finding of bowel obstruction in the last 4 weeks before the start of the treatment.
• Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368
DRUG: ACR-368, DRUG: Gemcitabine, DIAGNOSTIC_TEST: OncoSignature
Endometrial Adenocarcinoma
Endometrial Cancer, Endometrial Neoplasm, Ultralow dose gemcitabine, ACR-368
Double-blind, Randomized, Placebo-controlled Study Evaluating Efficacy and Safety of IgPro20 in Post-COVID-19 POTS
Trial Registration Coordinator - clinicaltrials@cslbehring.com
NCT06524739
Inclusion Criteria:
• Provide written informed consent and be willing and, in the opinion of the investigator, able to adhere to all protocol requirements.
• Males and females aged ≥ 18 at the time of providing written informed consent.
• Diagnosis of post-COVID POTS, defined by both a preceding COVID-19 infection based on confirmed historical documentation and onset of POTS symptoms developing within 4 months after COVID-19 infection as defined per consensus criteria.
• COMPASS-31 score of at least 40 at the Screening visit.
• Positive confirmatory standardized standing test (ie, HR increase of ≥ 30 bpm \[≥ 40 bpm for participants aged 18 to 19 years\] within 10 minutes in the absence of orthostatic hypotension) at the Screening visit.
Exclusion Criteria:
• Treatment with Immunoglobulin G (IgG) or plasmapheresis within 12 weeks before Screening
• Symptoms and / or diagnosis of or receiving treatment for POTS before COVID-19 infection
• Prior diagnosis of or receiving current treatment at Screening for the following conditions (unless onset was related to the inciting POTS-associated COVID-19 infection): certain neurologic, autoimmune, endocrine, cardiac, or other disorders, and pre-existing psychiatric disorders
• Presence of active infections, including human immunodeficiency virus infection, hepatitis B, hepatitis C, active SARS-CoV-2 infection, or any uncontrolled systemic infection
BIOLOGICAL: IgPro20, BIOLOGICAL: Placebo
Post-COVID Postural Orthostatic Tachycardia Syndrome
POTS
DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers
Boehringer Ingelheim - clintriage.rdg@boehringer-ingelheim.com
NCT05882058
Inclusion criteria:
• Male or female participants ≥18 years old and at least at the legal age of consent in countries where it is greater than 18 years at the time of signature of the informed consent form (ICF).
• Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.
• Part 1: Histologically or cytologically confirmed, cancer of the following histologies: * Small cell lung cancer (SCLC) * Extra-pulmonary neuroendocrine carcinoma (epNEC) (except Merkel cell carcinoma (MCC), Medullary thyroid cancer (MTC) and Neuroendocrine prostate cancer (NEPC)) * Large cell neuroendocrine carcinoma (LCNEC) of the lung Patients with tumours with mixed histologies for any above type are eligible only if the neuroendocrine carcinoma/small tumour cells component is predominant and represents at least 50% of the overall tumour tissue. Patients must have progressed or recurred after standard of care therapy * SCLC: after at least two prior lines of therapy, including at least one platinum-based regimen; in countries where standard of care in first line therapy includes PD-L1 inhibitor treatment patients should have received the combination of platinum-based regimen plus PD-L1 inhibitor unless they have been unable to receive checkpoint inhibitor treatment. * Therapy includes PD-L1 inhibitor treatment; patients should have received the combination of platinum-based regimen plus PD-L1 inhibitor unless they have been unable to receive checkpoint inhibitor treatment. * epNEC/LCNEC: after at least one platinum-based regimen. Part 2: Histologically or cytologically confirmed epNEC (except MCC, MTC and NEPC) with centrally assessed DLL3 high expression status. Patients must have progressed or recurred after at least one platinum-based regimen.
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• Measurable lesions as defined per Response Evaluation Criteria In Solid Tumours (RECIST) v 1.1 within 21 days prior to the first dose of BI 764532.
• Part 1: Availability of archival tumour tissue sample Part 2: Availability of archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample. Following specimens are not allowed: Fine Needle Aspiration (FNA), Cytology samples, decalcified bone samples.
• Adequate organ function as defined in the protocol.
• All toxicities related to previous anti-cancer therapies have resolved = Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 prior to trial treatment administration (except for alopecia, peripheral neuropathy, fatigue and endocrinopathies controlled by replacement therapy which must be = CTCAE Grade 2 and amenorrhea/menstrual disorders which can be any grade).
• Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria and instructions on the duration of their use is provided in the participant information Exclusion criteria:
• Untreated or symptomatic brain metastases. (Part 2: with mandatory assessment by brain MRI within 21 days before first trial drug administration.) Participants with treated, stable brain metastases are eligible provided they meet the following criteria: * Radiotherapy or surgery for brain metastases was completed at least 2 weeks prior to the first administration of BI 764532. * Patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off anti-epileptic drugs for at least 7 days or on stable doses of anti-epileptic drugs for malignant central nervous system (CNS) disease.
• Presence of leptomeningeal disease or, part 2: epidural disease including spinal cord compression.
• Part 1: Active/previous history of interstitial lung disease or non-infectious pneumonitis (any grade). Part 2: Active/previous history of interstitial lung disease, pulmonary fibrosis, organizing pneumonia or non-infectious pneumonitis (any grade). Patients with a history of therapy-related pneumonitis that is considered clinically resolved are eligible.
• Participants who experienced severe, life-threatening immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents.
• Prior anti-cancer therapy: * Patients who have been treated with any other anti-cancer drug within 4 weeks or within 5 half-life periods (whichever is shorter) prior to first administration of BI 764532. * Patients who have been treated with extensive field radiotherapy including whole brain irradiation within 2 weeks prior to first administration of BI 764532.
• Previous treatment with Delta-like ligand 3 (DLL3)-targeting T cell engagers or cell therapies.
• Diagnosis of immunodeficiency or systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of BI 764532. Physiological replacement of steroids is allowed.
• Unresolved toxicity from prior anti-tumour therapy, defined as per protocol. Further exclusion criteria apply.
• Male or female participants ≥18 years old and at least at the legal age of consent in countries where it is greater than 18 years at the time of signature of the informed consent form (ICF).
• Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.
• Part 1: Histologically or cytologically confirmed, cancer of the following histologies: * Small cell lung cancer (SCLC) * Extra-pulmonary neuroendocrine carcinoma (epNEC) (except Merkel cell carcinoma (MCC), Medullary thyroid cancer (MTC) and Neuroendocrine prostate cancer (NEPC)) * Large cell neuroendocrine carcinoma (LCNEC) of the lung Patients with tumours with mixed histologies for any above type are eligible only if the neuroendocrine carcinoma/small tumour cells component is predominant and represents at least 50% of the overall tumour tissue. Patients must have progressed or recurred after standard of care therapy * SCLC: after at least two prior lines of therapy, including at least one platinum-based regimen; in countries where standard of care in first line therapy includes PD-L1 inhibitor treatment patients should have received the combination of platinum-based regimen plus PD-L1 inhibitor unless they have been unable to receive checkpoint inhibitor treatment. * Therapy includes PD-L1 inhibitor treatment; patients should have received the combination of platinum-based regimen plus PD-L1 inhibitor unless they have been unable to receive checkpoint inhibitor treatment. * epNEC/LCNEC: after at least one platinum-based regimen. Part 2: Histologically or cytologically confirmed epNEC (except MCC, MTC and NEPC) with centrally assessed DLL3 high expression status. Patients must have progressed or recurred after at least one platinum-based regimen.
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• Measurable lesions as defined per Response Evaluation Criteria In Solid Tumours (RECIST) v 1.1 within 21 days prior to the first dose of BI 764532.
• Part 1: Availability of archival tumour tissue sample Part 2: Availability of archival formalin-fixed paraffin-embedded (FFPE) tumour tissue sample. Following specimens are not allowed: Fine Needle Aspiration (FNA), Cytology samples, decalcified bone samples.
• Adequate organ function as defined in the protocol.
• All toxicities related to previous anti-cancer therapies have resolved = Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 prior to trial treatment administration (except for alopecia, peripheral neuropathy, fatigue and endocrinopathies controlled by replacement therapy which must be = CTCAE Grade 2 and amenorrhea/menstrual disorders which can be any grade).
• Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria and instructions on the duration of their use is provided in the participant information Exclusion criteria:
• Untreated or symptomatic brain metastases. (Part 2: with mandatory assessment by brain MRI within 21 days before first trial drug administration.) Participants with treated, stable brain metastases are eligible provided they meet the following criteria: * Radiotherapy or surgery for brain metastases was completed at least 2 weeks prior to the first administration of BI 764532. * Patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off anti-epileptic drugs for at least 7 days or on stable doses of anti-epileptic drugs for malignant central nervous system (CNS) disease.
• Presence of leptomeningeal disease or, part 2: epidural disease including spinal cord compression.
• Part 1: Active/previous history of interstitial lung disease or non-infectious pneumonitis (any grade). Part 2: Active/previous history of interstitial lung disease, pulmonary fibrosis, organizing pneumonia or non-infectious pneumonitis (any grade). Patients with a history of therapy-related pneumonitis that is considered clinically resolved are eligible.
• Participants who experienced severe, life-threatening immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents.
• Prior anti-cancer therapy: * Patients who have been treated with any other anti-cancer drug within 4 weeks or within 5 half-life periods (whichever is shorter) prior to first administration of BI 764532. * Patients who have been treated with extensive field radiotherapy including whole brain irradiation within 2 weeks prior to first administration of BI 764532.
• Previous treatment with Delta-like ligand 3 (DLL3)-targeting T cell engagers or cell therapies.
• Diagnosis of immunodeficiency or systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of BI 764532. Physiological replacement of steroids is allowed.
• Unresolved toxicity from prior anti-tumour therapy, defined as per protocol. Further exclusion criteria apply.
DRUG: BI 764532, dose 1, DRUG: BI 764532, dose 2
Small Cell Lung Carcinoma, Neuroendocrine Neoplasms, Extra-pulmonary Neuroendocrine Carcinoma
ALS/MND Natural History Study Data Repository
Natalia Tarasenko - ntarasenko@mgh.harvard.edu
NCT05966038
Inclusion Criteria:
* A clinical diagnosis of El Escorial of suspected, possible, probable, or definite ALS or
* Other motor neuron disorders, including but not limited to Spinal-Bulbar Muscular Atrophy (SBMA, Kennedy's disease), Spinal Muscular Atrophy (SMA), Primary Lateral Sclerosis (PLS), Progressive Muscular Atrophy (PMA), and Progressive Bulbar Palsy (PBP)
Exclusion Criteria:
* Disease does not meet criteria for any motor neuron disorder ALS, PLS, MND (Motor Neurone DIsease), Kennedy Disease, PMA - Progressive Muscular Atrophy, PBP - Progressive Bulbar Palsy
Testing Longer Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients With Cancer That Has Spread to the Brain
ctrrecruit@vcu.edu
NCT06500455
Inclusion Criteria:
* Pathologically (histologically or cytologically) proven diagnosis of one of the following solid tumor malignancies within 5 years prior to registration:
* Non-small cell lung cancer
* Melanoma
* Breast cancer
* Renal cell carcinoma
* Gastrointestinal cancer
* If the original histologic proof of malignancy is greater than 5 years, then more recent pathologic confirmation (e.g., from a systemic site or brain metastasis) or unequivocal imaging confirmation of extracranial metastatic disease (e.g. CT of the chest/abdomen/pelvis, positron emission tomography \[PET\]/CT, etc.) is required
* Patients must have at least 1 and up to 8 total intact brain metastases detected on a contrast-enhanced MRI performed ≤ 21 days prior to registration
* At least 1 of the up to 8 lesions must be a study eligible lesion, defined as lesion with a maximum diameter as measured on any orthogonal plane (axial, sagittal, coronal) of ≥ 1.0 cm and ≤ 3.0 cm
* All brain metastases must be located outside of the brainstem and ≥ 5 mm from the optic nerves or optic chiasm and ≤ 3.0 cm in maximum dimension
* Note: brainstem metastases per the MRI within 21 days of registration are an exclusion criterion; however, if the MRI used for treatment planning performed within 7 days of SRS/FSRS reveals a brainstem metastasis, the patient remains eligible if the patient is considered an appropriate radiosurgery candidate per the local investigator
* Patients must have a diagnosis-specific graded prognostic assessment ≥ 1.5
* No more than 2 lesions planned for resection if clinically indicated
* No known leptomeningeal disease (LMD)
* Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion
* Age ≥ 18 years
* Karnofsky performance status (KPS) ≥ 60
* Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
* No prior radiotherapy to the brain (partial or whole brain irradiation, SRS, FSRS, or prophylactic cranial irradiation \[PCI\])
* New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
* No active infection currently requiring intravenous (IV) antibiotic management
* No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
* No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy PROCEDURE: Computed Tomography, RADIATION: Fractionated Stereotactic Radiation Therapy, PROCEDURE: Magnetic Resonance Imaging, RADIATION: Stereotactic Radiosurgery
Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic Digestive System Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Renal Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
Chest Drain Regular Flushing in Complicated Parapneumonic Effusions and Empyemas (RELIEF)
Samira Shojaee, MD, MPH - samira.shojaee@vumc.org
NCT06427538
Inclusion Criteria:
* Patients with complicated parapneumonic pleural effusion and empyema requiring chest tube placement as standard of care for inpatient management of their pleural space infection with or without intrapleural tissue plasminogen activator and deoxyribonuclease therapy
* Age \> 18 years old.
Exclusion Criteria:
* Patients who have surgical tubes that can't accommodate a three-way stopcock.
* Study subject has any disease or condition that interferes with the safe completion of the study.
* Inability to provide informed consent.
* Inability to undergo a chest X-ray.
* If the managing clinician believes the chest tube will be placed for less than 24 hours.
* Patients with an indwelling pleural catheter (IPC) OTHER: Saline Flush
Empyema, Pleural, Pleural Infection
empyema, pleural infection, chest tube, saline flush
Testing Shorter Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients With High Risk Prostate Cancer
ctrrecruit@vcu.edu
NCT05946213
Inclusion Criteria:
* Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of prostate cancer
* High-risk disease defined as having at least one or more of the following:
* cT3a-T3b by digital exam or imaging (American Joint Committee on Cancer \[AJCC\] 8th edition \[Ed.\]) Note: cT4 by imaging or on digital rectal exam is not allowed
* The patient's prostate specific antigen (PSA) value \> 20 ng/mL prior to starting androgen deprivation therapy (ADT) Note: Patients taking a 5-alpha reductase inhibitor (ex finasteride or dutasteride) are eligible The baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors
* Gleason Score of 8-10
* Pelvic node positive by conventional imaging with a short axis of at least 1.0 cm
* Prostate gland volume less than 100 cc prior to initiation of ADT as reported at time of biopsy or by separate measure with ultrasound or other imaging modalities including MRI or CT scan
* No definitive clinical or radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e. bone scan, CT scan, MRI); Negative prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is an acceptable substitute
* Age \>= 18
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
* No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
* No prior radical prostatectomy
* No prior ablative or focal therapy to the prostate (including, but not limited to, transrectal or transurethral high-intensity focused ultrasound \[HIFU\], laser ablation, cryotherapy, irreversible electroporation \[IRE\], and vascular-targeted photodynamic therapy)
* Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone releasing hormone \[LHRH\] agonist and oral anti-androgen) is =\< 185 days prior to registration; Please note: PSA prior to the start of any ADT will be used to define disease
* No contraindication to prostate MRI (required for planning of radiotherapy in both arms)
* Patients enrolled in NRG-GU009 must be enrolled in NRG-GU013 prior to radiation therapy treatment planning and start of radiation therapy PROCEDURE: Biospecimen Collection, PROCEDURE: Bone Scan, PROCEDURE: Computed Tomography, RADIATION: External Beam Radiation Therapy, PROCEDURE: Magnetic Resonance Imaging, PROCEDURE: Positron Emission Tomography, OTHER: Quality-of-Life Assessment, OTHER: Questionnaire Administration, RADIATION: Stereotactic Body Radiation Therapy
Prostate Adenocarcinoma, Stage III Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8
Adjuvant Pembrolizumab vs Observation Following Curative Resection for Stage I Non-small Cell Lung Cancer (NSCLC) With Primary Tumors Between 1-4 cm
Greg Durm, MD - gdurm@iu.edu
NCT04317534
Inclusion Criteria:
* The participant (or legally acceptable representative if applicable) must provide written informed consent for the study. The participant may also provide consent for future unspecified research samples. However, the participant may participate in the study without participating in the future unspecified research sample collection. NOTE: Initial informed consent will remain valid throughout the 12-week period between surgical resection and study registration unless, in the opinion of the treating investigator, the participant experiences a significant change in medical or mental status.
* Males and females age ≥ 18 years at the time of consent.
* ECOG Performance Status of 0-1 within 28 days prior to registration.
* Patients must have undergone complete surgical resection of their stage I NSCLC between 4-12 weeks prior to registration and have negative surgical margins (R0).
* NOTE: Both squamous and non-squamous histologies are allowed into the study. Cancers with a histology of "adenosquamous" are considered a type of adenocarcinoma and thus "non-squamous histology".
* NOTE: Staging will be according to the AJCC 8th edition.
* Pathological tumor size must be 1.0 - 4.0 cm in greatest dimension. NOTE: According to AJCC 8th edition, subjects with lepidic predominant adenocarcinoma should be staged based on their invasive tumor size and not their total tumor size (i.e., subjects with lepidic predominant tumors whose invasive tumor size is less than 1 cm are not eligible, even if their total tumor size is 1.0 cm or greater).
* Surgery for this lung cancer must be completed at least 28 days prior to registration.
* Must have either previous NGS and PD-L1 results available using the Dako 22C3 antibody or have archival tissue of surgical specimen from current diagnosis available to perform analyses. PD-L1 results via the Dako 22C3 antibody will be performed per standard of care from a CLIA-accredited laboratory and are required for stratification. If NGS results are not available, subjects must be able to provide at least 10 x 10µm unstained and 1 x 4µm H\&E slides from current diagnosis for future NGS and/or other genetic analyses.
* Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 28 days prior to registration.
* Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. For subjects randomized to the pembrolizumab arm: If there is \> 72 hours between the screening test and C1D1, another pregnancy test (urine or serum) must be performed and must be negative before the subject may start C1D1.
* NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See Section 5.1.4 for definitions.
* NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) OR
* A WOCBP who is using a highly effective contraceptive method (failure rate of \<1% per year), or is abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study drug. See contraceptive guidance in Section 5.1.4 of the protocol.
* Participants who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy after completion of study intervention.
Hepatitis B screening tests are not required unless:
* Known history of HBV infection
* As mandated by local health authority
* Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
Hepatitis C screening tests are not required unless:
* Known history of HCV infection
* As mandated by local health authority
* HIV-infected participants are eligible but must have well-controlled HIV on anti-retroviral therapy (ART), defined as:
* Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at screening.
* Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.
* It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months before study entry (Day 1/randomization).
* Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1/randomization) and agree to continue ART throughout the study.
* Note: HIV screening testing is not required unless mandated by local health authority.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
Exclusion Criteria:
* Current lung cancer is \<1 cm or \> 4 cm in size or is stage II, III, or IV.
* Patients with tumors that are known to harbor actionable EGFR mutations.
* Prior chemotherapy, radiation therapy, or immunotherapy for the treatment of this lung cancer.
* Has a known active additional malignancy that is progressing or has required active treatment within the past 2 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
* Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
* Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
* Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.
* Has had an allogenic tissue/solid organ transplant.
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has active TB (Bacillus Tuberculosis) infection.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. DRUG: Pembrolizumab
NSCLC, Stage I
A Phase 1/2 Study of VX-670 in Adult Participants With Myotonic Dystrophy 1 (DM1) (Galileo)
Medical Information - medicalinfo@vrtx.com
NCT06185764
Key
Inclusion Criteria:
\- Documented clinical diagnosis of DM1 with age of onset greater than (\>) 1 year of age and documented positive genetic test for DM1 in the subject with cytosine thymine guanine (CTG) repeat of at least 100
Key Exclusion Criteria:
\- History of any illness or any clinical condition as pre-specified in the protocol
Other protocol defined Inclusion/Exclusion criteria may apply. DRUG: VX-670, DRUG: Placebo
Myotonic Dystrophy Type 1 (DM1)
DM1, DM2, Myotonic Dystrophy 1, Myotonic Dystrophy 2, Myotonic Dystrophy Type 1 (DM1), Myotonic Dystrophy, DM, Myotonia, Dystrophy Myotonic, Myotonic Disorders, Steinert Disease, Vertex, Entrada, VX-670, VX670, PMO, ASO, Myotonic Muscular Dystrophy, Muscular Disorders, Atrophic, Muscular Diseases, Musculoskeletal Diseases, Neuromuscular Diseases, Nervous System Diseases, Genetic Diseases, Inborn, Heredodegenerative Disorders, Nervous System, Neurodegenerative Diseases, Muscular Dystrophies
A Trial to Evaluate the Safety and Activity of Fruquintinib in Minority Populations With Advanced, Previously Treated Colorectal Cancer
Takeda Contact - medinfoUS@takeda.com
NCT06562543
Inclusion Criteria:
• Provide written (or electronic) informed consent.
• Male or female aged more than or equal to (≥)18 years.
• Presence of histologically and/or cytologically documented metastatic colorectal adenocarcinoma. Rat sarcoma virus (RAS) status for each participant must be documented.
• Have been previously treated with standard approved therapies: * Fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, * An anti-vascular endothelial growth factor (VEGF) biological therapy (e.g., bevacizumab, aflibercept, ramucirumab \[regorafenib is NOT an anti-VEGF biologic\]), and * If RAS wild-type and medically appropriate, an anti-epidermal growth factor receptor (EGFR) therapy (e.g., cetuximab, panitumumab). * If known microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumor and medically appropriate, a programmed cell death protein 1 (PD1) inhibitor.
• Self-identify as Black and/or African American or Hispanic and/or Latino or as both.
• Body weight ≥40 kilograms (kg).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at screening.
• Have assessable disease according to RECIST version 1.1, assessed locally.
• In participants of childbearing potential, agreement to use highly effective form(s) of contraception, which results in a low failure rate (less than \[\<\]1 percent \[%\] per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire trial period, and for 2 weeks after taking the last dose of the trial intervention. Such methods include oral (PO) hormonal contraception (combined estrogen/progestogen or progestogen-only) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the participant. Those assigned male sex at birth must always use a condom.
Exclusion Criteria:
• Absolute neutrophil count (ANC) \<1.5 times 10\^9 per liter (10\^9/L), platelet count \<100 times 10\^9/L, or hemoglobin \<9.0 grams per deciliter (g/dL). Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed.
• Serum total bilirubin more than (\>)1.5 times the upper limit of normal range (ULN). Participants with previously documented Gilbert syndrome and bilirubin \<2 times ULN are eligible.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 times ULN in participants without hepatic metastases; ALT or AST \>5 times ULN in participants with hepatic metastases.
• Creatinine clearance \<30 milliliters per minute (mL/min). Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation. Where available and appropriate, other formulae may be used to estimate clearance after consultation with the trial medical monitor.
• Urine dipstick or urinalysis with protein ≥2 positive or 24-hour urine protein ≥1.0 gram per 24 hours (g/24 hours). Participants with 1+ positive proteinuria must undergo a 24-hour urine collection to assess urine protein level.
• Uncontrolled hypertension, defined as systolic BP ≥140 millimeter of mercury (mmHg) and/or diastolic blood pressure (BP) ≥90 mmHg despite optimal medical management. The participant must have BP below both limits. Repeated assessments are permitted.
• International normalized ratio (INR) \>1.5 times ULN or activated partial thromboplastin time (aPTT) \>1.5 times ULN, unless the participant is currently receiving or intended to receive anticoagulants for prophylactic purposes.
• History of or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas, or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation within the 6 months prior to screening.
• History or presence of hemorrhage from any other site (e.g, hemoptysis or hematemesis) within 2 months prior to screening.
• History of a thromboembolic event, including deep vein thrombosis, pulmonary embolism, or arterial embolism within 6 months prior to screening.
• Stroke and/or transient ischemic attack within 12 months prior to screening.
• Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction \<50% by echocardiogram.
• QT interval, corrected using the Fridericia method (QTcF) \>480 milliseconds or any factors that increase the risk of QT interval, corrected based on the patient's heart rate (QTc) prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, or family history of long QT syndrome.
• Systemic antineoplastic therapies (except for that described in exclusion criterion no. 15) or any investigational therapy within 2 weeks prior to the first dose of the trial intervention, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy, and immunotherapy.
• Systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors \[TKIs\]) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of the trial intervention.
• Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of the trial intervention.
• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of the trial intervention.
• Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 14 days prior to the first dose of the trial intervention or unhealed surgical incision.
• Any unresolved toxicities from previous antitumor treatments greater than NCI CTCAE, version 5.0, Grade 1 (except for alopecia or neurotoxicity Grade less than or equal to \[≤\]2).
• Known human immunodeficiency virus infection.
• Known history of active viral hepatitis. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load had to be undetectable on suppressive therapy, if indicated. Participants with hepatitis C virus (HCV) infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Clinically uncontrolled active infection requiring intravenous (IV) antibiotics.
• Tumor invasion of a large vascular structure (e.g., pulmonary artery or superior or inferior vena cava).
• Those who are currently pregnant or lactating.
• Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of SD for 14 days or longer; participants requiring steroids within 4 weeks prior to the start of the trial intervention are to be excluded.
• Other malignancy, except for non-melanoma skin cancer, in situ cervical carcinoma, or bladder carcinoma (tumor in situ and T1) that had been adequately treated during the 5 years prior to screening. Participants with another primary malignancy that has been adequately treated may be included after consultation with the trial medical monitor.
• Inability to take medication PO, dysphagia, or an active gastric ulcer resulting from previous surgery (e.g., gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe might affect absorption of the investigational medicinal product (IMP).
• Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect might prohibit use of the IMP, affect interpretation of trial results, or put the participant at undue risk of harm based on the investigator's assessment.
• Known hypersensitivity to fruquintinib or any of its inactive ingredients, including the azo dyes Tartrazine- Federal Food, Drug, and Cosmetic Act (FD\&C) Yellow 5 and Sunset yellow For Coloring Food (FCF)-FD\&C Yellow 6.
• Received prior fruquintinib.
• Live vaccine ≤28 days before the first dose of the trial intervention. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
• Use of strong inducers of cytochrome P450 3A4 (CYP3A4) within 2 weeks before the first dose of the trial intervention.
DRUG: Fruquintinib
Colorectal Cancer
colorectal cancer, fruquintinib
A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma (FIERCE-HN)
Clinical Trials Office - clinical@aveooncology.com
NCT06064877
Inclusion Criteria:
* Male or female and ≥ 18 years of age
* Histologically and/or cytologically confirmed primary diagnosis of R/M HNSCC
* Participants with oropharyngeal cancer will be required to have proof of p16 negative status submitted on the basis of a pathology report
* At least 1 measurable lesion by contrast CT or MRI scan according to RECIST v.1.1. Such lesions must not have been previously irradiated; if the measurable lesion(s) has been irradiated, clear progression must be documented
* Participants must have failed prior therapy with an anti-PD-1/PD-L1 ICI and with platinum-based chemotherapy administered in combination or sequentially, in either the locally advanced or R/M setting. Failure of prior treatment may be due to progression of disease or intolerance to treatment
* Patient's tumor must be considered inoperable and incurable
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with a life expectancy of at least 12 weeks
* For women of childbearing potential (WOCBP), documentation of negative serum pregnancy test within 30 days of randomization
* For WOCBP and male participants whose sexual partners are of childbearing potential, agreement to use an effective method of contraception during the study and for at least 5 months after the last dose of study treatment. Birth control methods which may be considered highly effective include methods that achieve a failure rate of less than 1% per year when used consistently and correctly.
* Ability to give written informed consent and comply with protocol requirements
* Patients with feeding tubes are eligible for the study.
* Archived tissue sample must be submitted to the Sponsor-designated laboratory within 60 days of randomization for c-Met analysis (if a tissue sample is not available, a fresh biopsy may be required prior to enrollment)
Exclusion Criteria:
* Participants who have received \> 2 prior lines of anticancer therapy or prior treatment with cetuximab/alternative EGFR inhibitors for the treatment of R/M HNSCC
* History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent or cetuximab
* Known or suspected untreated and uncontrolled brain metastases or leptomeningeal carcinomatosis Note: Participants with locally treated brain metastases are eligible provided 2 weeks have elapsed since local therapy. Participants are allowed to continue steroid taper during the start of study treatment.
* Prior treatment with any other investigational drug or biologic agent or radiation therapy before a washout has been completed (must be completed prior to randomization):
• 2 weeks (14 days) or 5 half-lives, whichever is shorter, for chemotherapeutic agents, small molecules, and checkpoint inhibitors
• 3 weeks (21 days) or 5 half-lives, whichever is shorter, for antibody-drug conjugates
• 4 weeks (28 days) for cell therapies
• 2 weeks (14 days) for radiation therapy * Any unresolved and significant toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] version 5.0) Grade \> 2 from previous anticancer therapy (including radiation therapy), other than alopecia * Significant cardiovascular disease, including: Cardiac failure New York Heart Association class III or IV; Myocardial infarction, severe or unstable angina within 6 months prior to randomization; History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) * Any other medical condition or psychiatric condition that, in the opinion of the Investigator, might interfere with the participant's involvement in the study or interfere with the interpretation of study results * History of prior malignancy within 2 years prior to randomization (except for adequately treated non-melanoma skin cancer, carcinoma in situ of the breast or cervix, superficial bladder cancer, or early-stage prostate cancer, without evidence of recurrence; participants may or may not be on maintenance therapy) * Participants who are positive for HBV or HCV with indication of acute or chronic hepatitis (as defined in protocol) * Radiographic evidence (historical or at screening) of interstitial lung disease or idiopathic pulmonary fibrosis * Female participants who are pregnant or breastfeeding A full list of inclusion and exclusion criteria can be found in the protocol.
BIOLOGICAL: Ficlatuzumab, BIOLOGICAL: Cetuximab, OTHER: Placebo
Metastatic Head-and-neck Squamous-cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma
Recurrent, Metastatic, HPV-negative, Head and Neck, Squamous Cell Carcinoma
Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis
ctrrecruit@vcu.edu
NCT04847453
Inclusion Criteria:
* Histologically-proven systemic anti-light chain amyloidosis (AL) confirmed by positive Congo red staining with green birefringence on polarized light microscopy and evidence of a measurable clonal disease that requires active treatment. An underlying plasma cell disorder can be identified by one of the following: clonal plasma cells in the bone marrow (BM), monoclonal protein in the serum or urine, or abnormal free light chain ratio. For patients who are African-American or males \>= 70 years with isolated cardiac involvement, mass spectrometry must be performed to confirm subtyping
* Presence of t(11;14) by fluorescence in situ hybridization (FISH) on bone marrow biopsy, either confirmed at screening or documented with a prior biopsy
* Patient requires therapy, as determined by the treating physician, following at least one line of treatment (No limit on the number of prior treatments)
* Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of venetoclax in combination with MLN9708 (ixazomib citrate) and dexamethasone in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Leukocytes \>= 3,000/mcL
* Absolute neutrophil count \>= 1,000/mcL. Screening absolute neutrophil count (ANC) should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks
* Platelets \>= 75,000/mcL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 2 weeks before study enrollment
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
* Creatinine Calculated clearance \>= 15 mL/min using Cockcroft-Gault equation
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* AL Amyloidosis Cardiac Risk stage I, II or IIIa disease based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement (Dispenzieri et al., 2004; Wechalekar et al., 2013)
* Staging system defined by: NT-proBNP cut off of \< 332 pg/mL and troponin I cut-off of \< 0.10 ng/mL (in the absence of troponin T, troponin I \>= 0.1 ng/mL can be used) as thresholds for stages I, II and III; NT-proBNP =\< 8500 pg/ml for stage IIIa
* Stage I, both under threshold;
* Stage I: Zero markers above threshold: NT-proBNP \< 332 ng/L AND troponin T (TnT) =\< 0.035 ng/mL; NT-proBNP \< 332 ng/L AND TnI =\< 0.1 ng/mL
* Stage II, either troponin or NT-proBNP (but not both) over threshold;
* Stage II: One marker above threshold: NT-proBNP \>= 332 ng/L OR TnT \>= 0.035 ng/mL; NT-proBNP \>= 332 ng/L OR TnI \>= 0.1 ng/mL
* Stage III, both over threshold;
* Stage IIIa, both over threshold but NT-proBNP =\< 8500 pg/ml
* Stage IIIa: Two markers above threshold: NT-proBNP \>= 332 ng/L BUT =\< 8,500 ng/L AND TnT \>= 0.035 ng/mL; NT-proBNP \>= 332 ng/L BUT =\< 8,500 ng/L AND TnI \>= 0.1 ng/mL
* Stage IIIb: Two markers above threshold: NT-proBNP \> 8,500 ng/L AND TnT \>= 0.035 ng/mL; NT-proBNP \> 8,500 ng/L AND TnI \>= 0.1 ng/mL
* Life expectancy \>= 3 months
* Plasma cell burden =\< 60%
* Absence of bone lesions and other end organ disease consistent with multiple myeloma (patients with plasma cell burden between 10 and 60% without end organ disease can be included)
* Measurable disease of AL amyloidosis as defined by at least one of the following: 1) serum or urine monoclonal protein \>= 500 mg/dL by protein electrophoresis, or 2) serum free light chain \>= 20 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) \>= 20 mg/L
* It is not known what effects MLN9708 (ixazomib citrate), venetoclax, and dexamethasone have on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below.
* Female patients must meet 1 of the following:
* Postmenopausal for at least 1 year before the screening visit, or
* Surgically sterile, or
* If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug, or
* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception)
* Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following:
* Practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception)
* Left ventricular ejection fraction \>= 35% by echocardiogram.
* Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Exclusion Criteria:
* Patients who have had major surgery or radiotherapy within 14 days prior to entering the study. If the involved radiotherapy field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708 (ixazomib citrate)
* Patients who have had anti-plasma cell therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
* Patients who are receiving any other investigational agents, within 30 days of the start of this trial and throughout the duration of this trial
* Patients with central nervous system involvement
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax, MLN9708 (ixazomib citrate) (including boron or boron-containing products) or dexamethasone
* Strong or moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), or strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort), or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine) should be avoided
* Venetoclax should be administered using caution with substrates or inhibitors of P-glycoprotein (P-gp)
* Patients with uncontrolled intercurrent illness including, but not limited to: ongoing or active serious or systemic infection (within 14 days prior to study enrollment), active hepatitis B or C virus infection, hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or myocardial infarction (within the past 6 months)
* Patients with psychiatric illness/social situations that would limit compliance with study requirements
* Female patients who are lactating or have a positive serum pregnancy test during the screening period are excluded from this study because MLN9708 (ixazomib citrate) is a proteasome inhibitor with the potential for embryo-lethal effects, and an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN9708 (ixazomib citrate). Patients must stop breastfeeding while on MLN9708 (ixazomib citrate) and until 90 days have passed since their last dose. These potential risks may also apply to other agents used in this study
* Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib citrate), including difficulty swallowing
* Peripheral neuropathy that is \>= grade 3, or grade 2 with pain on clinical examination during the screening period
* Patients that have previously been treated with MLN9708 (ixazomib citrate). Patients who have received prior treatment with venetoclax
* Patients without measurable disease by serum free light chain, serum m-spike or urine monoclonal protein
* Patients with New York Heart Association classification III/IV. Patients with advanced cardiac amyloidosis, Mayo stage IIIB based on European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement with NT-Pro BNP \> 8500 pg/mL (Wechalekar et al., 2013)
* Patients with grade 3 or worse diarrhea PROCEDURE: Biospecimen Collection, PROCEDURE: Bone Marrow Aspiration and Biopsy, PROCEDURE: Computed Tomography, DRUG: Dexamethasone, PROCEDURE: Echocardiography Test, DRUG: Ixazomib Citrate, PROCEDURE: Magnetic Resonance Imaging, PROCEDURE: Positron Emission Tomography, PROCEDURE: Transabdominal Ultrasound, DRUG: Venetoclax, PROCEDURE: X-Ray Imaging
Recurrent AL Amyloidosis, Refractory AL Amyloidosis
Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician's Choice in Patients With Triple Negative Breast Cancer Who Have Residual Invasive Disease After Surgery and Neoadjuvant Therapy (ASCENT-05/AFT-65 OptimICE-RD/GBG 119/NSABP B-63)
Gilead Clinical Study Information Center - GileadClinicalTrials@gilead.com
NCT05633654
Key
Inclusion Criteria:
* Age \> 18 years, with residual invasive triple negative breast cancer (TNBC) in the breast or lymph nodes after neoadjuvant therapy and surgery:
* TNBC criteria for the study is defined as estrogen receptor (ER) and progesterone receptor (PR) ≤ 10%, human epidermal growth factor receptor 2 (HER2)-negative per American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines (immunohistochemistry (IHC) and/or in situ hybridization (ISH)).
* Adequate excision and surgical removal of all clinically evident of disease in the breast and/or lymph nodes and have adequately recovered from surgery.
* Submission of both pre-neoadjuvant treatment diagnostic biopsy and resected residual invasive disease tissue.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Individuals must have received appropriate radiotherapy and have recovered prior to starting study treatment.
* Adequate organ function.
Key Exclusion Criteria:
* Stage IV (metastatic) breast cancer as well as history of any prior (ipsi- or contralateral) invasive breast cancer.
* Prior treatment with another stimulatory or coinhibitory T-cell receptor agent (eg, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), OX-40, cluster of differentiation 137 (CD137), prior treatment with any HER2-directed agent, prior endocrine therapy for \> 4 weeks or planned concurrent endocrine therapy while receiving on-study treatment.
* Evidence of recurrent disease following preoperative therapy and surgery.
* Prior treatment with topoisomerase 1 inhibitors or antibody-drug conjugates (ADCs) containing a topoisomerase inhibitor.
* Individuals with germline breast cancer gene (BRCA) mutations.
* Myocardial infarction or unstable angina pectoris within 6 months of enrollment or history of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias or Left ventricular ejection fraction (LVEF) of \< 50%
* Active serious infections requiring anti-microbial therapy.
Note: Other protocol defined Inclusion/Exclusion criteria may apply. DRUG: Sacituzumab govitecan-hziy (SG), DRUG: Pembrolizumab, DRUG: Capecitabine
Triple Negative Breast Cancer
AFT-65, GBG 119, NSABP B-63, OptimICE-RD
Effectiveness of the Eko Digital Stethoscope in Capturing Infant ECGs
Christopher Snyder - christopher.snyder@vcuhealth.org
NCT06382207
Inclusion Criteria:
* Age \<1 year
* No previous diagnosis of arrhythmia
* Parent/caregiver can provide informed consent
* Parent/caregiver can speak and understand simple English
Exclusion Criteria:
* Age ≥ 1 year
* Patient has a pacemaker or implantable cardioverter defibrillator (ICD)
* Parent/caregiver is unwilling or unable to provide informed consent
* Parent/caregiver is unable to speak and understand English DEVICE: Eko Duo electronic stethoscope, DEVICE: CORE 500 electronic stethoscope
Tachyarrhythmia
Infant Tachyarrhythmia, Cardiac Rhythm, Digital Stethoscope
HEAL-IST IDE Trial
Joseph Derr - jderr@atricure.com
NCT05280093
Inclusion Criteria:
• Age ≥ 18 years and ≤ 75 years at time of enrollment consent
• Subject has a diagnosis of IST
• Documentation of refractoriness (intolerance or failure) of a drug (e.g., rate control drugs such as beta-blockers/calcium channel blockers, ivabradine), and/or AADs
• Subject is willing and able to provide written informed consent
Exclusion Criteria:
• Subjects on whom cardiac surgery or single lung ventilation cannot be performed
• Subjects with indication for or existing ICDs/Pacemakers
• Presence of channelopathies
• Previous cardio-thoracic surgery
• Left Ventricular Ejection Fraction (LVEF) \< 50%
• Body Mass Index (BMI) ≥ 35
• Presence of supraventricular or ventricular tachycardia
• Presence of Postural Orthostatic Sinus Tachycardia (POTS)
• Presence of congenital heart disease
• History suggestive of secondary cause of tachycardia such as pheochromocytoma, anemia, thyrotoxicosis, chronic fever of unknown origin, COPD, long-term bronchodilators use, severe asthma or carcinoid syndrome
• Subjects who have had a previous catheter ablation in the right atrium for IST or other disorders
• Life expectancy \< 24 months
• Pregnant or planning to become pregnant during trial
• Subjects with substance abuse
• Subjects with previous weight loss surgery
• Subject is unwilling and/or unable to return for scheduled follow-up visits
• Current participation in another clinical investigation of a medical device or a drug, or recent participation in such a trial that may interfere with trial results
• Not competent to legally represent him or herself (e.g., requires a guardian or caretaker as a legal representative) and;
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements, or impact the scientific soundness of the clinical investigation results
DEVICE: AtriCure ISOLATOR Synergy Surgical Ablation System
Inappropriate Sinus Tachycardia
Androgen Suppression Combined With Nodal Irradiation and Dose Escalated Prostate Treatment (ASCENDE-SBRT)
Wendy Parulekar - wparulekar@ctg.queensu.ca
NCT06235697
Inclusion Criteria:
* Histologically confirmed adenocarcinoma of the prostate diagnosed within the last 9 months
* Participants with unfavourable risk prostate cancer are eligible according to the following NCCN classification guidelines (Version 4.2022 - May 10, 2022):
• Unfavourable-intermediate risk - has one or more of the following:
* 2 or 3 Intermediate Risk Factors (IRFs): cT2b-cT2c, Gleason 7 (grade group 2 or 3), and/or PSA 10-20 ng/ml;
* Gleason 4+3 (grade group 3)
* \> 50% biopsy cores positive
• High risk - has one of the following:
* cT3a
* Gleason 8-10 (grade group 4 or 5)
* PSA \> 20 ng/ml
• Very-high risk - has at least one of the following:
* cT3b-cT4
* Primary Gleason pattern 5
* 2 or 3 high risk features: cT3a, Gleason 8-10 (grade group 4 or 5), and/or PSA \> 20 ng/ml
* \> 4 cores with Gleason 8-10 (grade group 4 or 5)
* ECOG performance status of 0, 1 or 2
* Participants must be ≥ 18 years of age
* Judged to be medically fit for brachytherapy
* Participant is able (i.e. sufficiently fluent) and willing to complete the quality of life and/or health utility questionnaires in either English, French or Spanish
* Participants consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrollment in the trial to document their willingness to participate
* Participants must be accessible for treatment and follow-up. Investigators must assure themselves the participants enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
* In accordance with CCTG policy, protocol treatment is to begin within 12 weeks of participant enrollment
* Participants must be willing to take precautions to prevent pregnancy while on study
* ADT (LHRH agonists, antagonists, or anti-androgens) for prostate cancer is permitted for up to 30 days before study enrollment
* 5-alpha reductase inhibitors (5-ARI) are allowed, but baseline PSA will be corrected if 5-ARI use occurs within 6 months of enrollment
* Participants may NOT have received other therapies including chemotherapy, PARPi, radioligand or other investigational drugs for prostate cancer
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Urinary function defined as International Prostate Symptom Score (IPSS) \< 20. Alpha blockers are allowed to treat baseline urinary function
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Exclusion Criteria:
* Prior pelvic radiotherapy
* Contraindication to radical prostate radiotherapy (e.g. connective tissue disease or inflammatory bowel disease)
* Anticoagulation medication (if unsafe to discontinue for gold seed insertion or brachytherapy implant) and/or prior or current bleeding diathesis
* Prior steam vaporization (Rezum), transurethral resection of the prostate (TURP), prostatectomy (simple or radical), or any ablative therapy to the prostate (cryotherapy, HIFU, TULSA, focal laser ablation, photodynamic therapy)
* Prostate volume \> 60cc before start of androgen deprivation therapy
* Anatomy that would preclude precise brachytherapy implant (such as arch interference or large median lobe)
* Evidence of castrate resistance (defined as a rising PSA \> 3.0 ng/ml while testosterone is \< 3.0 nmol/l)
* Hip prosthesis (unilateral hip replacement is allowed if dose constrains can be reasonably achieved. RADIATION: Radiation, RADIATION: Radiation SBRT only, DRUG: ADT
Prostate Cancer
PREVENT ALL ALS Study
ALL ALS Patient Navigator - info@all-als.org
NCT06581861
Inclusion Criteria:
• Age 18 years or older
• Capable of providing informed consent
• Willing to follow study procedures
• First-degree relative of a known carrier of any ALS causative gene1 (regardless of whether ALS or FTD has actually been symptomatic in the family) OR First-degree relative of an individual with ALS and/or FTD in a family with a "compelling family history" of ALS/FTD, regardless of whether genetic testing has occurred in symptomatic family members. A "compelling family history" is defined as a pedigree with at least 2 close relatives who had ALS or FTD, with at least one of those family members having had ALS.
• Access to a smartphone, computer, or tablet, and internet (need not be in the home - access to a public library or other available computer with internet connection is sufficient)
Exclusion Criteria:
• Evidence of neurological signs or symptoms concerning for ALS of FTD, at the discretion of the site investigator which will be communicated to the applicant along with referral for appropriate clinical follow-up.
• Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, active suicidal ideation, suicide attempt, or untreated major depression \<= 90 days (about 3 months) of screening, which in the opinion of the Investigator would interfere with the study procedures
• Clinically significant, unstable medical condition (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, malignant and potentially progressive cancer) that would render the participant unlikely to be able to complete 12 months of follow-up, according to Investigator's judgment Exclusion Criteria for Participants Undergoing Optional Lumbar Puncture
• Medically unable to undergo lumbar puncture (LP) as determined by the site investigator (i.e., bleeding disorder, a skin infection at or near the LP site, known or suspected intracranial or intraspinal tumor or other cause of increased intracranial pressure).
• Allergy to Lidocaine or other local anesthetic agents.
• Use of anticoagulant medication or antiplatelet medications (aside from aspirin 81 mg) that cannot be safely withheld prior to lumbar puncture.
• Blood dyscrasia, abnormal bleeding diathesis, or the use of dialysis for renal failure.
• Current pregnancy based on participant self-report
• Clinical judgement of the site investigator that the participant would be unable to undergo multiple lumbar punctures. Inclusion Criteria for Genetic Testing Results Sub-study
• Age 18 years of age or older
• Capable of providing informed consent
• Willing to follow study procedures
• Currently enrolled in the PREVENT ALS Study
Amyotrophic Lateral Sclerosis
ALS, Amyotrophic Lateral Sclerosis, Biomarker, Observational, at-risk
Quizartinib or Placebo Plus Chemotherapy in Newly Diagnosed Patients With FLT3-ITD Negative AML (QuANTUM-WILD)
Daiichi Sankyo Contact for Clinical Trial Information - CTRinfo_us@daiichisankyo.com
NCT06578247
Key
• Must be competent and able to comprehend, sign, and date an Ethics Committee (EC)- or Institutional Review Board (IRB)-approved ICF before performance of any trial-specific procedures or tests.
• ≥18 years or the minimum legal adult age (whichever is greater) and ≤70 years (at Screening).
• Newly diagnosed, morphologically documented primary AML based on the World Health Organization (WHO) 2016 classification (at Screening)
• Eastern Cooperative Oncology Group (ECOG) performance status (at the time the participant signs their ICF) of 0-2.
• Participant is a candidate for standard "7+3" induction chemotherapy regimen as specified in the protocol per investigator assessment Key
• Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); participants who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).
• Diagnosis of AML secondary to prior chemotherapy or radiotherapy.
• Diagnosis of AML with known antecedent myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and others.
• Participants with newly diagnosed AML with FLT3-ITD mutations (FLT3-ITD \[+\]) present at ≥5% VAF (or ≥0.05 SR) based on a validated FLT3 mutation assay.
• Prior treatment for AML, except for the following allowances prior to Day 1 of chemotherapy:
• Leukapheresis;
• Treatment for hyperleukocytosis with hydroxyurea;
• Cranial radiotherapy for central nervous system (CNS) leukostasis;
• Prophylactic intrathecal chemotherapy
Inclusion Criteria:
• Must be competent and able to comprehend, sign, and date an Ethics Committee (EC)- or Institutional Review Board (IRB)-approved ICF before performance of any trial-specific procedures or tests.
• ≥18 years or the minimum legal adult age (whichever is greater) and ≤70 years (at Screening).
• Newly diagnosed, morphologically documented primary AML based on the World Health Organization (WHO) 2016 classification (at Screening)
• Eastern Cooperative Oncology Group (ECOG) performance status (at the time the participant signs their ICF) of 0-2.
• Participant is a candidate for standard "7+3" induction chemotherapy regimen as specified in the protocol per investigator assessment Key
Exclusion Criteria:
• Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis); participants who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).
• Diagnosis of AML secondary to prior chemotherapy or radiotherapy.
• Diagnosis of AML with known antecedent myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN) or MDS/MPNs including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and others.
• Participants with newly diagnosed AML with FLT3-ITD mutations (FLT3-ITD \[+\]) present at ≥5% VAF (or ≥0.05 SR) based on a validated FLT3 mutation assay.
• Prior treatment for AML, except for the following allowances prior to Day 1 of chemotherapy:
• Leukapheresis;
• Treatment for hyperleukocytosis with hydroxyurea;
• Cranial radiotherapy for central nervous system (CNS) leukostasis;
• Prophylactic intrathecal chemotherapy
DRUG: Quizartinib, DRUG: Placebo, DRUG: Chemotherapy
Leukemia
acute myeloid leukemia, quizartinib, FLT3, FLT3-ITD, Chemotherapy, FLT3-WT
Automated Robotic TCD in Traumatic Brain Injury (ART-TBI)
Shraddha Mainali, MD - shraddha.mainali@vcuhealth.org
NCT05848297
Inclusion Criteria:
* Adults ≥18
* Blunt TBI with Glasgow Coma Score (GCS) ≤8
* Injury within 72 hours
* Adequate TCD windows
* Ability to obtain informed consent from a Legally Authorized Representative (LAR)
Exclusion Criteria:
* Catastrophic brain injury with grim prognosis (e.g.: GCS 3 with bilateral mid-position pupil)
* C- spine fracture with evidence of spinal cord injury
* Severe skull or scalp injury precluding device placement
* Planned decompressive hemicraniectomy
* Continuous fever for \>6 hours at the time of enrollment (despite treatment)
* Lack of TCD window DEVICE: Transcranial Doppler ultrasonography (TCD)
Brain Injuries, Traumatic
The Rhythm Evaluation for AntiCoagulaTion With Continuous Monitoring of Atrial Fibrillation (REACT-AF)
Shea Smith - sgluhm@stanford.edu
NCT05836987
Inclusion Criteria:
• 22-85 years of age.
• English speaking participants. Spanish-only speakers may be included in the future at select sites appropriately translated.
• History of non-permanent atrial fibrillation.
• CHA2DS2-VASC score of 1-4 for men and 2-4 for women without prior stroke or Transient Ischemic Attack (TIA), The CHA2DS2-VASc score is a point-based system used to stratify the risk of stroke in Atrial Fibrillation (AF) patients. The acronym CHA2DS2-VASc stands for congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female). Congestive heart failure defined as: The presence of signs and symptoms of either right (elevated central venous pressure, hepatomegaly, dependent edema) or left ventricular failure (exertional dyspnea, cough, fatigue, orthopnea, paroxysmal nocturnal dyspnea, cardiac enlargement, rales, gallop rhythm, pulmonary venous congestion) or both, confirmed by non-invasive or invasive measurements demonstrating objective evidence of cardiac dysfunction and/or ejection fraction \< 40%.
• The participant is on a DOAC at the time of screening and willing to stay on DOAC for duration of study.
• Willing and able to comply with the protocol, including: * Possession of a smart watch-compatible smart phone (iPhone that supports the latest shipping iOS) with a cellular service plan * Be willing to wear the smart watch for the suggested minimum of 14 hours a day * Expected to be within cellular service range at least 80% of the time
• Willing and able to discontinue DOAC
• The participant is willing and able to provide informed consent.
Exclusion Criteria:
• Valvular or permanent atrial fibrillation.
• Current treatment with warfarin and unwilling or unable to take a DOAC.
• The participant is a woman who is pregnant or nursing.
• The participant is being treated with chronic aspirin, another anti-platelet agent, or chronic NSAIDS outside of current medical guidelines (e.g., primary stroke prevention in patients with atrial fibrillation, primary prevention of cardiovascular events, pain relief, fever, gout) and is unwilling or unable to discontinue use for the study duration.
• Existing cardiac rhythm device or indication for a permanent pacemaker, Implantable Cardioverter-Defibrillator (ICD) or Cardiac Resynchronization Therapy (CRT) device or planned insertable cardiac monitor. Insertable cardiac monitors are permitted unless they are being used to guide anticoagulation treatment.
• Known or suspected symptomatic or asymptomatic atrial fibrillation lasting ≥ 1 hour/month over the last 3 months.
• Any documented single AF episode lasting ≥ 1 hour on standard of care or study-provided external cardiac monitor of \> 6 days duration performed within 45 days prior to randomization. Shorter monitoring durations may be acceptable for inclusion at the discretion of the site PI based on the totality of monitoring data and approval of the study PI.
• Ablation for AF within the last 2 months.
• Prior or anticipated left atrial appendage occlusion or ligation.
• Mechanical prosthetic valve(s) or severe valve disease.
• Hypertrophic cardiomyopathy.
• Participant needs DOAC for reasons other than preventing stroke or arterial embolism resulting from AF (i.e., preventing Deep Vein Thrombosis (DVT) or PE) or needs permanent OAC (i.e., congenital heart defects, prosthetic heart valve).
• Participants deemed high risk for non-cardioembolic stroke (i.e., significant carotid artery disease defined as stenosis \> 75%) based on the investigator's discretion.
• The participant is enrolled, has participated within the last 30 days, or is planning to participate in a concurrent drug and/or device study during the course of this clinical trial. Co-enrollment in concurrent trials is only allowed with documented pre-approval from the study manager; there is no concern that co-enrollment could confound the results of this trial.
• The participant has a tattoo, birthmark, or surgical scar over the dorsal wrist area on the ipsilateral side that the AFSW may be worn.
• The participant has a tremor on their ipsilateral side that the AFSW may be worn.
• Any concomitant condition that, in the investigator's opinion, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse).
• Known hypersensitivity or contraindication to direct oral anticoagulants.
• Documented prior stroke (ischemic or hemorrhagic) or transient ischemic attack.
• Reversible causes of AF (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism). AF ablation does not constitute reversible AF.
• \> 5% burden of premature atrial or ventricular depolarizations on pre-enrollment cardiac monitoring.
• History of atrial flutter that has not been treated with ablation (participants in atrial flutter and have been ablated are eligible for enrollment).
• Stage 4 or 5 chronic kidney disease.
• Conditions associated with an increased risk of bleeding: * Major surgery in the previous month * Planned surgery or intervention in the next three months that would require cessation of anticoagulation \> 2 weeks. * History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra- articular bleeding * Gastrointestinal hemorrhage within the past year unless the cause has been permanently eliminated (e.g., by surgery) * Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days * Hemorrhagic disorder or bleeding diathesis * Need for anticoagulant treatment for disorders other than AF * Uncontrolled hypertension (Systolic Blood Pressure \>180 mmHg and/or Diastolic Blood Pressure \>100 mmHg)
DEVICE: AFSW Guided DOAC, DRUG: Continuous DOAC therapy
Atrial Fibrillation
Atrial Fibrillation, Anticoagulation, AF-sensing Smart Watch, Ischemic Stroke, Systemic Embolism
Ribociclib And Endocrine Treatment of Physician's Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR)
Oana Danciu, MD - ocdanciu@uic.edu
NCT05467891
Eligibility Criteria to Collect Optional Correlative Blood and Tissue at Local Recurrence
* Written informed consent (stage I) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Male or female age ≥ 18 years at the time of consent.
* Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory.
* Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. If there is insufficient tissue from the most recently collected sample, earlier tissue may be used on a case-by-case basis if permission is granted by the sponsor investigator.
* Patient has locoregional recurrence of breast cancer: locoregional recurrence is defined as invasive recurrence in the ipsilateral breast, axilla, regional nodes, or chest wall.
Inclusion Criteria for Treatment Phase:
Subject must meet all of the following applicable inclusion criteria to participate in this study:
* Written informed consent (stage II/ main consent) and HIPAA authorization for release of personal health information obtained prior to performing any study-specific screening procedures. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Male or female age ≥ 18 years at the time of consent. NOTE: Both pre- and post-menopausal women are eligible. Post-menopausal status is defined as:
* Prior bilateral oophorectomy
* Age ≥60
* Age \<60 and amenorrhea for the last 12 or more months(in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range.
* ECOG Performance Status of 0-1 within 28 days prior to registration.
* If patient is receiving tamoxifen or toremifene, a washout period of 5 half-lives (i.e. 35 days) prior to registration is required (during that period the participant can take AI).
* Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer based on the most recently analyzed tissue sample and all tested by local laboratory.
* Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. If there is insufficient tissue from the most recently collected sample, earlier tissue may be used on a case-by-case basis if permission is granted by the sponsor investigator.
* Patients have had adequate local treatment for locoregional recurrence (LRR) of breast cancer.
* Locoregional recurrence is defined as recurrence in the ipsilateral breast, axilla, regional lymph nodes, or chest wall.
* Local treatment is defined as either surgery, radiation therapy, or a combination of both if indicated.
* Adequate local therapy is surgery with negative microscopic margins. Radiation therapy is mandated for patients with microscopically involved margins and recommended for all patients who had not received radiotherapy as part of their primary treatment.
* Patients who have distant metastatic disease will not be eligible.
* Prior treatment with neoadjuvant and adjuvant chemotherapy and ET is allowed.
* Patients must enroll within 6 months of the last local treatment, either local surgery or radiation; or systemic chemotherapy (if patient is receiving chemotherapy), whichever occurred last. Chemotherapy after local therapy is allowed. ET for recurrent disease is allowed for up to 12 months prior to enrollment.
* Patient has no contraindication to the adjuvant ET in the trial and is planned to be treated or continue treatment with ET.
* Demonstrate adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
* Hematological
* Absolute Neutrophil Count (ANC): ≥ 1.5 x 109/L
* Platelets: ≥ 100 x 109/L
* Hemoglobin (Hgb): ≥ 9.0 g/dL
* Renal
---Estimated glomerular filtration rate (eGFR): ≥ 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula
* Hepatic
* Bilirubin: ≤ upper limit of normal (ULN) except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN
* Aspartate aminotransferase (AST): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the AST is \< 5 × ULN
* Alanine aminotransferase (ALT): ≤ 2.5 × ULN except for patients with liver metastasis, who are only included if the ALT is \< 5 × ULN
* Coagulation
---International Normalized Ratio (INR) : ≤ 1.5 × ULN (unless is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug)
* Electrolytes ---Potassium, Magnesium, and Total Calcium (corrected for serum albumin): Within normal limits or corrected to within normal limits with supplements.
* Standard 12-lead ECG values defined as
* QTcF interval at screening \< 450 msec (QT interval using Fridericia's correction)
* Resting heart rate 50-90 bpm (determined from the ECG)
* Females of childbearing potential who are sexually active with a male able to father a child must have a negative pregnancy test (serum or urine) within 14 days prior to registration and must be willing to use a highly effective method of contraception that does not contain estrogen and/or progesterone. See the protocol for definition of childbearing potential.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
* Ability to swallow and retain oral medication.
Exclusion Criteria for Treatment Phase:
Subjects meeting any of the criteria below may not participate in the study:
* Patient with a known hypersensitivity to any of the excipients of ribociclib.
* Patient who has received prior CDK4/6 inhibitor for recurrent disease. Patients who received a CDK4/6 inhibitor in the adjuvant setting may participate if they have been off therapy for at least 1 year prior to diagnosis of recurrent disease.
* Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
* Pregnant or breastfeeding or planning to become pregnant during the trial (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
* Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial.
* Patients with distant metastases of breast cancer beyond regional lymph nodes as defined by AJCC (8th edition).
* Treatment with any investigational drug within 30 days prior to registration or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. Enrollment or planned enrollment in another study that does not involve an investigational drug will be allowed at the discretion of the treating investigator.
* Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
* Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol: (e.g., chronic pancreatitis, chronic active hepatitis, HIV, active untreated or uncontrolled fungal, bacterial or viral infections, etc.). Testing to be done at investigator's discretion.
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
* History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry
* Documented cardiomyopathy
* History of Left Ventricular Ejection Fraction (LVEF) \< 50%
* Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
* Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
* Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug)
* Inability to determine the QTcF interval
* Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block)
* Systolic Blood Pressure (SBP) \>160 or \<90 mmHg
* Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
* Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
* Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
* Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (\<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
* Patient with an uncontrolled psychiatric condition that, in the investigator's judgment, may cause unacceptable safety risks, impede research integrity and compliance, or interfere with the objectives of the study.
DRUG: Ribociclib, DRUG: Fulvestrant, DRUG: Anastrozole, DRUG: Letrozole, DRUG: Exemestane
Locoregional Recurrence, Hormone Receptor-positive Breast Cancer, HER2-negative Breast Cancer
A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients
ctrrecruit@vcu.edu
NCT05711667
Inclusion Criteria:
* \>= 2 years and \< 18 years at the time of enrollment
* Weight must be \>= 18 kg. For patients \< 12 years of age and expected to receive cyclosporine, weight must be \>= 30kg
* Planned allogeneic HCT (bone marrow, peripheral blood stem cell, or cord blood transplant)
* Patient must be CMV sero-positive (i.e., recipient CMV immunoglobulin G positive)
* Patient is eligible for entry only if it is feasible for plasma CMV PCR testing to be sent and resulted within the protocol mandated time period
* Reminder: To limit the likelihood of positive plasma CMV PCR post-enrollment and prior to start of study treatment period, it is recommended that patient enrollment proceed after patients start their transplant preparative regimen
* Patient must have a performance status corresponding to Lansky/Karnofsky scores \> 50
* Note: Use Lansky for patients =\< 16 years of age and Karnofsky for patients \> 16 years of age. For further reference, see performance status scales scoring under the standard sections for protocols among protocol reference materials provided on the Children's Oncology Group (COG) member website: https://members.childrensoncologygroup.org/prot/reference\_materials.asp
* Estimated glomerular filtration rate \> 15 mL/min/1.73 m\^2 and not receiving dialysis
* Total bilirubin =\< 2.5 mg/dL and serum glutamate-pyruvate transaminase (SPGT) (alanine transaminase \[ALT\]) =\<10 x upper limit of normal (ULN) for age
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
Exclusion Criteria:
* Expected inability to tolerate oral formulation (e.g., unable swallow whole tablets) of letermovir
* Note: Determination of ability to tolerate the oral formulation will be based on a self-assessment or caregiver assessment; eligible subjects and their caregiver will be shown a life size picture of a tablet (or actual tablet) and confirm ability to swallow whole tablet in order to meet study eligibility
* Hypersensitivity to letermovir or any component of the formulation
* History of CMV end organ disease within 6 months (180 days) prior to enrollment
* Note: CMV end organ disease based on proposed definitions by Ljungman et al. and inclusive of proven, probable or possible disease
* Receipt of prior allogeneic HCT within one year of study enrollment
* Planned prophylactic administration of other anti-CMV medications or cellular products during the study, including:
* High dose acyclovir (defined as doses \>= 1500 mg/m\^2 IV or \>= 3200 mg oral (patients \>= 40 kg) or \>= 2400 mg/m\^2 (patients \< 40 kg) per day)
* High dose valacyclovir (defined as doses \>= 3000 mg/day in patients \> 20 kg)
* Foscarnet
* Ganciclovir
* Valganciclovir
* CMV-directed cytotoxic T lymphocytes
* Planned receipt of the following contraindicated medications during the study treatment period; contraindicated medications must be discontinued at least 14 days prior to Day +1
* Contraindicated medications for all patients:
* Pimozide
* Ergot alkaloids
* Contraindicated medications for patients planned to receive cyclosporine:
* Bosentan
* Lovastatin
* Pitavastatin
* Rosuvastatin
* Simvastatin
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted in certain animal reproduction studies with letermovir. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active female patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their letermovir treatment and through at least 4 weeks after the last dose of letermovir.
* Note: No contraception measures are needed specifically during letermovir treatment for male trial participants who have pregnant or non-pregnant female partner(s) of reproductive potential. Contraception measures may be required for other aspects of the HCT procedure.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met PROCEDURE: Biospecimen Collection, DRUG: Letermovir
Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm
A Research Study to Advance the CF Therapeutics Pipeline for People Without Modulators
Olena Boyarska - olena.boyarska@seattlechildrens.org
NCT06504589
Consent
A. Written informed consent (and assent when applicable) obtained from participant or participant's legal guardian
B. Is willing and able to adhere to the study visit schedule and other protocol requirements
Demographics
A. ≥ 12 years of age at Visit 1
Medical History
A. For persons of child-bearing potential: must not be pregnant at Visit 1 or plan to get pregnant during the 12-month study period
Disease History
A. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:
* Sweat chloride ≥ 60 mEq/liter by quantitative pilocarpine iontophoresis test (QPIT)
* Two well-characterized disease-causing pathogenic variants in the CFTR gene
or
* One well-characterized disease-causing mutation and a second CFTR variant (with variable or uncharacterized disease-causing potential) and sweat ≥ 30 mmol/liter with permission of the study sponsor-investigators
B. Clinically stable with no significant changes in health status within the 28 days prior to and including Visit 1
C. Does not have a history of lung transplantation
Concomitant Medications
A. Not genetically eligible for a CFTR modulator according to product label indications and/or No use of CFTR modulator for 28 days prior to Visit 1 with no intent to start or restart during the study period
B. No use of an investigational drug within 90 days prior to and including Visit 1
C. Not currently participating in an interventional drug or device trial. Participation in long-term safety follow-up studies (without redosing) and/or behavioral intervention trials is allowed.
D. No initiation of new chronic therapy (e.g., ibuprofen, azithromycin, inhaled tobramycin, Cayston®) within 28 days prior to and including Visit 1
E. No acute use of antibiotics (oral, inhaled or IV) or acute use of systemic corticosteroids for respiratory tract symptoms within 28 days prior to and including Visit 1
Cystic Fibrosis
ineligible and/or not taking CFTR modulators, People with CF
Effect of Moderate Renal Impairment and Race/Ethnicity on Treosulfan Pharmacokinetics
Clinical Trial Information - ClinicalTrialInformation@medac.de
NCT05534620
Inclusion Criteria:
• Participants with AML or MDS who qualify for treosulfan-based conditioning treatment, indicated for alloHSCT.
• Have available matched-related, matched-unrelated, haploidentical, or a mismatched unrelated donor. Match is defined as at least 9/10 allele matches in human leucocyte antigen (HLA)-A, -B, -C, -DRB1 and DQB1 or 7/8 allele matches in (HLA)-A, -B, -C and -DRB1. Haploidentical is defined as any family member with 2, 3 or 4 (out of 8) HLA-loci mismatch; at the same time, the donor and recipient must be HLA identical for at least one antigen at the following genetic loci: (HLA)-A, -B, -C, and -DRB1. High resolution deoxyribonucleic acid (DNA) typing must be used.
• Are adults of either sex, age 18-80 years (inclusive).
• Have a Karnofsky Index of greater than or equal to (\>=) 60 percent (%).
• Have a creatinine clearance (CLcre) \>=30 milliliters per minute (mL/min) (Cockcroft Gault: normal renal function: CLcre \>=90 mL/min, mild renal impairment: CLcre 60-89 mL/min, moderate renal impairment: CLcre 30-59 mL/min).
• Are willing to consent to using a highly effective method of birth control, such as condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner while on treatment and for at least 6 months thereafter, if females of childbearing potential (defined according to the Clinical Trials Facilitation and Coordination Group guidelines as a fertile woman, following menarche and until becoming postmenopausal unless permanently sterile) and males capable of reproduction.
• Have a negative pregnancy test, if females of childbearing potential.
• Have provided a written informed consent.
Exclusion Criteria:
• Participants considered not eligible for alloHSCT, for instance due to severe concomitant illness, within 3 weeks before the scheduled Baseline Visit: * Have severe renal impairment, example, are on dialysis, have renal transplantation history, or calculated CLcre of less than (\<) 30 mL/min. * Have severe pulmonary impairment, single-breath diffusion capacity of the lung for carbon monoxide (DLCO) (haemoglobin adjusted) or forced expiratory volume (FEV1) of \<50%, or severe dyspnoea at rest or requiring oxygen supplementation. * Have moderate or severe hepatic impairment (Child-Pugh B or C classification, respectively) and with documented medical history of chronic liver disease..
• Have a known coronary artery disease, history of myocardial infarction, cardiac dysfunction, including cardiomyopathies, heart failure (New York Heart Association Class II and above), and cardiac arrhythmias (including paroxysmal and permanent atrial fibrillation), interventricular conduction delay and / or bundle branch block (QRS duration \>120 milliseconds \[ms\]).
• Have Fredericia-corrected QTc (QTcF) interval \>450 ms in men and \>470 ms in women.
• Have active malignant involvement of the central nervous system.
• Are human immunodeficiency virus (HIV) positive or have an active non controlled infectious disease under treatment including fungal infection, active viral liver infection, or known severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) viral infection at the time of enrolment.
• Have previously had more than one alloHSCT.
• Have pleural effusion or ascites of \>1.0 liters (L).
• Are pregnant or breast-feeding.
• Have uncontrolled or severe intercurrent medical condition.
• Have known hypersensitivity to treosulfan, fludarabine, and / or related ingredients, Fanconi anaemia and other disorders resulting from DNA repair disorders.
• Are participating in another experimental drug trial (except those for coronavirus disease \[COVID 19\] vaccines) within 4 weeks prior to the Day 7 Baseline Visit. This exception serves to comply with subject's interests as this population is at a high risk of COVID 19 complications, if the disease occurs. COVID 19 vaccination details (including vaccine name, batch and manufacturer, dose, date of administration, and whether the right or left arm was injected) should be captured as a concomitant medication to enable better assessment of the overall effect of COVID 19 vaccination on oncology trial results.
• Exhibit non cooperative behaviour or non compliance.
• Have psychiatric diseases or conditions that might compromise the ability to give informed consent.
DRUG: Treosulfan, DRUG: Fludarabine
Acute Myeloid Leukaemia (AML), Myelodysplastic Syndrome (MDS), Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Pharmacokinetic