Ruxolitinib for Cancer Cachexia
To assess toxicity with use of Ruxolitinib in NSCLC cachexia patients; to associate levels of JAK/STAT signaling in blood, adipose, and muscle pre- and post-ruxolitinib treatment with changes in cachexia and anorexia.
• Male or female subjects at least 18 years of age;
• Ability to understand and the willingness to sign a written informed consent;
• Histological or biopsy proven Non-Small Cell Lung Cancer (squamous or non-squamous);
• ECOG performance status of 0-2;
• Patients with evidence of:
• cancer cachexia, defined by the International Cancer Cachexia Consensus Definition (>5% weight loss over the preceding 6 months prior to diagnosis); OR
• Patients with evidence of cancer pre-cachexia, defined by the International Cancer Cachexia Consensus Definition (0 to <=5% weight loss over the preceding 6 months prior to diagnosis);
• Any de novo stage IV NSCLC disease diagnosis as defined by AJCC 8th edition staging. Staged with PET/CT, MRI brain, or other acceptable staging tool; measurable disease as defined by RECIST 1.1;
• Adequate end-organ function, based on routine clinical and laboratory workup and institutional guidelines, as determined by oncology team offering patient standard of care therapy, including:
• ANC >1,000 cells/µl, Platelets > 100,000 cells/µl, Hemoglobin > 10.0 g/dl;
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 45 ml/min;
• Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤
• 5 x ULN;
• International normalized ratio (INR) (or prothrombin time (PT)) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy, if values are within the intended therapeutic range;
• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: a. Has not undergone a hysterectomy or bilateral oophorectomy; or b. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months);
• Male subjects who are surgically sterile or are using a medically acceptable form of contraception for 90 days following the completion of therapy;
• Life expectancy anticipated to be 6 months or greater;
• No prior therapy for advanced lung cancer.
• Subjects with confirmed stage I-III NSCLC;
• Patients whose tumors have actionable mutations treatable with targeted therapies;
• Patients with no evidence of cancer cachexia, defined by the International Cancer Cachexia Consensus Definition (>5% weight loss over the preceding 6 months prior to diagnosis); OR Patients with no evidence of cancer pre-cachexia, defined by the International Cancer Cachexia Consensus Definition (0 to <=5% weight loss over the preceding 6 months prior to diagnosis);
• Active malignancy other than lung cancer that requires concurrent treatment other than hormonal therapy and is deemed by the treating physicians to be likely to affect the subject's survival duration;
• Subjects who have not recovered or have disease control from prior treatment-related to toxicities judged by treating physician;
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib or other agents used in study;
• Uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements;
• Inadequate liver or renal function, if out of the acceptable ranges of the inclusion criteria;
• Significant bacterial, fungal, parasitic, or viral infection requiring treatment;
• Previous treatment with a JAK inhibitor;
• Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of ruxolitinib;
• Females who are pregnant, breast-feeding or plan to become pregnant;
• Participation in other clinical trials either to treat diagnosed lung or other cancers (patients on registry trials are eligible);
• Requirement for treatment with drugs that may, in the judgment of the treating investigator, create a risk for a precipitous change in patient's health;
• Any other conditions that, in the Investigator's opinion, might indicate the subject to be unsuitable for the study;
• Life expectancy of less than 6 months;
• Prior therapy for the newly diagnosed advanced lung cancer.
• Patients taking therapies that are strong CYP3A4 inhibitors and fluconazole.
Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia
The purpose of this study is to test the safety and determine the best dose of venetoclax and selinexor when given with chemotherapy drugs in treating pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has come back (relapsed) or did not respond to treatment (refractory). Primary Objective - To determine the safety and tolerability of selinexor and venetoclax in combination with chemotherapy in pediatric patients with relapsed or refractory AML or ALAL. Secondary Objectives - Describe the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the recommended phase 2 dose (RP2D). - Describe the overall survival of patients treated at the RP2D. Exploratory Objectives - Explore associations between leukemia cell genomics, BCL2 family member protein quantification, BH3 profiling, and response to therapy as assessed by minimal residual disease (MRD) and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA). - Describe the quality of life of pediatric patients undergoing treatment with selinexor and venetoclax in combination with chemotherapy and explore associations of clinical factors with patient-reported quality of life outcomes. - Describe the clinical and genetic features associated with exceptional response to the combination of venetoclax and selinexor without the addition of chemotherapy.
• Participants must have a diagnosis of AML or ALAL and meet the criteria below:
• Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR
• Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR
• Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR
• Relapsed leukemia following HCT, OR
• Second or greater relapse
• Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available. Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the blood. In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons.
• Adequate organ function defined as the following:
• Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Normal creatinine for age or a calculated creatinine clearance ≥ 30 mL/min/1.73m^2
• Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%
• Patients must be ≥ 2 years of age and ≤ 30 years old. The upper age limit may be defined by each institution, but may not exceed 30 years. Patients treated at St. Jude Children's Research Hospital must be ≤ 24 years old.
• Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are > 16 years old.
• At least 14 days must have elapsed since the completion of myelosuppressive therapy or hypomethylating agents and the first doses of venetoclax and selinexor.
• At least 24 hours must have elapsed since the completion of low-dose or non- myelosuppressive therapy, such as hydroxyurea or low-dose cytarabine (up to 100 mg/m^2/day), or leukapheresis, and the first doses of venetoclax and selinexor.
• For patients who have received prior HCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HCT.
• At least 14 days must have elapsed since the completion of any calcineurin inhibitors (e.g. tacrolimus, cyclosporine).
• Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of the first dose of venetoclax or during the administration of venetoclax. During the dose-escalation portion of the trial, we discourage the use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax. However, if an azole is required for the treatment or prevention of fungal infection during any phase of the trial, venetoclax dosing will be reduced to 60 mg/m^2 (100 mg max) in patients who require treatment with voriconazole and reduced to 40 mg/m^2 (70 mg max) in patients who require posaconazole.
• Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation.
• Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
• Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.
• Impairment of GI function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor.
• History of cerebellar toxicity or cerebellar neurological findings on exam.
• Previous toxicity or hypersensitivity directly attributed to venetoclax.
Evaluation of Co-formulated Pembrolizumab/Quavonlimab (MK-1308A) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer (CRC) (MK-1308A-008/KEYSTEP-008)
The purpose of this study is to assess the efficacy and safety of co-formulated pembrolizumab/quavonlimab versus other treatments in participants with MSI-H or dMMR Metastatic Stage IV Colorectal Cancer.
• Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by American Joint Committee on Cancer [AJCC] version 8)
• Has locally confirmed dMMR/MSI-H
• Has a life expectancy of at least 3 months
• Female participants are eligible to participate if not pregnant or breastfeeding, and not a woman of childbearing potential (WOCBP), or if a WOCBP then uses a contraceptive method that is highly effective or is abstinent on a long-term and persistent basis, during the intervention period and for at least 120 days after the last dose of study intervention
• Has measurable disease per RECIST 1.1 as assessed by the site and verified by BICR
• Submit an archival (within 5 years of Screening) or newly obtained tumor tissue sample that has not been previously irradiated; formalin-fixed, paraffin embedded (FFPE) blocks are preferred to slides.
• Has adequate organ function Cohort A:
• Has been previously treated for their Stage IV dMMR/MSI-H CRC and radiographically progressed on or after or could not tolerate standard treatment, which must include all of the following agents if approved and locally available in the country where the participant is randomized:
• Fluoropyrimidine, irinotecan and oxaliplatin (capecitabine is acceptable as equivalent to fluorouracil in prior therapy)
• With or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (e.g., bevacizumab)
• At least one of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) for rat sarcoma viral oncogene homolog (RAS) wild-type participants with left-sided tumors. Prior EGFR therapy is optional for patients with right sided RAS Wild-type (WT) tumors. Cohort B:
• Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for this disease
• Has received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
• Has not recovered adequately from a surgery procedure, and/or has any complications from a prior surgery before starting study intervention
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention
• 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 the first dose of study medication
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, quavonlimab, favezelimab, vibostolimab, MK-4830, and/or any of their excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
• Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
• Has a history of acute or chronic pancreatitis
• Has neuromuscular disorders associated with an elevated creatine kinase
• Has urine protein ≥1 gram/24 hours
• Has an active infection requiring systemic therapy (e.g., tuberculosis, known viral or bacterial infections, etc.)
• Has a known history of Human Immunodeficiency Virus (HIV) infection
• Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive and/or detectable Hepatitis B Virus [HBV] deoxyribonucleic acid [DNA]) and Hepatitis C virus (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid [RNA] infection
• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study intervention administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.
• Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before randomization/allocation
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
• Has had an allogenic tissue/solid organ transplant
PROGRESS: Management of Moderate Aortic Stenosis by Clinical Surveillance or TAVR (PROGRESS)
This study objective is to establish the safety and effectiveness of the Edwards SAPIEN 3 / SAPIEN 3 Ultra / SAPIEN 3 Ultra RESILIA Transcatheter Heart Valve systems in subjects with moderate, calcific aortic stenosis.
• 65 years of age or older at time of randomization
• Moderate aortic stenosis
• Subject has symptoms or evidence of cardiac damage/dysfunction
• The subject or subject's legal representative has been informed of the nature of the study, agrees to its provisions, and has provided written informed consent. Key
• Native aortic annulus size unsuitable for the THV
• Anatomical characteristics that would preclude safe transfemoral placement of the introducer sheath or safe passage of the delivery system
• Aortic valve is unicuspid or non-calcified
• Bicuspid aortic valve with an aneurysmal ascending aorta > 4.5 cm or severe raphe/leaflet calcification
• Pre-existing mechanical or bioprosthetic aortic valve
• Severe aortic regurgitation
• Prior balloon aortic valvuloplasty to treat severe AS
• LVEF < 20%
• Left ventricular outflow tract calcification that would increase the risk of annular rupture or significant paravalvular leak post-TAVR
• Cardiac imaging evidence of intracardiac mass, thrombus, or vegetation
• Coronary or aortic valve anatomy that increases the risk of coronary artery obstruction post-TAVR
TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)
TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) is a multi-center, three arm, randomized, controlled trial of immunosuppressive therapy for children with acute liver failure. The study will determine if suppressing inflammatory responses with either corticosteroids or equine anti-thymocyte globulin therapy improves survival for children with this rare, life-threatening condition.
• Patient with liver injury of ≤ 6 weeks duration resulting in an international normalized ratio (INR) of ≥ 1.5 and < 2.0 (not corrected by vitamin K) with evidence of hepatic encephalopathy (HE) or INR ≥ 2.0 without evidence of HE.
• Age is greater than or equal to 1 year and less than 18 years of age.
• Patient or their legally authorized representative(s) (LAR) must consent (and assent, if applicable) to be in the study and must have signed and dated an approved informed consent form which conforms to federal and institutional guidelines.
• Females of reproductive potential should not plan on conceiving children during the study and must agree to use a medically accepted form of contraception.
• Evidence of active infection with Hepatitis A, B, C, E or evidence of acute herpes simplex virus (HSV) or adenovirus infection
• Travel within the past 3 months to an area highly endemic for Hepatitis E
• Diagnosis of hemophagocytic lymphohistiocytosis (HLH) Note: Patients with a history of consanguinity and/or central nervous system (CNS) dysfunction that is exaggerated compared to the degree of liver dysfunction (as judged by the site investigator) will not be enrolled until results of rapid genetic testing are available. Turn-around time for genetic testing results is estimated to be 72-96 hours.
• Aplastic anemia as defined by standardized criteria  diagnosed prior to enrollment
• Diagnosis of autoimmune Hepatitis (AIH)
• Diagnosis of acute Wilson disease
• Diagnosis of inborn error of metabolism Note: Suspicion of metabolic disease is not an exclusion for entry into the Trial.
• Diagnosis of acute drug or toxin-induced liver injury
• History of recreational drug use within the past 4 weeks
• Therapy with an immunosuppressive agent, including chemotherapy, biological therapies or an experimental drug or device within the past 6 weeks
• Liver injury due to ischemia
• Liver dysfunction diagnosed more than 6 weeks prior to screening
• History of allergy to horse dander
• Imminent risk of death as judged by the clinical site investigator, including but not limited to; signs of cerebral herniation at the time of enrollment and presence of intractable arterial hypotension
• Solid organ or stem cell transplant recipient
• Pregnant or breast-feeding at the time of proposed study entry
• Clinical AIDS or HIV positive
• History of any form of malignant neoplasm and/or tumors treated within five years prior to study entry (other than non-melanoma skin cancer or in situ cervical cancer) or where there is current evidence of recurrent or metastatic disease
• Received a live-virus vaccine within 4 weeks of study entry
• Positive test result for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
• Psychiatric or addictive disorders that would preclude obtaining informed consent/assent
• Patient is unwilling or unable to adhere with study requirements and procedures
• Currently receiving other experimental therapies
CHIlled Platelet Study "CHIPS" (CHIPS)
A phase 3 randomized partial blind storage duration ranging study in patients undergoing complex cardiac surgery that will compare the transfusion of cold stored platelets to standard room temperature stored platelets. The primary objective is to establish that cold stored platelets have a non-inferiority (or superiority) to room temperature platelets.
• Age greater than 28 days and less than 85 years
• Planned complex cardiac surgery with planned use of cardiopulmonary bypass
• Expected order for washed or volume reduced platelets
• Patient with known anti-platelet antibodies
• Platelet transfusion refractoriness due to anti-HLA antibodies
• Known or suspected pregnancy
• Previously randomized in this study
• Conscious objection or unwillingness to receive blood products
• Known IgA deficiency
• Known congenital platelet disorder
• Known congenital bleeding disorder
• Planned post-operative extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), and/or continuous renal replacement therapy (CRRT)/ hemodialysis
• Patients intended to receive whole blood either intra-operative or post-operative for bleeding
• Platelet transfusion (of any type) within 24 hours prior to the date of surgery
• Pre-operative thrombocytopenia, defined as platelet count <75x10(9)/L, based on the most recent labs completed within 72 hours prior to the date of surgery.
Non-Contrast Perfusion Using Arterial Spin Labeled MR Imaging for Assessment of Therapy Response in Metastatic Renal Cell Carcinoma
Magnetic Resonance Imaging (MRI) including Arterial Spin Labeling (ASL) will be performed before, during, and after the treatment, in a total of up to 6 MRI sessions until 7 months after the first session, or when progression is clinically indicated. Thereafter, patients will be followed through standard clinical examinations for the next 3 years or until demise, whichever occurs first. Clinically, metastatic renal cell carcinoma (RCC) patients are imaged every 2-3 months after the initiation of anti-angiogenic therapy, since morphological (i.e. size) changes are not anticipated earlier. However, our preliminary experience has shown functional changes including perfusion as early as 2-weeks after the initiation of the treatment. T0, T1, and T2 sessions will be performed for this proposal, while T3, T4, and T5 will be performed along with the clinical imaging sessions. All MR imaging sessions will be scheduled within ±1 or ±2 weeks of the target time period. The research MR imaging may take approximately an additional 15 minutes per each imaging session, when done in conjunction with the clinical imaging. The T0, T1, and T2 research MR imaging sessions will be performed additionally for the purpose of this study, with each taking approximately one hour.
• Patients with locally advanced or metastatic renal cell carcinoma.
• Patients scheduled to undergo anti-angiogenic treatment or immunotherapy
• Eastern Cooperative Oncology Group (ECOG) Status 0, 1 and 2.
• Women of child-bearing potential must agree to undergo a urine pregnancy screening per standard Radiology departmental protocol, in place to prevent imaging of pregnant patients. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1) Has not undergone a hysterectomy or bilateral oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.
• Subjects may not be receiving any other anti-angiogenic agents, at the time of enrollment.
• Subjects must not be pregnant since pregnancy is a contraindication to administration of gadolinium-based contrast agents.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g. MRI-incompatible objects, including but not limited to medical devices (e.g. pacemakers, automated implantable cardioverter defibrillators, etc.) and other foreign bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with sickle cell disease and patients with other hemolytic anemias (low red blood count in body).
• Patients with uncontrollable claustrophobia, severe lower back pain, and uncontrollable tremors, to the point that it would render them unable to tolerate an MRI study.
Protonix Treatment of Maintenance of Healing in Pediatric Participants Aged 1-11 Years and 12-17 Years
The purpose of this study is to explore the outcomes, tolerability and safety of 2 different doses of oral pantoprazole (full healing dose, half healing dose), assigned based upon weight, for the maintenance of healing of erosive esophagitis in pediatric participants aged 1 to 17 years with endoscopically-confirmed, healed erosive esophagitis.
• Participants must have a documented erosive lesion with an Los Angeles (LA) Grade of A to D prior to starting Proton Pump Inhibitor treatment:
• Capable of giving signed informed consent/assent
• Willingness and ability of the participant or parent/legal guardian to complete the eDiary
• Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures, including the use of the eDiary.
• Male and female participants aged 1 to 17 years.
• Minimum body weight 7 kilogram and weight at least at the 5th percentile per the Center for Disease Control standard age and weight chart, for the participant's age.
• To be considered a female of non childbearing potential, the participant must meet at least 1 of the following criteria :
• Premenarchal: The investigator (or other appropriate staff) must discuss the participant's premenarchal status with the participant and parent/legal guardian at office visits and during telephone contacts, as participants who achieve menarche during the study would no longer be considered "female participants of non childbearing potential" and must comply with the protocol requirements applicable to women of childbearing potential.
• Previous administration of an investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
• Children that may be at high risk from procedural sedation should be carefully evaluated. Participants with a history of complications during prior procedural sedation
• History or presence of upper gastrointestinal anatomic or motor disorders
• Family history of malignant hyperthermia
• Known hypersensitivity to any Proton Pump Inhibitor, including pantoprazole or to any substituted benzimidazole or to any of the excipients.
• Any disorder requiring chronic (daily) use of warfarin, heparin, other anticoagulants, methotrexate, atazanavir or nelfinavir, clopidogrel, or potent inhibitors or inducers of CYP2C19 (eg, phenytoin, sulfamethoxazole, valproic acid, carbamazepine, and griseofulvin).
• Serum creatine kinase levels >3 x upper limit of normal.
• Known history of human immunodeficiency virus or clinical manifestations of acquired immune deficiency syndrome.
• Active malignancy of any type, or history of a malignancy. Participants with a history of malignancies that have been surgically removed or eradicated by irradiation or chemotherapy and who have no evidence of recurrence for at least 5 years before Screening are acceptable.
• Diagnosed as having or has received treatment for esophageal, gastric, pyloric channel, or duodenal ulceration within 30 days before the Screening visit.
• Alanine aminotransferase or blood urea nitrogen >2.0 upper limit of normal or estimated creatinine >1.5 X upper limit of normal for age or any other laboratory abnormality considered by the Investigator to be clinically significant within 14 days before the Baseline Visit (Day 1).
• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
• Has, in the Investigator's opinion, a serious chronic condition (eg, diabetes, epilepsy), which is either not stable or not well controlled and may interfere with the conduct of the study.
• Has any condition possibly affecting drug absorption (eg, gastrectomy). Prior or Concomitant Therapy:
• Frequent, repeated use of oral or parenteral glucocorticoids (eg, prednisone, prednisolone, dexamethasone). Steroid inhalers and topical steroids may be used.
• Pregnant female participants; breastfeeding female participants.
• Is unwilling or unable to comply with the Lifestyle Considerations section
A Study to Evaluate EDP 938 Regimens in Children With RSV (RSVPEDs)
A 2-part study to evaluate the safety, pharmacokinetics and efficacy of EDP-938 in children with RSV infection.
• Male or female who is either ≥6 months to ≤36 months (for Age Group 1) or ≥28 days to <6 months (for Age Group 2), defined at the time of randomization. Subjects in Age Group 2 must have been born ≥29 weeks of gestation to be eligible.
• Subjects diagnosed with RSV infection
• Subjects with signs of an acute respiratory illness with onset ≤7 days before the time of signing the ICF
• In the Investigator's opinion, the subject's caregiver understands and is able to comply with protocol requirements, instructions, and protocol-stated restrictions, and the subject is likely to complete the study as planned
• Use of or anticipated need for invasive mechanical ventilation, cardiopulmonary bypass, hemodialysis, or extracorporeal membrane oxygenation; or subjects who are not expected to survive the current illness
• Underlying immune deficiency, (e.g., from confirmed human immunodeficiency virus infection or use of an immunosuppressive medication except immunoglobulin A deficiency)
• Receipt of (within 12 months before Screening) or on a waiting list for a bone marrow, stem cell, or solid organ transplant, or who received radiation or chemotherapy (within 12 months before screening)
• Receiving chronic oxygen therapy at home before admission
• Receiving an investigational or approved medication that is intended to prevent or treat RSV infection within 30 days or 5 half-lives (whichever is longer) before the first dose of study drug, and/or is currently enrolled in a clinical trial of such a medication. RSV-specific monoclonal antibodies are not prohibited in Part 1.
A Study to Learn About How Well Riociguat Works, How Safe it is and How it is Used Under Real World Conditions in Patients in the United States Who Are Receiving Riociguat for High Blood Pressure in the Arteries That Carry Blood From the Heart to the Lungs (Pulmonary Arterial Hypertension, PAH) (ROAR)
Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the arteries that carry blood from the heart to the lungs. PAH occurs when the openings in the blood vessels of the lungs get smaller and smaller. These smaller openings can be caused by the following: - The walls of the arteries tightening - The walls of the arteries becoming stiff and narrow from an overgrowth of cells The increased pressure in the pulmonary arteries strains the right side of the heart and it begins to fail, causing difficulty breathing and other symptoms. As PAH progresses, symptoms get worse. There is no cure for PAH, but several medications like endothelin receptor antagonists (ERAs), prostacyclin analogues (PCAs) and riociguat, a soluable guanylate cyclase stimulator, are available to help slow the progression of changes in the pulmonary arteries and help reduce symptoms. Riociguat can be taken together with ERAs and PCAs. In this study, the researchers want to learn about how well riociguat works, how safe it is when patients take it in 1 of these ways: - alone - with ERA - with PCA - with ERA and PCA The dosage for each patient will be decided by their doctor. The researchers will review information collected from the patients who have decided with their doctor to start riociguat treatment for their PAH. The study will include about 500 patients in the United States who are at least 18 years old. All of the patients will have either just started taking riociguat or will have been taking it for less than 3 months No investigational products will be administered in this study. Patients will be treated with the Standard of Care (SOC) for PAH. The SOC is the currently appropriate treatment in accordance with scientific evidence and agreed upon in collaboration between medical experts for PAH. There will be no study-mandated visits or treatments. The patients will be in the study for up to 2 years. During this time, they will visit their doctor every 3 to 6 months as part of the Standard of Care. At these visits, the patients will answer questions about their PAH symptoms and whether they have any medical problems. They will also do exercise tests to see how well they are able to breathe and how tired they get while exercising. The doctors will perform other usual examinations which are part of the Standard of Care such as echocardiograms (images of the heart to show how the heart is working) and a right heart catheters (to measure the pressures in the heart) and will take the usual blood and urine samples.
• Patients aged ≥18 years at the time of riociguat treatment initiation
• Diagnosis of PAH per National Institute for Health and Care Excellence (NICE) 2018 classification
• Decision to initiate treatment with riociguat as per investigator's routine treatment practice made prior to enrollment in the study
• Initiation of riociguat, as per the FDA-approved US label:
• At enrollment OR
• ≤90 days prior to enrollment, with a documented titration regimen (defined as all documented dose changes including, but not limited to: starting dose and dates and highest tolerated dose and dates)
• Signed informed consent
• Previously treated with and discontinued use of riociguat for any reason prior to study enrollment (discontinuation defined as an interruption of therapy ≥30 days)
• Participating in any of the following:
• Blinded clinical trial
• Clinical trial involving an unapproved drug
• Investigational program with interventions outside of routine clinical practice
• Life expectancy <12 months
• Contraindicated to receive riociguat per the FDA approved US label
• Use of nitrates or NO donors in any form
• Use of PDE5 inhibitors
• PH associated with idiopathic interstitial pneumonias
• Unable or unwilling to provide informed consent
Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION)
The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) on time to clinical worsening (TTCW) in participants who are newly diagnosed with PAH and are at intermediate or high risk of disease progression.
• Age ≥ 18 years
• Documented diagnostic right heart catheterization (RHC) within 12 months of screening documenting a minimum PVR of ≥ 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤ 15 mmHg, with the diagnosis of WHO PAH Group 1 in any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with connective tissue disease
• PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
• Symptomatic PAH classified as WHO FC II or III
• Either Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 6 or Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 risk score ≥2 (intermediate to-low-risk or above)
• Diagnosis of PAH within 12 months of screening and on stable doses of a double combination of background PAH therapies and diuretics for at least 90 days prior to screening
• Six-minute walk distance ≥ 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value)
• Females of childbearing potential must meet the following criteria:
• Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
• If sexually active with a male partner, have used highly effective contraception without interruption, for at least 28 days prior to starting the investigational product AND agreed to use the same highly effective contraception in combination with a barrier method during the study (including dose interruptions) and for 16 weeks (112 days) after discontinuation of study treatment
• Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
• Male participants must meet the following criteria:
• Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
• Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements
• Ability to understand and provide written informed consent
• Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension, schistosomiasis-associated PAH, pulmonary veno occlusive disease, and pulmonary capillary hemangiomatosis
• Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 180 mmHg or sitting diastolic BP > 110 mmHg during the Screening Visit after a period of rest
• Baseline systolic BP < 90 mmHg at screening
• Pregnant or breastfeeding women
• Any of the following clinical laboratory values at the Screening Visit:
• Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as defined by MDRD equation)
• Serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels > 3 × ULN
• Platelet count < 50,000/mm3 (< 50.0 × 109 /L)
• Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for investigational biologics prior to the date of documented informed consent
• Known allergic reaction to sotatercept (ACE-011), its excipients, or luspatercept
• History of pneumonectomy
• Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
• Stopped receiving any PH chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the Screening Visit
• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the Screening Visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
• Untreated more than mild obstructive sleep apnea
• History of known pericardial constriction
• History of restrictive or congestive cardiomyopathy
• History of atrial septostomy within 180 days prior to the Screening Visit
• Electrocardiogram with Fridericia's corrected QT interval > 500 ms during the Screening Period
• Personal or family history of long QT syndrome or sudden cardiac death
• Left ventricular ejection fraction < 50% on historical echocardiogram (ECHO) within 1 year prior to the Screening Visit
• Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the Screening Visit
• Cerebrovascular accident within 3 months prior to the Screening Visit
• Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment
• Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit
• Has an active malignancy with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or prostate cancer that is not currently or expected, during the study, to be treated with radiation therapy, chemotherapy, and/or surgical intervention, or hormonal treatment
VITAS: Atezolizumab in Combination With Chemotherapy for Pediatric Relapsed/Refractory Solid Tumors
This trial is a multi-center, non-randomized, open-label Phase I/II study evaluating the feasibility and efficacy of vincristine, irinotecan, temozolomide, and atezolizumab in children with relapsed/refractory solid tumors.
• Signed informed consent
• Relapsed or refractory solid tumor after at least one prior course of therapy.
• Hodgkin lymphoma or non-Hodgkin lymphoma are not permitted.
• Patients with CNS malignancy or asymptomatic CNS metastases may be enrolled, provided all of the following criteria are met.
• No metastatic or primary disease affecting the brainstem, midbrain, pons, or cerebellum, or within 10 mm of optic nerve
• No history of leptomeningeal disease
• No history of intracranial or spinal cord hemorrhage
• No evidence of progression of neurologic deficit, in the investigator's judgment, within 7 days prior to initiation of study medications.
• Must have histologically confirmed rhabdomyosarcoma (RMS) for RMS efficacy cohort.
• Age ≥ 6 months and ≤ 18 years
• Lansky Performance Status (patients < 16 years old) or Karnofsky Performance Status (patients ≥ 16 years old) ≥ 50
• Ability to comply with the study protocol, in the investigator's judgment
• For RMS efficacy cohort, disease must be measurable as defined by RECIST v1.1.
• For the feasibility cohort, disease must be evaluable, but patients enrolled in the feasibility cohort will be prospectively assessed for measurable disease, RMS patients will also be included in the RMS efficacy cohort.
• Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
• Availability of a tumor specimen suitable for determination of PD-L1 status, either from initial diagnosis or from a recurrence.
• For PD-L1 staining to be performed at the central site, a formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report prior to study enrollment.
• Patients for whom the required number of slides are not available may still be eligible to enroll on study with PI approval
• For the RMS efficacy cohort, it will be required that at least 8 of 17 patients have PD-L1(+) tumor. PD-L1 status will be determined at time of enrollment for all patients. When the maximum allowable number of PD-L1(-) patients has been enrolled and treated on study, PD-L1 positivity will be required for all further enrolled patients.
• Staining will be performed in the central site CAP/CLIA-certified laboratory using the 22c3 antibody for immunohistochemical analysis
• PD-L1(+) status will be defined as staining on ≥1% of tumor cells or ≥1% of stroma.
• For the feasibility cohort, PD-L1 positivity is not required but will be performed centrally in all cases for exploratory biomarker studies.
• Adequate organ and marrow function as defined by the following laboratory values obtained within 21 days prior to initiation of study medication.
• For patients without known bone marrow involvement:
• Absolute neutrophil count ≥ 1.0 x 10^9 / L (1000/µL) without granulocyte colony-stimulating factor support (≥14 days after the last dose of a long-acting growth factor such as pegfilgrastim, or 7 days after short-acting growth factor)
• Absolute lymphocyte count ≥ 0.5 x 10^9 / L (500/µL)
• Platelet count ≥ 75 x 10^9 / L (75,000/µL) without transfusion in the last 7 days
• Patients with known bone marrow metastatic disease will be eligible for the study if they meet the following criteria:
• Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
• Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
• Absolute neutrophil count (ANC) ≥ 750/mm^3
• Absolute lymphocyte count ≥ 0.4 x 10^9 / L (400/µL)
• Platelet count ≥ 50,000/mm^3 (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions)
• These patients will not be evaluable for hematologic toxicity. At least 4 of 6 patients in the feasibility cohort must be evaluable for hematologic toxicity. If dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity.
• Total bilirubin ≤1.5 x upper limit of normal (ULN) for age (Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN)
• AST (SGOT) and ALT (SPGT) ≤ 2.5 x ULN for age
• Serum albumin ≥ 25 g/L (2.5 g/dL)
• Creatinine ≤ 1.5 x ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) ≥ 70 mL/min/1.73 m2
• Left ventricular ejection fraction ≥ 50% or shortening fraction ≥ 30%
• Hemoglobin ≥ 90 g/L (9 g/dL)
• Patients may be transfused to meet this criterion.
• For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative HIV and hepatitis B surface antigen (HBsAg) tests at screening
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
• Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final doses of atezolizumab, vincristine, and temozolomide. Women must refrain from donating eggs during this same period.
• A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus), regardless of sexual orientation or marital status.
• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
• For men who are not surgically sterile: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
• With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of less 1% per year during the treatment period and for 5 months after the final doses of atezolizumab, irinotecan, and temozolomide. Men must refrain from donating sperm during this same period.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception
• Pregnancy or breast-feeding:
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of study treatment
• Women of childbearing potential must have a negative serum pregnancy test result within 21 days prior to initiation of study treatment.
• Medical conditions that are excluded:
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Guillain-Barré syndrome, multiple sclerosis, or Kawasaki syndrome with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met at study initiation: (1) Rash must cover less 10% of body surface area, (2) Disease is well controlled at baseline and requires only low-potency topical corticosteroids, (3) No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Patients with indwelling catheters (e.g., PleurX®) are allowed.
• Uncontrolled tumor-related pain
• Patients requiring pain medication must be on a stable regimen at study entry for at least 2 weeks. Intermittent use of as-needed medication is allowed during this period.
• Clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (at the discretion of the treating physician)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• History of severe asthma or uncontrolled asthma
• Dyspnea at rest or requirement for supplemental oxygen
• Uncontrolled seizures. Patients taking a stable dose of anticonvulsants (for 2 weeks) are permitted, as long as they are not strong inducers or inhibitors of CYP3A4.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator
• Washout periods from prior therapies:
• Myelosuppressive chemotherapy or radiotherapy within 21 days prior to starting study treatment.
• Subjects must have recovered from all acute prior treatment-related toxicities to grade 1 or baseline (excluding alopecia and clinically stable toxicities requiring ongoing medical management, such as hypothyroidism).
• Non-myelosuppressive cancer therapy, such as kinase inhibitors, within 7 days prior to study treatment.
• Treatment with monoclonal antibodies with long half-lives, within 3 half-lives prior to study treatment.
• Treatment with targeted cellular therapies within 28 days prior to starting study treatment.
• Major surgical procedure, other than for diagnosis, within 30 days prior to initiation of study treatment, or anticipation of the need for a major surgical procedure during the first four cycles of the study.
• Biopsy tissue collection or placement of a vascular access device is permitted if the site has healed prior to initiation of study medications.
• For patients with CNS disease, no neurosurgical resection, brain biopsy, or stereotactic/whole-brain radiation within 30 days prior to Cycle 1, Day 1
• Treatment with a live, attenuated vaccine within 30 days prior to initiation of study treatment, or anticipation of the need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with investigational therapy within 21 days prior to initiation of study treatment or concurrent participation with another investigational agent
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-agents) within 2 weeks prior to initiation of study treatment, or anticipation of the need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.
• Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• Patients with CNS disease can be receiving concurrent treatment with corticosteroids with approval from the Principal Investigator. Patients must be receiving a stable or decreasing dose for ≥ 5 days prior to the baseline MRI scan and at the time of drug initiation. The Principal Investigator should be informed when steroid doses are increased because of declining patient status.
• Use of strong CYP3A4 inhibitors or inducers or strong UGT1A1 inhibitors within 12 days of Cycle 1, Day 1.
• Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3 months prior to initiation of study drug
• Treatment with herbal cancer therapy within 1 week prior to initiation of study medications.
• Treatment with a long-acting hematopoietic growth factor (such as pegfilgrastim) within 2 weeks prior to initiation of study medications, or a short-acting hematopoietic growth factor (such as G-CSF) within 1 week prior to initiation of study medications.
• Prior treatments:
• Prior allogeneic stem cell or solid organ transplantation
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies to include all anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2] within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Subjects must not have previously progressed while receiving regimens that include irinotecan or temozolomide. Patients who have received irinotecan or temozolomide and did not progress while on these medications are eligible.
• Known ongoing or untreated infection, including, but not limited to bacteremia, active tuberculosis, or severe pneumonia
• Active tuberculosis
• Current treatment with anti-viral therapy for HBV
• Active hepatitis C
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Known allergy or hypersensitivity to any component of the study medications
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
A Long-term Follow-up Study of Sotatercept for PAH Treatment (MK-7962-004/A011-12) (SOTERIA)
This study is being conducted to assess the long-term safety, tolerability, and efficacy of sotatercept (MK-7962, formerly called ACE-011) in participants with Pulmonary Arterial Hypertension (PAH). This open-label, long-term follow-up (LTFU) study is supported by data from the PULSAR study (Phase 2, NCT03496207) in which treatment with sotatercept resulted in hemodynamic and functional improvements in the study participants, including those receiving maximal PAH therapy with double/triple drug combinations and intravenous prostacyclin. The primary objective of this open-label, LTFU study is to evaluate the long-term safety and tolerability of sotatercept when added to background PAH therapy in adult participants with PAH who have completed prior sotatercept studies. The secondary objective is to evaluate continued efficacy in adult participants with PAH who have completed prior sotatercept studies.
• Have completed their current respective PAH sotatercept clinical study and its requirements, and must not have discontinued early
• Must be willing to adhere to the study visit schedule and understand and comply with all protocol requirements
• Must have the ability to understand and provide documented informed consent
• Females of childbearing potential must:
• Have a negative pregnancy test as verified by the investigator prior to starting study drug administration; she must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
• If sexually active, have used, and agree to continue to use highly effective contraception in combination with a barrier method without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study drug
• Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study drug
• Male participants must:
• Agree to use a condom, defined as a male latex condom or non latex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
• Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study drug
• Must agree not to participate in any other trials of investigational drugs/devices while they are enrolled in the MK-7962-004 study
• Did not participate in a sotatercept PAH parent trial
• Missed more than the equivalent of 4 consecutive doses between the end of parent study and the start of this study.
• Presence of an ongoing serious adverse event (SAE) that occurred during a PAH sotatercept clinical study that is assessed to be possibly or probably related to sotatercept
• Pregnant or breastfeeding females
DALY 2.0 USA/ MB-CART2019.1 for DLBCL
This is an open label, single arm, phase II study to determine the efficacy, safety and PK (persistence) of MBCART2019.1 cells in adults with relapsed or refractory DLBCL after receiving at least two lines of therapy.
• Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification:
• CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL)
• Relapsed or refractory disease after 2 or more lines of chemotherapy including rituximab and anthracycline and either having failed autologous stem cell transplant (ASCT), or ineligible, not intended for or not consenting to ASCT
• Chemotherapy-refractory disease is defined as persistent disease after last line of therapy or relapsed or persistent disease after prior ASCT for lymphoma
• Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen
• CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) first-line therapy.
• CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least 1 prior line of systemic therapy
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. ECOG performance status of 2 at screen is allowed if the decrease in performance status is due to DLBCL
• Measurable disease according to Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma (Cheson et al, 2014) for DLBCL and SCNSL while IPCG criteria for the primary PCNSL.
• Subject must have a tumor biopsy sample (at least 16 unstained slides of tissue or tissue block) from the most recent relapse available prior to MB-CART2019.1 infusion. If medically not feasible to obtain a biopsy from the most recent relapse and for cases when the amount of tissue is limited, the sponsor should be consulted, to confirm adequacy of the sample for study required analyses
• No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort)
• If the subject has history of CNS disease (not applicable to CNS cohort), then he/she must have no signs or symptoms of CNS disease, have no active disease on magnetic resonance imaging (MRI), have no large cell lymphoma present in cerebral spinal fluid (CSF) on cytospin preparation and flow cytometry, regardless of the number of white blood cells (WBCs)
• If has history of cerebral vascular accident (CVA), the CVA event must be greater than 12 months prior to leukapheresis. Any neurological deficits must be stable.
• A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) > 60mL/min
• Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA)
• Resting O2 saturation >90% on room air
• Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 times the Upper Limit of Normal (ULN) for age
• Total bilirubin <1.5 mg/dl, except in individuals with Gilbert's syndrome
• Absolute neutrophil count (ANC) > 1000/μL
• Absolute lymphocyte count > 100/μL
• Platelet count > 50,000/µL
• Estimated life expectancy of more than 3 months other than primary disease
• Primary CNS lymphoma (not applicable to CNS cohort)
• Richter's transformed DLBCL arising from chronic lymphocytic leukemia (CLL)
• Unable to give informed consent
• Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B (HBsAg positive). If there is a history of treated hepatitis B or hepatitis C, the viral load must be quantitative polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-HBc positive.
• Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing
• Known history of active seizures or presence of seizure activities except CNS lymphoma related, pharmacologically controlled seizure.
• Known history of CVA within prior 12 months.
• Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory disease
• Presence of CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity. For CNS Cohort: Bulky leptomeningeal disease and or CSF protein >100 mg/Dl. Recent (within 2 months) whole brain radiotherapy (WBRT)
• Active systemic fungal, viral, or bacterial infection
• Pregnant or breast-feeding woman
• Previous or concurrent malignancy with the following exceptions:
• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing required prior to study entry)
• In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study
• Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years
• A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years
• History of non-neurologic autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus)requiring systemic immunosuppressive or system disease modifying agents within the last 2 years
• Medical condition requiring prolonged use of systemic corticosteroids equivalent to prednisone >10 mg/day
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment
• Concurrent radiotherapy (normal tissue sparing palliative radiotherapy allowed up to time of lymphodepletion). For systemic therapy, at least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed at the time of scheduled leukapheresis.
• Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline
• History of severe immediate hypersensitivity reaction to any of the agents used in this study
• Refusal to participate in additional lentiviral gene therapy LTFU protocol
• Prior CAR-T therapy for any indication or systemic gene modifying therapy for DLBCL
• Prior allogeneic stem cell transplant for any indication
• Prior BITE antibodies for cancer therapy
• Prior T cell receptor-engineered T cell therapy
Durvalumab and Stereotactic Radiotherapy for Advanced NSCLC
This is a randomized Phase II study which is designed to determine the impact of stereotactic radiotherapy and durvalumab on quality-of-life and oncologic outcomes in patients with advanced non-small cell lung cancer. Durvalumab (Imfinzi) and stereotactic radiotherapy, with each fraction of radiotherapy is given every other day on a standard stereotactic ablative radiotherapy (SAbR) schedule or every four weeks on the personalized ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) schedule. Subjects will be followed for a period of 2 years after completion of treatment or until death, whichever occurs first. Specifically, subjects will be followed at 1, 3, 6, 9, 12, 15, 18, 21, and 24 months following treatment. After the 2 year follow up, the patient can continue routine follow up with their physicians, per standard of care. Subjects removed from therapy for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.
• Patients must have biopsy-proven metastatic non-small cell lung cancer and eligible for receipt of immunotherapy, based on standard of care
• Patients can present with either de novo metastatic disease or recurrent disease
• Patients must have at least one (1) symptomatic or progressive metastatic sites with no more than 10 metastatic sites, based on standard imaging studies
• Patients cannot have received any prior radiation therapy or surgery to the intended radiation treatment area (index lesion)
• Patients with brain metastases may be enrolled if all lesions are treated with radiation therapy or surgery prior to start of protocol therapy
• Metastases in major lower extremity weight-bearing bones or spine should undergo surgical stabilization if indicated
• Age greater than or equal to 18 years.
• Both men and women and members of all races and ethnic groups will be included
• Eastern Cooperative Oncology Group Performance status 0 to 2 (Appendix A)
• Adequate normal organ and bone marrow function as defined by:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.0 × 109 /L
• Platelet count ≥75 × 109/L
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) ≤2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5X ULN
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
• Creatinine CL (mL/min) = (Weight (kg) x (140 - Age)) ÷ (72 x serum creatinine (mg/dL))
• Creatinine CL (mL/min) = ((Weight (kg) x (140 - Age)) ÷ (72 x serum creatinine (mg/dL))) x 0.85
• All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Medically accepted forms of birth control include male condoms plus spermicide, diaphragm, cervical cap, the placement of a Copper T intrauterine device (IUD), birth control pills, Levonorgesterel-releasing intrauterine system (IUS), hormone implants or injections, or combined pill, minipill patch, or a partner who has undergone a vasectomy (surgical sterility).
• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Life expectancy greater than six (6) months
• Body weight greater than 30 kg
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone
• Administration of two or more lines of systemic therapy for the diagnosis of metastatic non-small cell lung cancer
• Prior receipt of systemic therapy for the management of high-risk early stage or locally advanced non-small cell lung cancer, prior to the development of metastatic disease, would not count towards the number of receipt of systemic therapy
• Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
• Patients with untreated brain metastases
• Patients with progressive metastatic disease involving the skin or subcutaneous tissues, esophagus, stomach, intestines, or mesenteric lymph nodes that are felt to be too high risk to treat with radiation therapy to protocol dose.
• Patients cannot have pathologic fracture at the evaluated site
• Patients cannot have untreated spinal cord compression
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab or other agents used in study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants
• Male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
• Participation in another clinical study with an investigational product during the last 3 months
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤7 days prior to the first dose of study drug If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of immunotherapy. Note: Local surgery of isolated lesions for palliative intent is acceptable
• History of allogenic organ transplantation
• History of another primary malignancy except for:
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of immunotherapy and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• History of leptomeningeal carcinomatosis
• History of active primary immunodeficiency
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• Receipt of live attenuated vaccine within 30 days prior to the first dose of immunotherapy. Other forms of vaccines, such as mRNA, recombinant protein, and non-replicating vector-based vaccines, are permitted. Note: Patients, if enrolled, should not receive live vaccine whilst receiving immunotherapy and up to 30 days after the last dose of immunotherapy
• Receipt of any medications listed below:
• Patients on this study should not be on any targeted systemic therapies such as those directed at EGFR mutations, ALK or ROS1 gene rearrangements, BRAF V600E mutation, or NTRK gene fusions. Other anti-cancer treatments are also not allowed on the study and are listed below. Supportive medications may be given at any point during treatment at the discretion of the treating physician, such as anti-emetics, pain medications, anti-diarrheals, nutritional supplementations, and anti-depressants. Anti-oxidant medications in excess of daily recommended values are not allowed.
• Any investigational anticancer therapy other than those under investigation in this study should not be given concomitantly whilst the patient is on study treatment.
• mAbs against CTLA-4, PD-1, or PD-L1 other than those under investigation in this study should not be given concomitantly whilst the patient is on study treatment.
• Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment other than those under investigation in this study should not be given concomitantly whilst the patient is on study treatment. (Concurrent use of hormones for non-cancer-related conditions [e.g., insulin for diabetes and hormone replacement therapy] is acceptable. Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable [e.g., by local surgery or radiotherapy])
• Immunosuppressive medications including, but not limited to, systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumor necrosis factor-α blockers.
• Immunosuppressive medications should not be given concomitantly, or used for premedication prior to the IO infusions. The following are allowed exceptions:
• Use of immunosuppressive medications for the management of IP-related AEs,
• Use in patients with contrast allergies.
• In addition, use of inhaled, topical, and intranasal corticosteroids is permitted.
• A temporary period of steroids will be allowed if clinically indicated and considered to be essential for the management of non-immunotherapy related events experienced by the patient (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.).
• EGFR tyrosine kinase inhibitors (TKI) should not be given concomitantly, and should be used with caution in the 90 days post last dose of durvalumab. Increased incidences of pneumonitis (with third generation EGFR TKIs) and increased incidence of transaminase increases (with 1st generation EGFR TKIs) has been reported when durvalumab has been given concomitantly.
• Live attenuated vaccines should not be given through 30 days after the last dose of IP (including SoC)
• Herbal and natural remedies which may have immune-modulating effects should not be given concomitantly unless agreed by the sponsor
Characterizing Inflammatory Profiles and Suicidal Behavior in Adolescents
Despite increasing suicide rates in adolescents, there remains a paucity of approaches to use to prevent re-attempts. Any hope for breaking the code to prevent youth suicide lies in understanding biological factors that play a role. Evidence suggests that inflammation and immune system dysfunction may be linked to suicide. The investigators will develop immune profiles for adolescents with suicidal behavior and those at risk in order to develop tools that can be implemented for prevention efforts. This study involves blood draws, answering questions, and completing questionnaires - no treatment or intervention is provided as part of this study. Participants will be screened to see if they qualify for this study using questionnaires. Participants will be teens (ages 12-18 years) with recent suicidal behavior, teens at-risk for developing depression, and healthy control teens. Participants complete all study-related tasks four times over a period of 12 months. Electronic surveys will be sent to participants to complete monthly. Both the adolescent and if applicable, their parent (or legally authorized representatives, LARs), will answer questions regarding depression, anxiety, and suicidal thoughts/behaviors.
• Be adolescents (aged 12-18 years);
• Have the ability to speak, read, and understand English. The parent(s) or legal guardians of minors must also speak, read and understand English;
• Be willing to provide consent/assent. Consent will be provided by parents/LAR/guardian for youth under age 18 or by young adult participant, aged 18. Youth, aged 8-17, must be willing to provide assent;
• Have the ability to complete clinical evaluations and self-report measures;
• Meet criteria for one of these three groups:
• Adolescent with suicidal behaviors, defined as having a recent (within 3 months) suicide attempt or suicidal ideation warranting urgent evaluation;
• Adolescents at risk for mood disorders, defined by either personal history of anxiety disorder or substance use disorder or a history of trauma, or a first degree relative with a history of a mood disorder or suicidal history;
• Healthy adolescents with no lifetime history of any psychiatric or substance use disorders or a history of trauma. Additionally, no first-degree family member with a history of a mood disorder or suicidal history.. Exclusion Criteria Study participants must not:
• Have current poorly controlled asthma, acute/chronic infection or other medical condition(s) that may affect immune marker levels;
• Have a current medication (e.g., corticosteroids) that may affect immune marker levels of reactivity;
• Have any condition for which, in the opinion of the investigator or designee, study participation would not be in their best interest (including but not limited to cognitive impairment, unstable general medical condition, intoxication, active psychosis) or that could prevent, limit, or confound the protocol-specified assessments;
• Be unable to provide a stable home address and contact information
A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)
FIREFLY-1 is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma or an advanced solid tumor harboring a known BRAF alteration.
• Age 6 months to 25 years with:
• Arms 1 & 2: a relapsed or progressive LGG with documented known activating BRAF alteration
• Arm 3: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion
• Confirmation of histopathologic diagnosis of LGG and molecular diagnosis of activating BRAF alteration
• Must have received at least one line of systemic therapy and have evidence of radiographic progression
• Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1 (Arm 3) criteria
• Patient's tumor has additional previously-known activating molecular alterations
• Patient has symptoms of clinical progression in the absence of radiographic progression
• Known or suspected diagnosis of neurofibromatosis type 1 (NF-1)
• Other inclusion/exclusion criteria as stipulated by protocol may apply
A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
This is a Phase 1/2, multicenter, open-label trial of avapritinib in participants 2 to < 18 years of age with advanced relapsed/refractory (R/R) solid tumors, including central nervous system (CNS) tumors, that harbor a PDGFRA and/or KIT mutation (including non-synonymous point mutations, insertions, and deletions) or amplification, or DMG-H3K27a who have no available curative treatment options. This is a single-arm trial in which all participants will receive avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).
• Participant must be 2 to < 18 years of age at the time of signing the informed consent.
• Participant has confirmed diagnosis of R/R solid tumor, including CNS tumors, with a mutation (including non-synonymous point mutations, insertions, and deletions) in PDGFRA and/or KIT (confirmed by local mutational testing of tumor sample) that has progressed despite standard therapy and no alternative treatment option is available. Participant with R/R solid tumors with only PDGFRA and/or KIT amplifications may be included with approval from the Sponsor. OR
• Participant has confirmed diagnosis of DMG-H3K27a (confirmed by local testing of tumor sample) that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the investigator.
• Participants with CNS disease should be on a stable (≤ 10% change) or decreasing dose of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
• Disease extent: a. Part 1: All participants must have at least 1 measurable lesion as defined by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) (for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion. b. Part 2: All participants must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). For Participants with DMG-H3K27a or PDGFRA and/or KIT mutant/amplified solid tumors, including CNS tumors that have progressed despite prior therapy, who have received radiation therapy, at least 1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion. For up to 5 Participants with newly diagnosed DMG-H3K27a where there is no standard therapy that may convey clinical benefit exists as judged by the investigator, progression of disease of a measurable lesion after irradiation is not required.
• A Lansky (< 16 years of age) or Karnofsky (≥ 16 years of age) score of at least 50. If the Participant is unable to walk due to paralysis, but is mobile in a wheelchair, the participant is considered ambulatory for the purpose of assessing their performance status.
• Participant agrees to utilize contraception consistent with local regulations.
• Male participants: Are vasectomized, or agree to use condoms, as defined in Section 5.4.2, from the start of Screening until 6 weeks after the last dose of study treatment, or practice true abstinence (when this is in line with the preferred and usual lifestyle of the Participant, see Section 5.4.2), or have a female partner who is NOT of childbearing potential.
• Female participants: Agree to use effective contraception, as defined in Section
• 4.2, from the start of Screening until 6 weeks after the last dose of study treatment and have a male partner who uses a condom, or practice true abstinence (when this is in line with the preferred and usual lifestyle of the Participant), or have a male partner who is vasectomized with confirmed azoospermia.
• Participant can give written informed consent/assent before any study-specific Screening procedures (if feasible). Parental/legal guardian consent will be determined by local, regional, and/or national guidelines. Exclusion Criteria
• Participant has any of the following within 14 days before the first dose of study treatment:
• Platelet count < 75 × 10^9/L (< 100 × 10^9/L if a CNS tumor) with no platelet transfusion within 14 days prior to the measurement.
• Absolute neutrophil count (ANC) < 1.0 × 10^9/L.
• Hemoglobin < 8.0 g/dL with no RBC transfusion ≤ 7 days prior to the measurement.
• AST or ALT > 3 × the ULN for age; except in Participants with tumor involvement of the liver who must not have AST and ALT > 5 × ULN for age.
• Total bilirubin > 1.5 × ULN for age; and in presence of Gilbert's syndrome, total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN.
• Serum creatinine > 1.5 × ULN for age.
• International normalized ratio or prothrombin time (PT) > ULN (> 1.5 × ULN if on prophylactic reversible anticoagulants).
• Participant has a QTcF > 470 msec. Participant has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
• Participant has clinically significant, uncontrolled cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension (> 95th percentile for age), or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second-degree heart block or third-degree heart block).
• Participant received the following systemic antineoplastic therapies:
• Temozolomide within 4 weeks prior to the first dose of study drug
• Nitrosurea within 6 weeks prior to the first dose of study drug
• Any other systemic antineoplastic therapy (including experimental therapy) within 5 half-lives or 28 days prior to the first dose of study drug, whichever is shorter.
• Focal external beam radiotherapy, including stereotactic radiosurgery, within 6 weeks prior to the first dose of avapritinib to either target or nontarget lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery, within 2 weeks of the first dose of avapritinib (within 6 weeks for Participants with CNS tumors). Craniospinal irradiation within 6 weeks prior to the first dose of avapritinib.
• All AEs related to other antineoplastic therapies (eg, systemic antineoplastics, radiotherapy) must have resolved to Grade ≤ 1 (Grade ≤ 2 for peripheral neuropathy and/or ototoxicity) prior to the first dose of avapritinib.
• Participant has previously received treatment with avapritinib.
• Participant received autologous stem cell transplant following myeloablative therapy or chimeric antigen receptor T cell therapy within 3 months prior to the first dose of avapritinib or prior allogeneic stem cell transplant within 1 year and no evidence of Grade 1 or greater graft-versus-host disease and no immunosuppressants for graft-versus-host disease (steroids for primary malignancy being permitted). Participants who received stem cell reinfusion following nonmyeloablative therapy are eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
• Participant requires ongoing treatment or has received treatment within 28 days before the start of avapritinib administration with drugs or foods that are strong CYP3A inhibitors or inducers.
• Participant has had a major surgical procedure within 14 days of the first dose of study treatment (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
• Participant has a history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of avapritinib. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Male subjects who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment.
• Participant is pregnant, as documented by a serum β-hCG pregnancy test consistent with pregnancy obtained at Screening and within 72 hours before the first dose of study treatment. Participants with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Female subjects of nonchildbearing potential (premenarchal, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do not require a serum β-hCG test.
• Participant is breastfeeding.
• Participant has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the Participant; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
• History of thrombosis requiring treatment within the past 6 months. This exclusion does not apply to catheter-related thrombosis if the catheter has been removed and did not require any other treatment in the previous 3 months.
• Participants who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
• Participants who are unable to swallow tablets (in Part 1) or minitablets (in Part 2) within the sprinkle capsules.
• Participants with a known risk of intracranial bleeding, such as a brain aneurysm that has not been removed or repaired, or a history of intracranial bleeding within the past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are: Participants with primary CNS tumors (provided they have not had CNS bleeding within 2 weeks of the first dose of avapritinib) or Participants with punctate hemorrhages < 3 mm.
• History of a seizure disorder that is not well controlled on current antiepileptic medications.
• Participant is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions.
Nivolumab in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma
This phase III trial compares the effects of nivolumab with chemo-immunotherapy versus chemo-immunotherapy alone in treating patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Treatment for PMBCL involves chemotherapy combined with an immunotherapy called rituximab. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nivolumab with chemo-immunotherapy may help treat patients with PMBCL.
• Age >= 2 years
• Patient must have histologically confirmed primary mediastinal B-cell lymphoma (PMBCL) as defined by World Health Organization (WHO) criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or ECOG performance status of 3 if poor performance is related to lymphoma
• Children's Oncology Group (COG) Institutions: Use Karnofsky for patients >= 17 and < 18 years of age and Lansky for patients < 17 years of age
• Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
• Pediatric Patients (age < 18 years): The following must have been obtained within 14 days prior to registration:
• Measured or calculated (based on institutional standard) creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2, or
• Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum creatinine based on age/gender as follows:
• Age : 2 to < 6 year; Maximum serum creatinine (mg/dL): 0.8 (male; 0.8 (female)
• Age : 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
• Age : 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
• Age : 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
• Age : >= 16 years to < 18 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Patients with abnormal liver function will be eligible to enroll if the lab abnormality is thought to be due to the lymphoma or Gilbert's syndrome
• Age >= 18 years: Ejection fraction of >= 50% by echocardiogram
• Age < 18 years: Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide angiogram
• 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
• 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
• Administration of prior anti-cancer therapy except as outlined below:
• A short course (=< 2 weeks) of corticosteroids for the relief of lymphoma-related symptoms
• A single course of COP (cyclophosphamide, vincristine, and prednisone)
• One cycle of chemo-immunotherapy including R-CHOP, DA-EPOCH-R, a pediatric mature B-cell non-Hodgkin lymphoma (B-NHL) induction therapy (such as ANHL1131), or intrathecal chemotherapy that has not started more than 21 days prior to enrollment
• Active ischemic heart disease or heart failure
• Active uncontrolled infection
• Central nervous system (CNS) involvement of lymphoma
• Previous cancer that required systemic chemotherapy and/or thoracic radiation. Other cancers will be permitted if in remission x 3 years
• Active autoimmune disease that has required systemic treatment (such as disease modifying agents, corticosteroids, or immunosuppressive agents) in the past 2 years. Replacement therapy such as thyroxine, insulin or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment
• In patients < 18 years of age hepatitis B serologies consistent with past or current infections
• Patients with severe hepatic impairment (Child-Pugh class C or serum total bilirubin >
• 0 mg/dL) unless thought to be due to lymphoma or Gilbert's syndrome
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study participation
• Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last dose of rituximab
LEGEND Study: EG-70 in NMIBC Patients BCG-Unresponsive and High-Risk NMIBC Incompletely Treated With BCG or BCG-Naïve
This study will evaluate the safety and efficacy of intravesical administration of EG-70 and in the bladder and its effect on bladder tumors in patients with NMIBC. This study study consists of two phases; a Phase 1 dose-escalation to establish safety and recommended the phase 2 dose, followed by a Phase 2 study to establish how effective the treatment is. The Study will include patients with NMIBC for whom BCG therapy is unresponsive and are recommended for radical cystectomy, or high-risk NMIBC patients who are BCG-naïve or have received incomplete BCG treatment.
• BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without resected papillary tumors who are ineligible for or have elected not to undergo cystectomy:
• persistent high-grade disease (Ta, T1, or Tis) after receiving intravesical BCG induction (at least 5 of 6 induction doses) plus maintenance (at least 2 of 3 doses) or recurrence of high-grade papillary disease within 6 months or Tis within 12 months of BCG instillation or
• T1 high grade disease residual at the first evaluation following induction BCG (at least 5 of 6 doses). BCG-Naïve or BCG-incompletely treated Patients (Phase 2 Only):
• NMIBC with Cis with or without resected papillary tumors who are ineligible for or have elected not to undergo cystectomy:
• persistent high-grade disease (Ta, T1, or Tis):
• after incomplete BCG treatment (at least 1 dose) or
• who have not yet received any treatment with BCG, but who have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor (TURBT) All Patients:
• Patients who have previously been treated with an investigational or approved checkpoint inhibitor (e.g., pembrolizumab) and failed treatment are eligible for inclusion 30 days post-treatment (Phase 1) or 3 months post-treatment (Phase 2).
• Male or non-pregnant, non-lactating female, 18 years or older.
• Women of childbearing potential must have a negative pregnancy test at Screening. A female patient is considered to be of child-producing potential unless she:
• has had a hysterectomy or bilateral oophorectomy or
• is age ≥ 60 years and is amenorrhoeic or
• is age < 60 years and has been amenorrhoeic for ≥ 12 months (including no irregular menses or spotting) in the absence of any medication which induces a menopausal state and has documented ovarian failure by serum oestradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range).
• All patients of childbearing potential must be willing to consent to using effective double-barrier contraception, i.e., intrauterine device, birth control pills, depo-provera, and condoms while on treatment and for 3 months after their participation in the study ends.
• In Phase 2, for patients with T1 lesions, Screening biopsy must be considered adequate (contain the muscularis layer).
• Performance Status: Eastern Cooperative Oncology Group (ECOG) 0, 1, and 2.
• Hematologic inclusion within 2 weeks of start of treatment:
• Absolute neutrophil count >1,500/mm3.
• Hemoglobin >9.0 g/dl.
• Platelet count >100,000/mm3.
• Hepatic inclusion within 2 weeks of Day 1:
• Total bilirubin must be ≤1.5 x the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN for the institution, alkaline phosphatase ≤2.5 x ULN for the institution, unless bone metastasis is present in the absence of liver metastasis.
• Adequate renal function with creatinine clearance >30 mL/min
• Prothrombin time and partial thromboplastin time within the normal limits at Screening.
• Must have satisfactory bladder function with ability to retain study drug for a minimum of 60 minutes.
• Patient or legally authorized representative (LAR) must be willing and able to comply with all protocol requirements.
• Patient or LAR must be willing and able to give informed consent and any authorizations required by local law for participation in the study.
• Any other malignancy diagnosed within 1 year of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix) is excluded.
• Concurrent treatment with any chemotherapeutic agent.
• History of partial cystectomy.
• Treatment with pembrolizumab within 30 days (Phase 1) or 3 months (Phase 2) prior to Screening.
• Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (Phase 1 and Phase 2) or treatment with an investigational checkpoint inhibitor within 3 months of Screening (Phase 2 only).
• Evidence of persistent or ongoing renal failure.
• History of unresolved vesicoureteral reflux or an indwelling urinary stent.
• History of unresolved hydronephrosis due to ureteral obstruction.
• Participation in any other research protocol involving administration of an investigational agent within 1 month prior to Day 1.
• History of external beam radiation to the pelvis at any time or prostate brachytherapy within the last 12 months.
• History of interstitial lung disease and/or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy.
• Evidence of metastatic disease.
• History of difficult catheterization that in the opinion of the Investigator will prevent administration of EG-70.
• History of interstitial cystitis.
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• Known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection.
• Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).
Ferric Citrate and Chronic Kidney Disease in Children (FIT4KID)
We will conduct a 12-month, double-blind, randomized, placebo-controlled trial to assess the effects of therapy with ferric citrate (FC) on changes in intact FGF23 levels (iFGF23, primary endpoint) in 160 pediatric patients (80 in each of the two arms) aged 6-17 years of either sex with chronic kidney disease (CKD) stages 3-4 and age-appropriate normal serum phosphate levels. Participants will be randomized to one of the two groups: 1) FC or 2) FC placebo. Participants will be recruited from 12 core clinical sites.
• Ages 6 to 17 years (inclusive);
• Estimated GFR of 15-59 ml/min per 1.73 m2 by modified CKiD formula;56
• Serum phosphate within age appropriate normal levels;
• Serum ferritin <500 ng/ml and TSAT <50%;
• For those patients treated with growth hormone, calcitriol, nutritional vitamin D, iron, and/or ESAs such treatments must have stable dosing for at least 2 weeks prior to screening;
• Able to swallow tablets;
• Able to eat at least two meals a day;
• In the opinion of the investigator, willing and able to follow the study treatment regimen and comply with the site investigator's recommendations.
• Perform physical exam and obtain vitals.
• Check urine pregnancy test in menstruating female participants and administer corresponding questionnaire.
• Administer GI Symptom questionnaire.
• Ascertain AEs.
• Obtain information on concomitant medications.
• Process 24-hour urine sample for 24 hour urine creatinine and phosphate.
• Measure run-in adherence using eCAP system and pill count.
• Administer the Medical Adherence Measure tool.
• Reinforce adherence.
• Prepare one month's supply of drug and enter them into eCAP system.
A Study of the Efficacy and Safety of MK-5475 in Participants With Pulmonary Arterial Hypertension (INSIGNIA-PAH: Phase 2/3 Study of an Inhaled sGC Stimulator in PAH) (MK-5475-007)
This is a two-part (Phase 2/Phase 3) study of MK-5475, an inhaled soluble guanylate cyclase stimulator, in participants with pulmonary arterial hypertension (PAH). The first part (Phase 2) will assess three different doses of MK-5475 compared to placebo in a base period of 12 weeks, followed by comparison of three different doses of MK-5475 during an optional 24 month extension period. The treatment dose with the best efficacy and safety profile in the phase 2 cohort base period will be selected for use in the second part (Phase 3) of the study. The primary hypothesis of Phase 2 is that at least one MK-5475 dose is superior to placebo in reducing pulmonary vascular resistance (PVR) from baseline at week 12. The purpose of the second part (Phase 3) of the study is to confirm the efficacy, safety, and tolerability of MK-5475 at the selected dose compared to placebo during a 12 week base period followed by an extension period of up to 5 years. The primary hypothesis of Phase 3 is that MK-5475 is superior to placebo in increasing 6-minute walk distance (6MWD) from baseline at week 12.
• Pulmonary arterial hypertension (PAH) in one of the following groups:
• Idiopathic PAH
• Heritable PAH
• Drug and toxin-induced PAH
• PAH associated with connective tissue disease, HIV infection, or congenital heart disease.
• Diagnosis of PAH documented by right heart catheterization (RHC).
• Eligibility RHC meeting all of the following criteria:
• Mean pulmonary artery pressure (mPAP) ≥25 mmHg
• Pulmonary vascular resistance (PVR) of ≥3 Wood units
• Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤15 mmHg.
• World Health Organization functional class (WHO-FC) symptoms between Class II and IV.
• Two 6-Minute walk distance (6MWD) measurements between 150 and 500 meters, one at screening and one at randomization.
• Stable concomitant background PAH-specific therapy.
• Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m² .
• Agree to be abstinent from heterosexual intercourse or use contraception during the intervention period and for at least 14 days after the last dose of study intervention.
• Female participants may not be pregnant or breastfeeding.
• Group 2 to 5 pulmonary hypertension.
• PAH in one of the following groups:
• Long term responders to calcium channel blockers
• Overt features of venous/capillary involvement
• Evidence of more-than-mild obstructive lung disease.
• Evidence of more-than-mild parenchymal lung disease.
• Evidence of more-than-mild obstructive sleep apnea (OSA) that is untreated.
• Evidence or history of left heart disease, including any of the following:
• Left ventricular ejection fraction (LVEF) ≤45%
• Moderate or severe left-sided valvular disease (aortic or mitral valve stenosis or regurgitation)
• Significant left ventricular diastolic dysfunction on echocardiographic evaluation
• Presence of 3 or more of the following risk factors for heart failure with preserved ejection fraction: BMI>30 kg/m², essential systemic hypertension, diabetes mellitus of any type, or coronary artery disease.
• Oxygen saturation measured by pulse oximetry (SpO₂) <90%, despite supplemental oxygen therapy.
• Chronic renal insufficiency (eGFR <30 mL/min)
• Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis, or significant hepatic laboratory abnormalities.
• Current smoker or currently uses electronic cigarettes (vapes).
• History of cancer, except: nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated, with appropriate follow up, and unlikely to recur for the duration of the study.
ACCEL Absorbable Hemostat
The ACCEL® Absorbable Hemostat Powder Clinical IDE Trial is designed as a prospective, multi-center, randomized, non-inferiority, controlled pivotal clinical trial to evaluate the safety and efficacy of the ACCEL® Absorbable Hemostat Powder as compared to gelatin sponge, for achieving hemostasis in subjects undergoing cardiovascular, liver, or soft tissue surgery, when control of oozing to moderate bleeding by standard surgical techniques is ineffective and/or impractical.
• Subject is greater than or equal to 22 years old
• Subject is undergoing a cardiovascular surgery, liver surgery or soft tissue surgical procedure
• Subject is willing and able to provide appropriate (Institutional Review Board (IRB) approved) informed consent.
• The subject is willing and able to comply with the requirements of the protocol, including follow-up evaluations and schedule.
• The subject is willing to be treated with ACCEL® Absorbable Hemostat Powder
• The subject is willing to be treated with a commercially available absorbable gelatin sponge During Surgery:
• Subject has not received blood transfusions between screening and application of investigational product or commercially available absorbable gelatin sponge
• There is an estimated TBS surface area of ≤ 60 cm2
• Visual observation of oozing (0.01 g/10s ˂ Flow ˂ 0.04 g/10s), mild (0.04 g/10s ≤ Flow ˂ 0.32 g/10s), or moderate (0.32 g/10s ≤ Flow ˂ 1.01 g/10s) bleeding as validated and when control by conventional surgical techniques, including but not limited to suture, ligature and cautery, is ineffective and/or impractical
• There is an absence of intra-operative complications other than bleeding, which, in the opinion of the Investigator, may interfere with the assessment of efficacy or safety
• There has been no intra-operative use of adjunct hemostat(s) on the target bleeding site identified for application of the study treatment
• The subject is pregnant (verified in a manner consistent with institution's standard of care)
• Subject is lactating
• Subject is currently participating in another investigational device or drug trial or has participated in one in the past 4 weeks (prior to surgery) or is planning to participate in another research study involving any investigational product within 4 weeks after surgery
• Subject is a prisoner, a minor or unable to adequately give informed consent due to mental or physical condition
• Subject has medical, social, or psychosocial issues that the Investigator believes could impact the subject's safety or compliance with study procedures
• Subject has a known allergy to potatoes
• Subject has a known allergy to porcine collagen/gelatin
• Subject has a religious or other objection to porcine products
• Subject is unwilling to receive blood products
• Subject has history of heparin-induced thrombocytopenia (only for cardiovascular subjects where heparin use is required)
• Subject with a baseline abnormality of INR > 2.5 or an aPTT> 100 seconds during screening that is not explained by current drug treatment (e.g. heparin, warfarin, etc.).
• Subjects with platelets < 100 X 109 PLT/L during screening
• Subject with Aspartate Aminotransferase (AST) or Alanine aminotransferase (ALT) > 3 X upper limit normal range during screening, except for subjects undergoing liver resection surgery or with a diagnosis of liver metastases where there is no upper limit normal for these analytes due to the nature of their disease
• Subject is unwilling or unable to return for the required follow-up after surgery During Surgery:
• Subject has an operative bleeding site which the surgeon is unable or unwilling to control with a hemostatic agent
• Extracorporeal cardiopulmonary bypass circuits or blood salvage circuits are to be used during or after identification of the TBS.
• There has been intra-operative use of thrombin on the patient.
The Pediatric Acute Leukemia (PedAL) Screening Trial - A Study to Test Bone Marrow and Blood in Children With Leukemia That Has Come Back After Treatment or Is Difficult to Treat - A Leukemia & Lymphoma Society and Children's Oncology Group Study
This study aims to use clinical and biological characteristics of acute leukemias to screen for patient eligibility for available pediatric leukemia sub-trials. Testing bone marrow and blood from patients with leukemia that has come back after treatment or is difficult to treat may provide information about the patient's leukemia that is important when deciding how to best treat it, and may help doctors find better ways to diagnose and treat leukemia in children, adolescents, and young adults.
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must have one of the following:
• Patient has known or suspected relapsed/refractory (including primary refractory) AML
• This includes isolated myeloid sarcoma
• Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome
• Patient has known or suspected relapsed ALL that meets one of the following criteria:
• Second or greater B-ALL medullary relapse, excluding KMT2Ar.
• Any first or greater B-ALL medullary relapse involving KMT2Ar.
• Any first or greater T-ALL medullary relapse with or without KMT2Ar.
• Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML) or treatment-related myelodysplastic syndrome (t-MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
• 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
Contrast Ultrasound for Pediatric Trauma - Comparative Evaluation (CAPTURE Study)
This multicenter study aims to evaluate the accuracy of contrast-enhanced ultrasound (CEUS) in diagnosing abdominal solid organ injuries in pediatric patients. Up to 130 subjects will complete the study across approximately 5-10 sites in the US, with up to 30 patients in the training phase (3 per site) and 100 patients in the treatment phase of the study. All subjects will have had a CT scan as part of standard of care, confirming at least one solid organ abdominal injury. The study procedure will occur within 48 hours from time of injury. All subjects will have an abdominal ultrasound without contrast, followed by a contrast-enhanced ultrasound using the contrast agent Lumason. Ultrasound and contrast-enhanced ultrasound results will be compared to the CT scan results. The CT and ultrasound scans will be read locally and will undergo central review.
• Hemodynamically stable, as determined by the trauma team
• Age 8 through 18 years (inclusive)
• Interpretable CT of the abdomen and pelvis that demonstrates at least one solid organ injury among the liver, spleen, pancreas, and kidneys
• Plan for observation or admission to the hospital
• Candidate for abdominal ultrasound based on body habitus, as determined by the investigator
• Glasgow Coma Score of 15
• Able to complete the study procedures within 48 hours of injury
• Known cardiac abnormality
• Pulmonary Hypertension
• Known sensitivity to any Lumason components - including sulfur hexafluoride, polyethylene glycol 4000, distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na), or palmitic acid
• Unable to be rolled onto side to allow lateral ultrasound windows if necessary
• Unable to assent or consent
• CT images not available for transmission to central image repository
Monitoring Neoadjuvant Chemotherapy of Breast Cancer Using 3D Subharmonic Aided Pressure Estimation
This phase II/III trial studies if contrast-enhanced ultrasounds using a contrast dye, perflutren lipid microspheres (Definity), can predict the response to chemotherapy by estimating the pressure in the cancer in patients with breast cancer that has spread to nearby tissues and lymph nodes (locally advanced). The efficacy of cancer therapy is affected by the pressure in the cancer. Definity is a contrast dye used to create better images during ultrasounds. The purpose of this trial is to determine if a special kind of ultrasound, called contrast-enhanced ultrasound, an experimental imaging test, can detect pressures in cancer to determine the response to neoadjuvant chemotherapy in patients with breast cancer.
• Provide signed and dated informed consent form
• Willing to comply with all study procedures and be available for the duration of the study
• At least 21 years old
• Be diagnosed with breast cancer (T1 or greater LABC, any N and M0)
• Be scheduled for neoadjuvant chemotherapy
• Be medically stable
• Be conscious and able to comply with study procedures
• If a female of child-bearing potential, must have a negative urine pregnancy test
• Females who are pregnant or nursing
• Patients with other primary cancers requiring systemic treatment
• Patients with any distal metastatic disease
• Patients undergoing neoadjuvant endocrine therapy
• Patients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable. For example:
• Patients on life support or in a critical care unit;
• Patients with unstable occlusive disease (e.g., crescendo angina);
• Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia;
• Patients with uncontrolled congestive heart failure (New York Heart Association [NYHA] Class IV);
• Patients with recent cerebral hemorrhage;
• Patients who have undergone surgery within 24 hours prior to the study sonographic examination
• Patients with known hypersensitivity or allergy to any component of Definity
• Patients with unstable cardiopulmonary conditions or respiratory distress syndrome
• Patients with uncontrollable emphysema, pulmonary vasculitis, pulmonary hypertension or a history of pulmonary emboli
Celliant Socks to Increase Tissue Oxygenation and Complete Wound Closure in Diabetic Foot Wounds
This study is a prospective, multicenter, double-blind, 1:1 randomized clinical trial. The purpose of this study is to demonstrate that the use of Celliant Socks increases tissue oxygenation (via oxygen saturation, StO2) and incidence of wound closure in subjects with diabetic foot ulcers. This study will use hyperspectral imaging and wound assessment to measure these outcomes. The study will enroll 254 evaluable subjects total, 127 per arm to meet the Primary Endpoint. Enrollment may continue up to twenty-five hundred (2500) evaluable subjects total to meet the Key Secondary Endpoint of complete wound closure.
• Diagnosis of diabetes mellitus
• Subject is willing and able to wear a sports-style tube sock at least 22 hours a day.
• Ankle Brachial Index (ABI) ≥0.5 (bedside ABI is acceptable for screening purposes as the formal imaging ABI may not be resulted prior to surgery) or toe pressure of ≥30mmHg
• One or more diabetic foot ulcers (only one will be treated) that are located in the ankle area or below that has persisted a minimum of 30 days prior to the Screening visit
• Diabetic Foot Ulcers ≥1cm2 and ≤16cm2
• Ulcer grade I or II, Stage A, I or II Stage B, according to University of Texas Wound Classification System
• 22 years of age or older
• Has clinically significant renal disease to require hemo or peritoneal dialysis
• Subject has untreated osteomyelitis
• Ulcers within 5cm of target ulcer or connected by fistulas
• Ulcer has decreased by 30% or more at the end of the run-in period
• Subject has untreated cellulitis
• Subject has untreated charcot
• Major immunodeficiency including HIV
• Is pregnant or plans to become pregnant
• Is nursing or actively lactating
• Developmental disability/significant psychological disorder that in the opinion of the investigator could impair the subject's ability to provide informed consent, participate in the study protocol or record study measures, including untreated schizophrenia, bipolar disorder and psychiatric hospitalization within the last 2 years.
• Active alcohol or substance abuse in the opinion of the investigator that could impair the subject's ability to provide informed consent, participate in the study protocol or record study materials
Study of Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis (TETON)
Study RIN-PF-301 is designed to evaluate the superiority of inhaled treprostinil against placebo for the change in absolute forced vital capacity (FVC) from baseline to Week 52.
• Subject gives voluntary informed consent to participate in the study.
• Subject is ≥40 years of age, inclusive, at the time of signing informed consent.
• The subject has a diagnosis of IPF based on the 2018 ATS/ERS/JRS/ALAT Clinical Practice Guideline (Raghu 2018) and confirmed by central review of high-resolution computed tomography (HRCT) (performed within the previous 12 months), and if available, surgical lung biopsy.
• FVC ≥45% predicted at Screening.
• Subjects on pirfenidone or nintedanib must be on a stable and optimized dose for ≥30 days prior to Baseline. Concomitant use of both pirfenidone and nintedanib is not permitted.
• Women of childbearing potential must be non-pregnant (as confirmed by a urine pregnancy test at Screening and Baseline) and non-lactating, and will abstain from intercourse (when it is in line with their preferred and usual lifestyle) or use 2 medically acceptable, highly effective forms of contraception for the duration of the study, and at least 30 days after discontinuing study drug.
• Males with a partner of childbearing potential must use a condom for the duration of treatment and for at least 48 hours after discontinuing study drug.
• In the opinion of the Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.
• Subject is pregnant or lactating.
• Subject has primary obstructive airway physiology: FEV1/FVC <0.70 at Screening.
• The subject has shown intolerance or significant lack of efficacy to a prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to effectively titrate that therapy.
• The subject has received any PAH-approved therapy, including prostacyclin therapy (epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), IP receptor agonists (selexipag), endothelin receptor antagonists, phosphodiesterase type 5 inhibitors (PDE5-Is), or soluble guanylate cyclase stimulators within 60 days prior to Baseline. As needed use of a PDE5-I for erectile dysfunction is permitted, provided no doses are taken within 48 hours of any study-related efficacy assessments.
• Use of any of the following medications: azathioprine (AZA), cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids (OCS) >20 mg/day or the combination of OCS+AZA+N-acetylcysteine within 30 days prior to Baseline; cyclophosphamide within 60 days prior to Baseline; or rituximab within 6 months prior to Baseline.
• The subject is receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline.
• Exacerbation of IPF or active pulmonary or upper respiratory infection within 30 days prior to Baseline. Subjects must have completed any antibiotic or steroid regimens for treatment of the infection or acute exacerbation more than 30 days prior to Baseline to be eligible. If hospitalized for an acute exacerbation of IPF or a pulmonary or upper respiratory infection, subjects must have been discharged more than 90 days prior to Baseline to be eligible.
• Uncontrolled cardiac disease, defined as myocardial infarction within 6 months prior to Baseline or unstable angina within 30 days prior to Baseline.
• In the opinion of the Investigator, the subject has any condition that would interfere with the interpretation of study assessments or would impair study participation or cooperation.
• Use of any other investigational drug/device or participation in any investigational study in which the subject received a medical intervention (ie, procedure, device, medication/supplement) within 30 days prior to Screening. Subjects participating in non-interventional, observational, or registry studies are eligible.
• Life expectancy <6 months due to IPF or a concomitant illness.
• Acute pulmonary embolism within 90 days prior to Baseline.
Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
The dose escalation phase of this trial identifies the best dose and safety of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
• DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumor including but not restricted to breast cancer, gastric or gastroesophageal cancer, colon cancer, endometrial cancer, salivary gland tumors, and hepatobiliary tumors
• DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastatic gastroesophageal cancer (cohort A) or colorectal cancer (cohort B)
• DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent for on treatment biopsy
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of AZD6738 in combination with DS-8201a in patients < 18 years of age, children are excluded from this study
• Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2 immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA) criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed (Note: in escalation phase, for breast cancer patients that are included, breast cancer criteria can be used). Specific requirement of HER2 status is outlined below:
• HER2 expression (1-3+) by IHC locally and confirmed centrally OR
• HER2 expression (1-3+) by IHC tested centrally OR
• HER2 amplification based on fluorescence in situ hybridization (FISH) or next generation sequencing
• Must have received at least one line of systemic chemotherapy for either locally advanced or metastatic disease and should have either progressed on this therapy or been intolerant to this therapy
• For tumors where anti-HER2 therapy is standard of care, patients must have progressed on at least 1 line of anti-HER2 therapy if eligible. For patients where DS8201a is approved as standard of care, prior treatment with DS8201a is not allowed
• Must have unresectable, advanced/metastatic disease
• Must have at least 1 measurable lesion on computed tomography (CT) scan per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patient without measurable but evaluable disease are allowed for dose-escalation phase
• Must be willing and able to provide an adequate archival tumor sample available to confirm HER2 status by Central Laboratory (if local testing is used for enrollment), else must be willing and able to provide an adequate archival tumor sample for HER2 testing centrally
• Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Must have life expectancy of at least 3 months
• Must have left ventricular ejection fraction (LVEF) >= 50% within 28 days before enrollment (study drug treatment) by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan
• Must have a negative pregnancy test (if female)
• Platelets >= 100,000/mcL (within 14 days before enrollment)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• Hemoglobin >= 9.0 g/dL (within 14 days before enrollment)
• Absolute neutrophil count >= 1,500/mcL (within 14 days before enrollment)
• No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
• Creatinine clearance > 45/mL/min (using the Cockcroft-Gault equation) (within 14 days before enrollment)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal (ULN) (within 14 days before enrollment)
• Total bilirubin =< 1.5 x ULN if no liver metastases or < 3 x ULN with Gilbert's Syndrome or liver metastases at baseline (within 14 days before enrollment)
• Leukocytes >= 3,000/mcL (within 14 days before enrollment)
• Albumin > 2.5 g/dL (GEJ patients only) (within 14 days before enrollment)
• International normalized ratio (INR) and either partial thromboplastin time (PTT) or activated (a)PTT =< 1.5 x ULN (within 14 days before enrollment)
• Must have adequate treatment washout period before study treatment, defined as: Major surgery (>= 4 weeks), radiation therapy (>= 3 weeks; in case of palliative radiation >= 2 weeks), systemic therapy (>= 3 weeks; in case of investigational drug use >= 2 weeks or 5 half-lives, whichever is longer)
• Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:
• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
• They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/mcl over the past 2 years, unless it was deemed related to THE CANCER AND/OR CHEMOTHERAPY-induced bone marrow suppression
• For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/mcl during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy
• They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within 7 days of enrollment
• They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts
• 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
• Subjects with clinically inactive brain metastases may be included. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiation therapy and study treatment
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the investigator favors participation in the clinical trial
• 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
• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as AZD6738 are known to be teratogenic; thus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 7 months (women of childbearing potential [WOCBP] only) after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study drug administration
• Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
• Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 6 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study
• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
• 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
• Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient using e-cigarettes/vaping are also excluded
• Patients with a medical history of myocardial infarction within 6 months before enrollment (study treatment), symptomatic congestive heart failure (New York Heart Association Class II to IV, corrected QT interval (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) as corrected by Framingham's formula
• Patients with spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Patients with multiple primary malignancies within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors
• Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product
• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator
• Patients with a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator
• 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. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator after discussion with study principal investigator (PI) (e.g., grade 2 chemo-induced neuropathy).
• Any previous treatment with an ATR inhibitor
• Patients with any clinically apparent pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
• Patients with previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable within the last 28 days as long as they are not within 1 week prior to screening assessment)
• Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs)
• Uncontrolled hypertension (grade 2 or above) requiring clinical intervention
• Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mm Hg
• Patients who have received corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason within 2 weeks prior to first dose
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to AZD6738
• Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receiving these drugs must have a washout period of > 14 days before enrollment/randomization
Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Reduced Ejection Fraction (MUSIC-HFrEF1)
It is believed that targeted SERCA2a enzyme replacement in HFrEF patients will correct defective intracellular Ca2+ hemostasis, resulting in improved cardiac contractile function and energetics which will, in turn, translate to improved clinical outcomes. Additionally, it is hypothesized that correcting SERCA2a dysfunction will also improve coronary blood flow through correction of the impaired endothelium-dependent nitric oxide-mediated vasodilatation observed in heart failure.
• Chronic ischemic or non-ischemic cardiomyopathy
• NYHA class III/IV
• LVEF ≤35%
• Guideline-directed medical therapy for heart failure; ICD Main
• Restrictive cardiomyopathy, hypertrophic cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete left ventricular (LV) aneurysm
• Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), mechanical circulatory support device (MCSD) or cardiac shunt
• Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, conventional revascularization procedure or valvular repair in the 6 months following treatment
• Likely need for an immediate heart transplant or MCSD implant due to hemodynamic instability
• Inadequate hepatic and renal function
• Diagnosis of, or treatment for, any cancer within the last 5 years except for basal cell carcinoma or carcinomas in situ where surgical excision was considered curative