Androgen Receptor Directed Therapy on Cognitive Function in Patients Treated With Darolutamide or Enzalutamide (ARACOG)
To compare the effects of treatment with enzalutamide (ENZ) versus darolutamide (DARO) on the cognitive function of men with non-metastatic and metastatic castration-resistant prostate cancer (mCRPC) by comparing the change in the maximally changed cognitive domain from baseline in patients in each study arm by 24 weeks.
• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
• Progressive disease per PCWG3 criteria
• Metastatic CRPC or non-metastatic CRPC (M0CRPC)
• Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA >2 ng/mL.
• For mCRPC: metastatic disease documented by standard or novel imaging techniques OR for M0CPRC: no evidence of metastatic disease on standard imaging.
• Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2
• Able to complete cognitive testing and patient reported outcome surveys in English.
• Ability to swallow study tablets whole.
• Able to provide informed consent. Key exclusion criteria include:
• Prior chemotherapy for treatment of CRPC. Patients who received chemotherapy for castrate-sensitive prostate cancer are still eligible provided chemotherapy was completed >6 months prior to study entry.
• Use of investigational agents for the treatment of prostate cancer within 4 weeks of study entry.
• Prior usage of ENZ or DARO.
• Prior use of apalutamide
• Prior use of investigational agents that act on the androgen axis.
• Progression during treatment with abiraterone (PSA or radiographic progression). Must have < 12 weeks of abiraterone exposure prior to enrollment if given for treatment of CRPC. If used with radiation for high risk localized hormone sensitive disease, can enroll if no progression of disease during treatment with abiraterone (PSA or radiographic) and >6 months since last exposure to abiraterone.
• Planned radiation treatment > 21 days during enrollment in the study.
• Any active, or prior history of, brain metastasis that have not been treated and stabilized.
• Active or history of seizures or seizure disorder.
• Prior diagnosis of dementia or other neurologic impairment.
• Use of chronic opiates (other than stable doses of opioids that in the view of the patient and investigator do not affect cognition).
• Clinically significant history of falls or risk of falls at baseline (timed up-and-go (TUG) test time of >12 seconds).
Improving Outcome for Family Caregivers of Older Adults With Complex Conditions: The Adult Day Plus (ADS Plus) Program (ADS Plus)
To evaluate the efficacy of ADS Plus, a family-based intervention program, in 30 adult day service programs throughout the United States among 240 family caregivers over a 12-month evaluation period.
• are initially enrolling their relative in one of the 30 participating ADS sites
• expect to use ADS for a minimum of 1 week for 6 months
• have primary responsibility for care of the ADS client
• speak English
• provided > 8 hours of assistance to client in past week
• have a telephone and are willing to participate in 4 telephone interviews (baseline, 3 month check-in; 6 and 12 month follow-ups)
• are 21 years of age or older (male or female).
• they plan to move from the area within 6 months
• either caregiver or client has been hospitalized >3 times in past year
• either caregiver or client is in active treatment for a terminal illness or are in hospice
• caregiver is involved in other caregiver support services/trials.
UrApp for Childhood Nephrotic Syndrome Management (Incident Cohort)
• Caregivers of patients ages 1-17 with steroid sensitive nephrotic syndrome (clinical diagnosis with edema, nephrotic range proteinuria [urine protein to creatinine ratio >2 mg/mg, or ≥ 300 mg/dL or ≥ 3+ protein on urine dipstick], and hypoalbuminemia ≤ 2.5 g/dL; resolution of proteinuria [negative/trace protein on urine dipstick] within 4 weeks of corticosteroid treatment)
• Caregivers of pediatric patients with steroid sensitive nephrotic syndrome diagnosed within 42 days at the time of enrollment
• Access to internet/wireless fidelity (Wi-Fi) in the home
• Caregiver proficiency with the English language
• Caregivers of pediatric patients with end-stage kidney disease
• Caregivers of pediatric patients with renal transplantation
• Caregivers of pediatric patients with clinical or histologic evidence of secondary nephrotic syndrome (e.g., systemic lupus erythematosus)
Neoadjuvant Combination Targeted and Immunotherapy for Patients With High-Risk Stage III Melanoma (NeoACTIVATE)
To estimate the percentage of patients with stage III BRAFm melanoma that achieves a pathologic complete response after 12 weeks of neoadjuvant vemurafenib/cobimetinib/atezolizumab. To estimate the percentage of patients with stage III BRAFwt melanoma that achieves a pathologic complete response after 12 weeks of neoadjuvant cobimetinib/atezolizumab. Adjuvant phase primary objectives: To assess recurrence-free survival (RFS) in patients with stage III BRAFm melanoma after neoadjuvant vemurafenib/cobimetinib/atezolizumab, surgery, and adjuvant atezolizumab. To assess RFS in patients with stage III BRAFwt melanoma after neoadjuvant cobimetinib/atezolizumab, surgery, and adjuvant atezolizumab.
• PRE-REGISTRATION: High-risk stage III melanoma, defined as (any of the following):
• Recurrent nodal metastasis, or
• Clinically detectable nodal metastasis, or
• Metastatic involvement of more than one nodal basin
• NOTE: For the purpose of pre-registration, high-risk stage III melanoma is defined based on clinical and imaging assessment (positron emission tomography/computed tomography [PET/CT], CT, or magnetic resonance imaging [MRI]). Histologic confirmation of nodal metastatic disease is not needed at the time of pre-registration, provided there is histologic confirmation of primary melanoma or a prior lymph node metastasis.
• PRE-REGISTRATION: Willing to submit archival tissue from a lymph node biopsy or undergo a needle biopsy for BRAF testing and for research purposes.
• PRE-REGISTRATION: Willing to forego anticancer treatments or investigational agents during pre-registration period.
• PRE-REGISTRATION: The following laboratory values obtained =< 28 days prior to pre-registration:
• Only for patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable international normalized ratio (INR).
• REGISTRATION: Histologic confirmation of stage III melanoma, as defined by the American Joint Committee on Cancer, 8th revised edition.
• REGISTRATION: Documentation of BRAFV600 mutation status in melanoma tumor tissue (archival or newly obtained) through use of a Clinical Laboratory Improvement Amendments (CLIA)-approved clinical mutation test.
• REGISTRATION: Surgically resectable disease, as determined by a melanoma surgical oncologist.
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• REGISTRATION: Life expectancy >= 26 weeks.
• REGISTRATION: Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to registration.
• REGISTRATION: Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration.
• REGISTRATION: Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to registration.
• REGISTRATION: Direct bilirubin =< institutional upper limit of normal (ULN) obtained =< 14 days prior to registration.
• REGISTRATION: Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2 x ULN obtained =< 14 days prior to registration.
• REGISTRATION: Alkaline phosphatase < 2.5 x ULN obtained =< 14 days prior to registration.
• Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault glomerular filtration rate estimation obtained =< 14 days prior to registration.
• REGISTRATION: Left ventricular ejection fraction (LVEF) >= 50% or institutional lower limit of normal (LLN) =< 6 months prior to registration.
• REGISTRATION: Average corrected QT interval (QTc) =< 450 ms on triplicate 12 lead electrocardiography (ECG) =< 28 days prior to registration.
• REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only.
• REGISTRATION: For persons of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment.
• REGISTRATION: For persons able to father a child: agreement to remain abstinent (refrain from heterosexual intercourse with a person of childbearing potential) or use contraceptive measures, and agreement to refrain from donating sperm.
• REGISTRATION: Provide written informed consent.
• REGISTRATION: Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
• REGISTRATION: Willing to provide tissue, blood, and stool samples for correlative research purposes.
• PRE-REGISTRATION: Prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal therapy, targeted therapy, immunotherapy including anti-PD-1, anti-PDL1 agents, or other biologic therapies), with the following exceptions: adjuvant treatment with interferon, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF) or vaccine therapies are allowed, if discontinued >= 28 days prior to pre-registration.
• PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• PRE-REGISTRATION: For patients with concurrent diagnosis of primary melanoma with nodal involvement, major surgical procedure other than lymph node biopsy or wide local excision of primary melanoma =< 4 weeks prior to pre-registration, or anticipation of need for a major surgical procedure for reasons other than melanoma during the course of the study.
• PRE-REGISTRATION: For patients with nodal recurrence, surgical procedure or anti-cancer therapy for this recurrence (other than lymph node biopsy) or anticipation of need for a major surgical procedure for reasons other than melanoma during the course of the study.
• PRE-REGISTRATION: Prior radiotherapy for melanoma.
• PRE-REGISTRATION: History non-nodal melanoma metastasis or central nervous system (CNS) lesion(s) proven or clinically suspected to be metastasis.
• PRE-REGISTRATION: Active malignancy (other than melanoma) or malignancy =< 3 years prior to pre-registration.
• NOTE: with the exception of resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, non-muscle-invasive bladder cancer, or other curatively treated malignancies from which the patient has been disease-free for at least 3 years prior to pre-registration.
• PRE-REGISTRATION: Prior allogeneic stem cell or solid organ transplantation.
• PRE-REGISTRATION: 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 CT scan.
• PRE-REGISTRATION: History of autoimmune disease requiring systemic immunosuppressive or immune-modulatory therapy =< 5 years prior to pre-registration.
• PRE-REGISTRATION: Active psoriasis requiring therapy (systemic or topical).
• PRE-REGISTRATION: Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease.
• PRE-REGISTRATION: History of or evidence of retinal pathology on ophthalmologic examination including but not limited to:
• Neurosensory retinal detachment
• Central serous chorioretinopathy
• Retinal vein occlusion (RVO)
• Neovascular macular degeneration
• PRE-REGISTRATION: Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.
• NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection
• Clinically significant cardiac dysfunction including:
• Symptomatic congestive heart failure defined as New York Heart Association class II or higher
• Unstable angina pectoris or new-onset angina =< 3 months prior to pre-registration
• Unstable cardiac arrhythmia
• Myocardial infarction =< 3 months prior to pre-registration
• Congenital long QT syndrome
• Clinically significant stroke, reversible ischemic neurological defect, or transient ischemic attack =< 6 months prior to pre-registration
• Any grade 3 hemorrhage or bleeding event =< 4 weeks prior to pre-registration
• Uncontrolled diabetes or symptomatic hyperglycemia
• Psychiatric illness/social situations that, in the judgement of the investigator, would a) limit compliance with study requirements, b) make the patient inappropriate for entry into this study, or c) interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• PRE-REGISTRATION: Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells (example [ex]: recombinant follicle-stimulating hormone [FSH]).
• PRE-REGISTRATION: Known hypersensitivity to any components of the atezolizumab, cobimetinib, or vemurafenib formulations.
• PRE-REGISTRATION: History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• REGISTRATION: Received anticancer treatments or investigational agents during pre-registration period.
• REGISTRATION: Clinically suspected non-nodal metastatic melanoma.
• REGISTRATION: For BRAF-mutant patients only: anticipated use of any concomitant medication =< 7 days prior to registration that is known to cause QT prolongation (which may lead to torsade de pointes).
• REGISTRATION: History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment or inability or unwillingness to swallow oral medication.
• REGISTRATION: Signs or symptoms of infection or has received antibiotics ≤14 days prior to registration.
• NOTE: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• REGISTRATION: Any of the following because this study involves investigational agents whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
• Pregnant persons
• Nursing persons
• Persons of childbearing potential who are unwilling to employ adequate contraception
• REGISTRATION: Treatment with a live, attenuated vaccine =< 4 weeks prior to registration, or anticipation of need for such a vaccine during the course of the study.
• REGISTRATION: Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF)-alpha agents) =< 2 weeks prior to registration, or anticipation of need for systemic immunosuppressive medication during the course of the study.
• NOTE: Patients who have received acute, low-dose systemic steroids (=< 10 mg/day oral prednisone or equivalent) prior to registration 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.
• NOTE: The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
• REGISTRATION: Requirement for concomitant therapy or food that is prohibited during the study, or inability to abstain from alcohol during neoadjuvant phase.
Nivolumab With Ruxolitinib in Relapsed or Refractory Classical Hodgkin Lymphoma
This is a Phase I, multicenter, open-label, dose escalation study to evaluate the safety and tolerability of ruxolitinib when given with fixed dose nivolumab in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). Up to 3 dose levels of ruxolitinib will be tested: 10 mg bid, 15 mg bid, and 20 mg bid. A dose level -1 of ruxolitinib 5 mg bid will be used only if dose level 1 proves too toxic. Participants will receive ruxolitinib at their assigned dose on a 28-day cycle with nivolumab 480 mg IV every 4 weeks until disease progression, unacceptable toxicity or for a maximum of 2 years. Cycle 1 only is expanded to 35 days to permit 1 week of ruxolitinib administration as a single agent before beginning every 4 week nivolumab. The dose escalation will use the continual reassessment method (CRM). The 1st 2 patients will enroll at dose level 1 (ruxolitinib 10 mg twice daily). The next cohort of 2 patients will not begin treatment until the last patient in the current cohort has reach day 35 after the 1st dose of ruxolitinib. Each new cohort of 2 patients will be assigned by the study statistician or designee at the same dose, 1 dose level higher, or 1 dose level lower. Once 10 patients are continuously enrolled at the same dose level, the MTD will be declared. Enrollment will continue at the MTD without staggering until a cumulative total of evaluable 20 patients are treated. Based on resources, the maximum number of allowable evaluable patients is 20. The simulations show it should be sufficient and safe to define the MTD for future efficacy trials. It is expected that 12 patients will be treated at the MTD. A sample size of 12 will achieve 79% power to detect a difference of ORR of 42% (equivalent of 5 responders) vs. null hypothesis of 12% using a two sided exact test with a significance level of 0.05. Participants will continue to receive the drugs until withdrawal criteria are met (e.g. toxicity, disease progression) or until 2 years duration of therapy.
• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0, 1 or 2.
• Histologically confirmed diagnosis of classical Hodgkin lymphoma that is relapsed or refractory
•historical biopsy at last relapse is acceptable. NOTE: a repeat biopsy is not required for Phase I if the historical biopsy was performed at the most recent relapse, without remission in between. A fresh biopsy is not required for Phase II.
• Presence of radiographically measurable disease (defined as the presence one or more ≥ 1.5 cm lesions, as measured in the longest dimension by PET/CT) within 4 weeks of study registration.
• Prior therapy with check-point inhibitors (nivolumab, pembrolizumab, others) and subsequent progressive disease, stable disease or mixed response
• Failed at least 2 prior therapies including cytotoxic chemotherapy including ABVD or similar, autologous transplantation, brentuximab vedotin, allogenic transplantation without active graft versus host disease Note: Patients who are eligible and willing to undergo autologous transplant should not be enrolled on this trial
• Prior cancer treatment must be completed at least 14 days prior to registration and the patient must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤Grade 1 or baseline. Radiation therapy must be completed at least 7 days prior to registration.
• Absolute Neutrophil Count ≥ 1000/μL
• Platelets ≥ 75,000/μL (or ≥50,000/mm3 if known BM involvement)
• Calculated creatinine clearance ≥ 40 cc/min using the Cockcroft-Gault formula
• Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN
• Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Males who are sexually active with partners of child-bearing potential must be willing to abstain from heterosexual activity or adhere to contraception from the time of written consent until 7 months after treatment discontinuation.
• Patient must provide voluntary written informed consent prior to the performance of any research related tests or procedures.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Inability or unwillingness to swallow oral medication or any condition that precludes the administration and/or absorption of oral medications
• A life-threatening illness, medical condition or organ system dysfunction, which in the investigator's opinion, could compromise the patient's safety, interfere with the metabolism of study drugs, or put the study outcomes at undue risk
• Active central nervous system (CNS) involvement by lymphoma
• Uncontrolled cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
• Concomitant therapy with immunosuppressive agents, including systemic corticosteroids (doses ≤ 10 mg/day prednisone or equivalent are permitted).
• Has a history of autoimmune disease now or in past 3 years such as hepatitis, nephritis, hyperthyroidism, interstitial lung disease or colitis except vitiligo or alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
• Active Hepatitis B or C infection (defined as a positive Hepatitis B surface antigen (Ag) or detectable viral load by PCR). NOTES: Hepatitis B and C testing is required. Patients with positive Hepatitis B Ag may enroll if PCR is negative. Suppressive antiviral therapy should be considered for these patients as clinically indicated.
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C
• Currently receiving a strong CYP3A4 Inhibitor (such as but not limited to boceprevir clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) or Fluconazole >200 mg/day. Washout period of 1 week is required.
• History of stroke or intracranial hemorrhage within 6 months of study registration
Cognitive Effects of Androgen Receptor Directed Therapies for Advanced Prostate Cancer
To compare cognitive function of men with advanced prostate cancer during treatment with enzalutamide or abiraterone acetate, adjusted for associated mediators of cognitive function (quality of life, depression, pain, and fatigue).
• Have diagnosis of prostate cancer and have received treatment with GnRH agonist or antagonist therapy for at least 1 month prior to enrollment.
• Willing and able to complete survey questionnaires in English without assistance through the duration of the study. This stipulation is in place because not all of the proposed quality of life or cognitive tests are available or validated in other languages.
• Age ≥ 18 years.
• Ability to understand and the willingness to sign a written informed consent document written in English that is approved by an institutional review board.
• Have either newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) or castration-resistant metastatic prostate cancer (mCRPC) and eligible to undergo treatment with abiraterone acetate (mHSPC or mCRPC) or enzalutamide (mCRPC)
• Patients may have received the following prior AR directed therapy prior to enrollment: bicalutamide, ketoconazole. Prior to enrollment, patients may have received treatment with abiraterone acetate or enzalutamide for no more than 14 days before completing baseline studies.
• Patients may have received chemotherapy for hormone-sensitive metastatic prostate cancer only, but it must not have lasted for more than 6 months. At least 12 months must have elapsed since completion of chemotherapy.
• Patients may have received prior definitive radiation therapy or surgery. At least 60 days must have elapsed since completion of definitive radiation therapy or surgery and patient must have only grade 2 or less adverse effects at the time of registration. Enrollment during palliative radiation of ≤ 10 days, or radiation of ≤ 10 days during the duration of the study is allowed.
• Patients must be able to take oral medication.
• Prior treatment with enzalutamide or abiraterone acetate for > 14 days prior to enrollment and completion of baseline tests.
• Receipt of chemotherapy for prostate or other cancer within the past 12 months with residual cognitive deficits, or receipt of chemotherapy for mCRPC. Patients/physicians planning treatment with chemotherapy during the 12 month period of the investigation are also ineligible.
• History of cognitive impairment or dysfunction, including a history of dementia, Alzheimer's disease, stroke with residual cognitive deficits, cognitive dysfunction related to alcohol or substance abuse, or cognitive dysfunction related to prior treatment for any cancer.
• Patients with a seizure history, history of recurrent falls, or known brain metastases are excluded from this clinical trial because of their poor prognosis and because of their heightened risk of seizure or progressive cognitive and/or neurologic dysfunction that would confound the evaluation.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations/substance abuse that would limit compliance with study requirements.
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not eligible. Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year. Patients with cognitive dysfunction related to treatment of another malignancy, including a history of "chemo-brain", are ineligible.
• Patients taking psychotropic medications or illicit drugs that may alter cognition, concentration, or behavior. Appropriate treatment by a licensed provider with medications for depression or anxiety, including but not limited to SSRIs, SNRIs, and standard dose benzodiazepines at a stable dose, is permitted
Phase 1/2 Clinical Trial of PR001 in Infants With Type 2 Gaucher Disease (PROVIDE)
This is a study to assess the safety and efficacy of PR001A, an Aden-associated (AAV9) viral vector to treat neuronopathic Gaucher disease type 2 (GD2) in infants. PRA001A will be administered via suboccipital injection to the cisterna magna during a single neurosurgical session. GD2 is a fatal disease of early infancy that does not have any therapeutic options beyond palliative care. This study will enroll infants 0-24 months of age.
• Bi-allelic GBA1 mutations consistent with a diagnosis of GD2 confirmed by the central laboratory.
• Neurological signs and/or symptoms consistent with diagnosis of GD2
• Parent/legal guardian has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations.
• Patient has a reliable informant (i.e., parent/legal guardian) willing and able to participate in the study as a source of information on the patient's health status and cognitive and functional abilities (including providing input into the rating scales).
• Diagnosis of a significant CNS disease other than GD2 that may be a cause for the patient's GD symptoms or may confound study objectives.
• Achieved independent gait.
• Severe peripheral symptoms of GD which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study.
• Concomitant disease, condition, or treatment which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study.
• Use of any GD treatment-related substrate reduction therapy.
• Use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) medications, herbals, or over-the-counter agents.
• Any type of prior gene or cell therapy.
• Immunizations (live vaccines) in the prior 4 weeks.
• Use of blood thinners. Antiplatelet therapies are acceptable if the patient is medically able to temporarily stop them from 7 days prior to dosing and through at least 48 hours after the intracisternal injection and lumbar puncture.
• Use of systemic immunosuppressant or corticosteroid therapy other than protocol-specified (topical preparations for dermatological conditions are allowed).
• Participation in another investigational drug or device study within the past 6 months.
• Brain MRI (magnetic resonance imaging) and MRA (magnetic resonance angiography) showing clinically significant abnormality considered to prevent intracisternal injection.
• Clinically significant laboratory test result abnormalities assessed at screening.
• Contraindications or intolerance to radiographic visualization methods (e.g. MRI, MRA, CT), and intolerance to contrast agents used for MRI or CT scans.
• Contraindications to general anesthesia or sedation. Other protocol-defined inclusion/exclusion criteria may apply.
Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
This is a Phase 1/2 multicenter, open-label study to evaluate palbociclib in combination with either irinotecan (IRN) and temozolomide (TMZ) or topotecan (TOPO) and cyclophosphamide (CTX) chemotherapy in children, adolescents and young adults with recurrent or refractory solid tumors. The study consists of a non- randomized Phase 1 portion for recurrent or refractory solid tumors followed by potential non- randomized tumor specific cohort(s) and a randomized, Phase 2 portion for recurrent or refractory EWS.
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts. 2. Age ≥2 and <21 years at the time of study entry. 3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age. 4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent);
• Hemoglobin ≥8.5 g/dL (transfusion allowed). 5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits. 6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age. 7. Measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. 8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia. 9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. 10. Evidence of a personally signed and dated informed consent document indicating that the patient or a legally acceptable representative/parent(s)/legal guardian of minors, has been informed of all pertinent aspects of the study. Minor study patients also must provide age appropriate assent according to the local guidelines, where applicable. 11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures. Exclusion: 1. For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. 2. Prior intolerability to IRN and/or TMZ, for palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for palbociclib with TOPO and CTX combination. 3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.) 4. Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry. 5. Radiation therapy within 14 days before study entry. 6. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 7. Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1. 8. Prior irradiation to >50% of the bone marrow (see Appendix 9). 9. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 10. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 11. Known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. 12. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days. 13. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable. 14. Hereditary bone marrow failure disorder. 15. QTc >470 msec. 16. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%. 17. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 18. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. 19. Other severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study. 20. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study. 21. Fertile male patients and female patients of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 after the last dose of investigational product.
Treatment of ARDS With Instilled T3 (ARDS+T3)
Study objective: To determine the safety and tolerability of Thyroid Hormone (T3) delivery into the lungs of Acute Respiratory Distress Syndrome (ARDS) patients, and to measure the effect of T3 on extravascular lung water in ARDS patients.
• Chest x-ray: bilateral pulmonary infiltrates
• Hypoxemia: PaO2:FIO2 ratio <200
• Volume status: wedge and CVP<18 Main inclusion criteria:
• Adults (≥18 years of age), non-pregnant
• On mechanical ventilatory support
A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease
• Have a diagnosis of SCD, with either βS/βS, βS/β0, or βS/β+ genotype.
• Be ≥2 and ≤50 years of age at time of consent.
• Weigh a minimum of 6 kg.
• Have a Karnofsky performance status of ≥60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age).
• Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history.
• In the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 protocol-defined VOEs in the 24 months prior to informed consent.
• Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment).
• Female and male subjects of childbearing potential agree to use 1 method of highly effective contraception from Screening to at least 6 months after drug product infusion.
• Provision of written informed consent for this study by subject, or as applicable, subject's parent(s)/legal guardian(s).
• Subjects for whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically appropriate per PI judgment and a willing, human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available.
• Severe cerebral vasculopathy, defined by any history of overt ischemic or hemorrhagic stroke, a history of abnormal transcranial Doppler (TCD) or TCD imaging (TCDI) for subjects ≤ 16 years of age (e.g. TCD velocity >200 cm/sec) requiring ongoing chronic transfusions, a Screening TCD or TCDI velocity > 200 cm/sec (central read), a Screening MRA showing > 50% stenosis or occlusion in the circle of Willis (central read), or a Screening MRA showing the presence of Moyamoya (central read).
• Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotropic virus-1 (HTLV-1), active syphilis.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection
• Advanced liver disease, such as 1. clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy) 2. liver iron concentration ≥15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis
• Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L.
• Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.
• Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment
• Unable to receive pRBC transfusion.
• Prior receipt of an allogeneic transplant.
• Prior receipt of gene therapy.
• Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• Immediate family member with a known or suspected Familial Cancer Syndrome.
• Female subject is breastfeeding, pregnant or will attempt to become pregnant from Screening to at least 6 months after drug product infusion.
• Any other condition that would render the subject ineligible for HSCT.
• Participation in another clinical study with an investigational drug within 30 days of screening.
• Presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) per Investigator's judgment.
• Presence of genetic mutations that result in the inactivation of 2 or more α-globin genes
JSP191 Antibody Targeting Conditioning in SCID Patients
Phase 1: To evaluate the safety and tolerability of JSP191 and to determine Phase 2 doses of JSP191 as a conditioning agent prior to allogeneic hematopoietic cell transplantation (HCT) in two populations of subjects with severe combined immunodeficiency (SCID): • SCID subjects with history of prior allogeneic HCT but with poor graft function • SCID subjects who are HCT-naïve Phase 2: • To evaluate the efficacy of JSP191 conditioning to enable engraftment of allogeneic CD34+ hematopoietic cells, as determined by CD15+ donor myeloid chimerism • To evaluate the efficacy of JSP191 conditioning to enable immune reconstitution determined by the production of naïve T cells
Rare CFTR Mutation Cell Collection Protocol (RARE) (RARE)
We are doing the RARE study to learn more about Cystic Fibrosis (CF). CF is caused by mutations in a gene that produces a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). In people with CF, the CFTR does not function correctly. Medications are being developed to help the CFTR function better, but those medications mostly benefit people with common CFTR mutations. There are more than 1,900 mutations of the CF gene. Some of these mutations are rare and found only in a few people. The goal of this research study is to collect specimens (blood, nasal cells, rectal cells) from people with rare CFTR mutations. Another purpose of this study is to create induced pluripotent stem cells or iPS cells. “Pluripotent” stem cells are cells that can be changed into almost any cell type of the body (such as lung or intestine). They can be kept alive and stored indefinitely. There are different kinds of pluripotent stem cells. Inducted pluripotent stem cells can be created from many different kinds of specimens (such as blood, nasal cells, rectal cells). This is different from embryonic stem cells, which can only be derived from embryos. The specimens collected during this study and iPS cells created from them will be stored for use in future research to learn more about CF and study the effect of new medications. This could identify new medications that may help people with rare CFTR mutations.
• Male or female ≥ 12 years of age at time of consent
• Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with CF and one or more of the following criteria (1. Sweat chloride ≥ 60 milliequivalents/Liter (mEq/L) by quantitative pilocarpineiontophoresis test (QPIT) OR upon permission of the RARE Investigator- Sponsors, 2. Two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene, 3.Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride solution and isoproterenol of lessthan -6.6 mV)
• Confirmed genotype of the current recruitment focus for certain target rare mutations. The initial recruitment focus will be CF patients who are homozygous for pre-mature stop codons. Operations Memos will detail any future current genotype targets.
• Written informed consent (and assent when applicable) obtained from participant or participant's legal representative and ability to comply with the requirements of the study.
• Willing to travel (if needed) to a regional study site for cell collection.
Androgen Deprivation Therapy (ADT) and Pembrolizumab for Advanced Stage Androgen Receptor-positive Salivary Gland Carcinoma
• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Locally advanced, recurrent, or metastatic salivary gland carcinoma that is not amenable to curative surgery or radiation
• ECOG Performance Status of 0 or 1 within 28 days prior to registration.
• Local, pathologic testing of androgen receptor-positive salivary gland carcinoma will be performed as standard of care. Archival tissue must be available for central confirmation of androgen receptor-positive disease and for correlative studies. AR positivity will be defined according to IHC staining of tumor tissue with at least 20% of tumor staining positive with moderate intensity (1+ or greater).
• Measurable disease according to RECIST v1.1 for solid tumors within 28 days prior to registration.
• For patients who have been treated with prior therapy, patients must have documented progression of disease on their prior therapy for entry into the study.
• Patients with prior chemotherapy, radiation, or surgery as part of curative intent therapy are allowed. Any number of prior lines of systemic therapy is permitted for entry into this study so long as prior therapy did not include anti-androgen therapy or immune checkpoint blockade.
• If prior cancer treatment, the subject must have recovered from toxic effects of prior cancer treatment (other than alopecia) to ≤ Grade 1.
• Adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.
• Absolute neutrophil count (ANC) ≥1500/µL
• Platelets ≥75,000/µL
• Hemoglobin ≥8.0 g/dL or ≥5 mmol/L
• Creatinine (Cr) OR Measured or calculated creatinine clearance (GFR can also be used in place of Cr or creatinine clearance) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) o International normalized ratio (INR) OR prothrombin time (PT) & aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• A male participant must agree to use contraception during the treatment period and for at least 8 months after the last dose of study treatment and refrain from donating sperm during this period.
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Females of childbearing potential and males with partners of childbearing potential must be willing to abstain from heterosexual activity or to use a highly effect form of contraception from the time of informed consent until 8 months after treatment discontinuation.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
• Women of childbearing age with a positive serum pregnancy test within 72 hours prior to study registration.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
• Has received prior androgen deprivation therapy including orchiectomy, gonadotropin-releasing hormone (GnRH) agonists/antagonists, androgen receptor blocker, abiraterone, or enzalutamide.
• Has received prior systemic anti-cancer therapy including investigational agents within 14 days prior to registration.
• Has received prior palliative radiotherapy within 7 days of start of study treatment. Participants must have recovered from all radiation-related toxicities and require less than 10mg of prednisone (or equivalent corticosteroid) daily.
• Has received a live vaccine within 28 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella (MMR), varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• 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 drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast ductal carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 14 days by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Has ≥Grade 3 hypersensitivity to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has a known history of active TB (Bacillus Tuberculosis).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Subjects With GM1 Gangliosidosis (Imagine-1)
This study is a prospective multi-cohort, open-label, dose-escalation assessment of the safety and efficayc of PBGM01, an AAVHu68, intra-cisternal magna delivered gene therapy for the treatment of GM1 gangliosidosis in infants 1-24 months of age.
• All Patients: Documented GM1 gangliosidosis diagnosis based on genotyping confirming 2 mutations in the GLB1 gene and documented deficiency of beta-galactosidase enzyme by laboratory testing
• Age: 4 to 36 months (first cohort will be 12-36 months) Subjects:
• Early onset infantile (Type 1): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started at or before 6 months of age and have specific developmental milestones remaining
• Late onset infantile (Type 2a): Subjects who have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age and have specific developmental milestones remaining
STABILITY 2: Anterior Cruciate Ligament Reconstruction +/- Lateral Tenodesis With Patellar vs Quad Tendon (STABILITY 2)
• Age 14-25,
• An ACL-deficient knee,
• Skeletal maturity (i.e. closed epiphyseal growth plates on standard knee radiographs),
• At least two of the following: participate in a competitive pivoting sport; have a pivot shift of grade 2 or greater; have generalized ligamentous laxity (Beighton score of ≥4) and/or genu recurvatum >10 degrees.
• Previous ACLR on either knee,
• Partial ACL injury (defined as one bundle ACL tear requiring reconstruction/augmentation of the torn bundle with no surgery required for the intact bundle),
• Multiple ligament injury (two or more ligaments requiring surgery),
• Symptomatic articular cartilage defect requiring treatment other than debridement,
• >3 degrees of asymmetric varus,
• Inflammatory arthropathy,
• Inability to provide consent,
• Pregnancy at baseline.
Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
Define natural history, validate patient reported outcome and share knowledge on congenital disorders of glycosylation. We will recruit and enroll patients with CDG in this study evaluating clinical variation and natural history when a patient is being seen as part of routine clinical care.
• Patients diagnosed with congenital disorders of glycosylation based on genetic confirmatory testing
• Patients without congenital disorders of glycosylation
A Sequenced Strategy for Improving Outcomes in People With Knee Osteoarthritis Pain (SKOAP)
There is an urgent public health need to reduce our reliance on opioids for effective long-term pain management, particularly in knee osteoarthritis (KOA). This effectiveness trial will compare recommended treatments to reduce pain and functional limitations in KOA and identify clinical and patient-level factors associated with treatment response. These results will lead to improved patient selection for treatment and inform evidence based guidelines by offering well-tested, effective, non-opioid alternatives.
• Meets American College of Rheumatology Classification criteria for knee osteoarthritis
• Any inability to complete study procedures, including, but not limited to low English language literacy.
• Inability to access the internet on a daily basis
• Unstable medical condition that presents as an absolute or relative contraindication for participation (e.g., unstable angina, poorly controlled diabetes mellitus, end stage renal failure, automated implantable cardioverter-defibrillator that cannot be disabled before RFA).
• Severe untreated bleeding disorder (anticoagulants may be continued during phase II treatments in most patients)
• Severe vision or hearing impairment or serious cognitive impairment that could interfere with consent or outcome assessment
• Poorly controlled serious psychiatric condition
• Active substance abuse
• Scheduled joint replacement on the affected knee
• History of unilateral total knee arthroplasty (TKA) with complaints of KOA pain limited to the operated knee
• Ulcers or an open wound in the region of the index knee
Pediatric Long-Term Follow-up and Rollover Study
• Written informed consent, according to local guidelines, signed by the subjects and/or by the parents or legal guardian prior to any study related screening procedures are performed.
• Participation in a Novartis sponsored study such as CTMT212X2101, CDRB436G2201, CDRB436A2102, regardless of current age.
• Parent study (or cohort of parent study) is planned to be closed.
• Subject has demonstrated compliance, as assessed by the investigator, within the parent study protocol requirement(s).
• Willingness and ability to comply with scheduled visits, treatment plans and any other study procedures. For Subjects Entering the Treatment Period:
• Subject is currently receiving treatment with dabrafenib/trametinib monotherapy or combination within a Novartis Sponsored Drug Development study. Note that subjects who were on the chemotherapy arm of the CDRB436G2201 study are eligible for treatment period of this study only after crossing over into the experimental treatment arm of the CDRB436G2201 study
• In the opinion of the investigator is likely to benefit from continued treatment. Key
•Subject has participated in a combination trial where dabrafenib and/or trametinib was dispensed in combination with another study medication. For Subjects Entering the Treatment Period:
• Subject has permanently discontinued from study treatment in the parent protocol due to any reason.
• Treatment with dabrafenib and/or trametinib for the subject's indication is approved for marketing and the appropriate dosage form is commercially available and reimbursed in the local country
• Subject currently has unresolved drug related severe toxicities for which dabrafenib and/or trametinib dosing has been interrupted in the parent study. If the subject should meet criteria to resume treatment on the parent protocol then they may be eligible for treatment in this study. Other protocol-defined inclusion/exclusion may apply.
Pediatric cGVHD Symptom Scale
To develop a psychometrically valid Pediatric cGVHD Symptom Scale (PCSS) and a companion parent-proxy measure as counterparts to the Lee cGVHD Symptom Scale.
• INCLUSION CRITERIA: Pediatric Subject
• Children aged 5 to 17 years old, who have undergone prior allogeneic stem cell transplant
• Clinical diagnosis of cGVHD
• Currently receiving systemic treatment for cGVHD (including phototherapies), or has had systemic therapy for cGVHD tapered to discontinuation within the past 12 months
• No evidence of malignant disease relapse including molecular relapse and minimal residual disease. Patients with mixed chimerism are eligible to participate
• Parent or guardian ability and willingness to sign a written informed consent document
• Subjects must be able to comprehend and speak the English language
• Subjects may participate in both Project 1 and Project 2 of the study. Participation in Project 1 is not required in order to be eligible to participate in Project 2.
• Parent or Guardian Proxy Inclusion Criteria
• Parent or guardian of participating subject
• Must be willing and able to provide informed consent. Parent or guardian (proxy) must be able to comprehend and speak the English language EXCLUSOIN CRITERIA:
• Patients who completed systemic treatment more than 3 months prior to enrollment or are receiving topical therapy only.
• Patients may be excluded from this study if in the judgment of the Principal or Associate Investigator, the subject is too ill, or subject s cognitive ability would compromise their ability to participate in study related procedures.
A Safety and Efficacy Study Evaluating CTX110 in Subjects With Relapsed or Refractory B-Cell Malignancies (CARBON)
Primary objective, Part A (dose escalation): To assess the safety of escalating doses of CTX110 in subjects with relapsed or refractory B cell malignancies to determine the recommended Part B dose Primary objective, Part B (cohort expansion): To assess the efficacy of CTX110 in subjects with relapsed or refractory B cell malignancies, as measured by objective response rate (ORR)
Study in Parkinson Disease of Exercise (SPARX3)
• A diagnosis of idiopathic Parkinson Disease based on the modified * United Kingdom (UK) PD brain bank criteria and which are consistent with recent criteria proposed for clinically established early established Parkinson's disease that no longer exclude individuals with a family history of Parkinson's disease.
• Hoehn and Yahr stages less than 3
• Disease duration: less than 3 years since disease diagnosis
• Age 40-80 years
• Positive DaTscan™ SPECT by quantitative readout for idiopathic Parkinson disease.
• Currently being treated with PD medications such as levodopa or dopamine receptor agonists, monoamine oxidase-B (MAO-B) inhibitors, amantadine, or anticholinergics.
• Expected to require treatment with medication for PD in the first 6 months of the study.
• Use of any PD medication 60 days prior to the baseline visit including but not limited to levodopa, direct dopamine agonists, amantadine, Rasagiline (Azilect), Selegiline (Eldepryl), Artane (trihexyphenidyl).
• Duration of previous use of medications for PD exceeds 60 days.
• Use of neuroleptics/dopamine receptor blockers for more than 30 days in the year prior to baseline visit, or any use within 30 days of baseline visit
• Presence of known cardiovascular, metabolic, or renal disease or individuals with major signs or symptoms suggestive of cardiovascular, metabolic, or renal disease without medical clearance to participate in the exercise program.
• Uncontrolled hypertension (resting blood pressure >150/90 mmHg)
• Individuals with orthostatic hypotension and standing systolic BP below 100 will be excluded. Orthostatic hypotension (OH) is a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.
• Hypo- or hyperthyroidism (TSH <0.5 or >5.0 mU/L), abnormal liver function (AST or ALT more than 2 times the upper limit of normal), abnormal renal function (estimated glomerular filtration rate (eGFR) using the MDRD4 equation or the CKD-EPI equation <45mL/min/1.73m2 ).
• Complete Blood Count (CBC) out of range and physician's judgment that abnormal value is clinically significant.
• Recent use of psychotropic medications (e.g., anxiolytics, hypnotics, benzodiazepines, antidepressants) where dosage has not been stable for 28 days prior to screening.
• Serious illness (requiring systemic treatment and/or hospitalization) within the last 4 weeks.
• Any other clinically significant medical condition, psychiatric condition, drug or alcohol abuse, assessment or laboratory abnormality that would, in the judgment of the investigator, interfere with the subject's ability to participate in the study.
• Montreal Cognitive Assessment (MoCA) score of <24.
• Beck Depression Inventory II (BDI) score > 28, indicating severe depression that precludes ability to exercise. Any subject with such a score will be referred to a PCP or physician for further evaluation and management of depression. Individuals with a BDI-II score of 17-28 will be excluded if any of the following conditions are met: (1) individual is suicidal, (2) is in need of depression treatment modification currently or (3) depressive symptoms likely to interfere with adherence to study protocol. Any subject with such a score will be referred to a PCP or physician for further evaluation and management of depression.
• Individuals who have been exercising at greater than moderate intensity for 120 minutes or more per week consistently over the last 6 months will be excluded. Greater than moderate intensity is defined as a range greater than 60-65% HRmax. These individuals are excluded since their exercise activities are greater than the activities they would experience if they were assigned to the 60-65% treatment group. As such, they would be expected to lose fitness.
• Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, any amphetamine or amphetamine derivative, or use of buproprion within 8 days prior to the DAT neuroimaging screening evaluation. These can compromise DaTscan™ SPECT.
• Known allergy to iodinated products.
• Known hypersensitivity to DaTscan™ SPECT (either to the active substance of 123I-ioflupane or any of the excipients.
• (For women only) Actively breast-feeding an infant, and/or pregnant, or plan to become pregnant in the next 12 months.
• Other disorders, injuries, diseases, or conditions that might interfere with ability to perform endurance exercises (e.g. history of stroke, respiratory problems, traumatic brain injury, orthopedic injury, or neuromuscular disease).
Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children Per Standard of Care (POPS) (POPS or POP02)
The majority of drugs administered to children are used off label, and PK studies to define appropriate dosing are lacking across pediatric age groups and special populations of children. Challenges associated with clinical trials in children limit the ability to conduct PK and dosing trials in this population. Studies capitalizing on standard-of-care procedures have proven successful in characterizing the PK of drugs used in children. The purpose of this study is to characterize the PK of understudied drugs administered to children per SOC as prescribed by their treating provider. This study will serve as a tool to better understand drug exposure in children receiving drugs per SOC. The data collected through this initiative will provide valuable PK and dosing information for drugs in different pediatric age groups as well as special populations of children, such as premature infants, critically ill children receiving ECMO or CRRT, children with Down syndrome and children with obesity, for which dosing may vary due to altered PK. In addition, the data collected in this study will serve as preliminary data to design and plan the best and most efficacious BPCA trials, proof-of-concept studies associated with biomarkers, and data to support applications for extramural funding. All of the drugs studied in this protocol are used as standard of care in children and are approved in adults. There will be multiple INDs held by the core study Principal Investigator: Danny Benjamin, MD, PhD (IND Sponsor) Kiser-Arena Distinguished Professor of Pediatrics, Duke University Faculty Associate Director, Duke Clinical Research Institute PO Box 17969 Durham NC 27715 Phone: 919-668-8295 Fax: 919-681-9457 danny.benjamin@duke.edu The Funding Sponsor is The National Institute of Child Health and Human Development (NICHD) NOTE: We will be participating in the COVID 19 arm of this study, which includes 6 drugs of interest (DOI). All other arms are on hold currently; and focus has been placed on the COVID 19 arm. However, in the future we may be interested in participating in other DOIs. The details of this arm of the study will be provided at the end of this document. (See Appendix P, pages 82-86 of main protocol)
Registry of Patients With a Diagnosis of Spinal Muscular Atrophy (SMA)
• Patients with SMA, genetically confirmed on or after 24 May 2018.
• Appropriate consent/assent has been obtained for participation in the registry
•Currently enrolled in an interventional clinical trial involving an investigational medicinal product to treat SMA. Note: Patients that are participating in a Compassionate Use Program (CUP) for AVXS-101 (Zolgensma) such as a Managed Access Program (MAP), an Expanded Access Program (EAP), Single Patient Investigational New Drug (IND) (SPI) or Named Patient Program (NPP) are eligible to enroll in the registry regardless of the date of genetic confirmation of SMA.
Treatment of GVHD in Hematopoietic Stem Cell Transplant (HSCT) Recipients Using AAT Plus Corticosteroids (CS) Compared With Corticosteroids Alone
This study is a phase III, multicenter, double-blinded, randomized, placebo-controlled trial designed to compare AAT and corticosteroids (CS) to placebo and CS as first line therapy for patients with high-risk acute GVHD. The primary objective of this trial is to compare the rate of complete response (CR) and partial response (PR) on Day 28 post-randomization between AAT and CS versus placebo to match (PTM) and CS in patients with high-risk acute GVHD.
• Patients 18 years of age or older
• Initial presentation of acute GVHD after allogeneic hematopoietic cell transplantation for any indication
• Any graft or donor source or conditioning intensity
• Clinical diagnosis of acute GVHD requiring systemic therapy with corticosteroids
• Prior exogenous AAT exposure for GVHD prophylaxis
• Relapsed, progressing, or persistent malignancy
• de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment
• Receiving other drugs for the treatment of GVHD
• Receiving systemic CS for any indication within 7 days before the onset of acute GVHD
Evaluation of Stool Based Markers for the Early Detection of Colorectal Cancers and Adenomas
The purpose of this study if to determine if stool or blood can be used to detect colon cancers as early or earlier than colonoscopy. The researchers plan to use these samples to learn about specific proteins (also known as biomarkers) that may indicate colon polyps, colon cancer or an increased risk of developing colon cancer. In order to learn more about preventing and detecting colon and rectal cancer, we are collecting samples from subjects with cancer, adenomas, and colonoscopies who may be at risk for polyps.
• Willing to sign informed consent
• Able to physically tolerate removal of up to 60 ml of blood
• Adults at least 18 years old
• Willing to collect 1-2 stool samples and prepare a Fecal Immunochemical Test (FIT)
• Pregnant or nursing women who otherwise meet the eligibility criteria may participate
• Subjects with one of the following:
• Colorectal adenocarcinoma-not treated and in colon at time of stool collection (CRC bin)
• Adenoma-pathologically confirmed adenoma present in colon at time of stool collection (Adenoma Bin)
• Higher Risk Normal Bin
• Subjects with a personal history of adenomas (confirmed by pathology) with none present on qualifying colonoscopy
• Subjects with a personal history of CRC (longer than 3 years ago because of exclusion criteria of cancer within last 3 years) with none present at time of qualifying colonoscopy
• Any family history of CRC (1st degree relative)
• Normal Control Bin
• No history or current finding of any colon neoplasia including CRC, adenomas, no personal or family history of HNPCC or FAP
• Subjects who had CRC that was successfully treated at least three years ago may be considered eligible for the adenoma bin if their polyps are adenomas and there is no evidence of CRC or for the higher risk normal bin as noted above.
• Subjects whose screening colonoscopy shows any of these types of polyps may be included in the normal or the higher risk normal bin if they meet the other criteria noted above.
• Hyperplastic polyps
• Benign mucosal polyps
• Polypoid granulation tissue
• Prolapsed mucosal polyps
• Inflammatory polyp
• Transitional mucosal polyp
• Lipoma
• Gangleoneuroma
• Neuroma
• Hamartomatous polyp
• Cancer patients who have had any surgery, radiation, or chemotherapy for their current colorectal cancer prior to collecting the baseline samples
• Patients with a history of or clinically active Inflammatory Bowel Disease
• Patients with known HNPCC or FAP
• Inability to provide informed consent.
• Other active malignancy within 3 years of enrollment except any of the following:
• Squamous cell carcinoma of the skin
• Basal cell carcinoma of the skin
• Carcinoma in situ of the cervix, Stages Ia or Ib invasive squamous cell carcinoma of the cervix treated by surgery only. (Excluded if had pelvic radiation)
• Stage Ia Grade 1 adenocarcinoma of the endometrium treated with surgery
• Subjects with known HIV or chronic viral hepatitis
Evaluating Effectiveness and Long Term Safety of Damoctocog Alfa Pegol in Patients, Who Have Been Diagnosed With Hemophilia A (HEM-POWR)
Multinational, open-label, prospective, non-interventional, multicenter, cohort study. The objectives of this study are to assess the effectiveness and long term safety of prophylaxis with damoctocog alfa pegol in the real-world setting through the collection of total bleeding events and analysis of the annualized bleeding rate (ABR) in the different prophylaxis regimens (following approved local label or any other regimen prescribed by the physician as part of normal clinical practice) in patients with hemophilia A. The analyses will be stratified, based on severity of hemophilia, severity of patient bleeding profile, disease characteristics, prophylaxis regimen, age, and time on treatment (i.e., damoctocog alfa pegol-naive or not).
• Diagnosis of hemophilia A.
• Patients previously treated for Hemophilia A.
• Patients without previous history of inhibitors or patients with previous history of inhibitors on standard prophylaxis therapy for at least 1 year prior to study entry.
• No current evidence of FVIII inhibitor or clinical suspicion of FVIII inhibitor.
• Initiation of or currently on damoctocog alfa pegol with any kind of treatment modality (on-demand, prophylaxis, or intermittent prophylaxis).
• Signed informed consent/assent.
• Concurrent participation in an investigational program with interventions outside of routine clinical practice.
• Diagnosis of any other bleeding/coagulation disorder other than hemophilia A.
• Contra-indications according to the local marketing authorization.
• Patient on immune tolerance induction (ITI) treatment at the time of enrollment.
A Prospective, Multi-center, Randomized Controlled Blinded Trial Demonstrating the Safety and Effectiveness of VNS Therapy® System as Adjunctive Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER)
Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1
This study will evaluate the clinical activity/efficacy of MRTX849 in cohorts of patients having selected solid tumor malignancies with KRAS G12C mutation.
• Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation
• Unresectable or metastatic disease
• Standard treatment is not available or patient declines
• Adequate organ function
• History of intestinal disease or major gastric surgery or inability to swallow oral medications
• Other active cancer
Dose-escalation Study of Safety of PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL
To evaluate the safety and tolerability of PBCAR0191 in subjects with r/r B-ALL and r/r NHL and find an appropriate dose to optimize safety and efficacy. To evaluate the clinical benefit of PBCAR0191 in subjects with r/r B-ALL and r/r NHL. To evaluate the clinical activity of PBCAR0191 in subjects with r/r B-ALL and r/r NHL.
• Relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia (B-ALL).
• Philadelphia chromosome positive (Ph+) disease can be eligible if they are intolerant to tyrosine kinase inhibitor (TKI) therapy or if they have relapsed/refractory disease. Criteria for NHL:
• r/r CD19+ B-cell NHL that is histologically confirmed by archived tumor biopsy tissue from last relapse and corresponding pathology report. The following types of lymphoma are included:
• Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation
• Primary mediastinal B-cell lymphoma (PMBL)
• FL including Grade 3B or transformed FL
• High-grade B-cell lymphoma
• Small lymphocytic lymphoma (SLL)
• Mantle cell lymphoma (MCL)
• Received at least 2 prior chemotherapy-containing regimens. Subjects with SLL must have previously failed at least 2 lines of chemotherapy/immunotherapy that included ibrutinib and idelalisib plus rituximab.
• Measurable or detectable disease according to the Lugano Classification.
• Criteria for both B-ALL and NHL:
• Eastern Cooperative Oncology Group performance status score of 0 or 1.
• An estimated life expectancy of at least 12 weeks according to the investigator's judgment.
• Seronegative for human immunodeficiency virus antibody (i.e., intact immune function).
• Subject has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as: 1. Estimated glomerular filtration rate (eGFR) >50 mL/min/1.73 m2. 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both ≤3 times of upper limit of normal, unless there is suspected disease in the liver. 3. Total bilirubin <2.0 mg/dL, except in subjects with Gilbert's syndrome. 4. Platelet count ≥30,000/µL (platelet transfusions acceptable). 5. Left ventricular ejection fraction >45% as assessed by echocardiogram (ECHO) or multiple gated acquisition scan performed within 1 month before starting lymphodepleting chemotherapy. ECHO results performed within 6 months before Screening and at least 28 days after the last cancer treatment may be acceptable if the subject has not received any treatment with cardiotoxicity risks. 6. No clinically significant evidence of pericardial effusion or pleural effusion. 7. Baseline oxygen saturation >92% on room air. Key Exclusion Criteria* Criteria for B-ALL:
• Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.
• Active CNS leukemia. Criteria for NHL:
• Active hemolytic anemia.
• Active CNS lymphoma.
• Criteria for B-ALL and NHL:
• Previous malignancy, besides the malignancies of inclusion (B-ALL or NHL), that has a high risk of relapse in the next 2 years.
• Uncontrolled and serious fungal, bacterial, viral, protozoal, or other infection.
• Any form of primary immunodeficiency.
• Active hepatitis B or C.
• Uncontrolled cardiovascular disease.
• Hypertension crisis or hypertensive encephalopathy within 3 months.
• Concomitant genetic syndrome or any other known bone marrow failure syndrome.
• Active uncontrolled autoimmune disease requiring active immunosuppression (excluding subjects needing steroids for physiologic replacement).
• Received stem cell transplant within 90 days.
• Active GvHD symptoms.
• Received systemic biologic agent within 30 days or 5 half-lives.
• Received systemic immunostimulatory agent within 30 days or 5 half-lives.
• Radiotherapy within 4 weeks determined on a case-by-case basis.
• Presence of pleural/peritoneal/pericardial catheter.
• Received live vaccine within 4 weeks before Screening.
• Current use of any anticoagulant or antiplatelet therapy.
• Additional criteria apply
A Longitudinal Observational Study of Patients Undergoing Therapy for IMISC (TARGET-DERM)
A 5-year Longitudinal Observational Study
• 1. Adults and children (all ages) with Atopic Dermatitis or other Immune-mediated Inflammatory Skin Conditions been prescribed any dermatologic treatment.
• 2. Participant has plans for future visits at the site for continued management of IMISC.
• 1. Inability to provide written informed consent/assent.
• 2. Subjects participating in any interventional study or trial for IMISC treatment trial at the time of enrollment. Patients may be enrolled in TARGET-DERM once participation in the trial is complete. Note: Participants may be enrolled in other registries or studies where IMISC treatment outcomes are observed and/or reported (such as center-based registries).