Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and GVHD in Allo-HCT for Hematologic Malignancies

Study Overview
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Brief Summary
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The investigators hypothesize that adding carfilzomib to standard conditioning regimen for allo-HCT for advanced or high-risk hematologic malignancies will decrease post-transplant relapse and treatment-related mortality by decreasing severe GVHD, leading to overall improvement in transplant outcomes.

Official Title
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Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and Graft-versus-host Disease in Allogeneic Hematopoietic Cell Transplantation for High-risk Hematologic Malignancies

Conditions
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Hematologic Malignancies, Relapse, Graft-Versus-Host Disease

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Lymphoid or Myeloid malignancy requiring allogeneic hematopoietic cell transplantation Pathology review by the study institution is required Prior high-dose chemotherapy and autologous HCT(s) is (are) allowed Disease status: Stable disease or better at the time of enrollment Age: >18 and <70 years old at the time of transplant (< 71 years at transplant admission) Life expectancy ≥ 6 months after transplant A 8/8 or 7/8 HLA-matched donor is available Karnofsky Performance Status >70% (A measure of quality of life that ranges from 0 to 100 where 100 equals perfect health and 0 is death.) Adequate cardiac [LVEF (Left Ventricular Ejection Fraction) >0.4], pulmonary [FEV1 (Forced Expiratory Volume in 1 Second), FVC (Forced Vital Capacity), corrected DLCO (Diffusing Capacity) ≥ 50% predicted], hepatic [DB (Direct Bilirubin) <1.5xULN, AST (Aspartate Aminotransferase) / ALT (Alanine transaminase) ≤3xULN] and renal function [GFR (Glomerular Filtration Rate) ≥ 60 mL/min/1.73 m2] Exclusion Criteria: Progressive disease Active central nervous system involvement by malignancy Non compliance to medications or medical instructions Lack of appropriate caregivers Life expectancy <6 months Pregnant or lactating females Uncontrolled infection requiring active treatment (systemic antibiotics, anti-virals, or anti-fungals) within 14 days HIV-1/HIV-2 or HTLV-1/HTLV-2 seropositivity Active hepatitis A, B or C infection Unstable angina or myocardial infarction within 6 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, uncontrolled or persistent atrial fibrillation/flutter, history of ventricular fibrillation, ventricular tachycardia/torsade de pointes, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker History of pulmonary hypertension Uncontrolled hypertension or uncontrolled diabetes mellitus Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen (PSA) levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all available anti-microbial drugs or intolerance to IV hydration due to pre-existing pulmonary or cardiac impairment Subjects with pleural effusion requiring thoracentesis or ascites requiring paracentesis within 14 days prior to admission Uncontrolled psychiatric condition Any other clinically significant medical or psychiatric disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carfilzomib<br>Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7. | Drug: Carfilzomib<br>* Carfilzomib will be administered starting at dose level 1 (20 mg/m2 IV) on day +1, +2, +6 and +7. Dose escalation will be performed on the day +6 and day +7 doses only in each dose level. Day +1 and day+2 doses will be fixed at 20 mg/m2 IV in all dose levels.<br>* Other names: Kyprolis®;Drug: Tacrolimus<br>* Tacrolimus will be administered at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib | Subjects were enrolled on the first dose level (20 mg/m^2), following a standard 3+3 dose escalation. For any given dose level, if none of the 3 subjects developed a treatment-related dose limiting toxicity (DLT), defined per protocol, dose escalation would follow. If a DLT occurred in any given dose level, the cohort would be expanded to 6. Further dose escalation would be made only if DLTs occurred in <2 out of 6 subjects. If >=2 of 6 develop DLTs, dose de-escalation would be made to the previous level. The highest dose level at which no more than one of six participants experience a DLT defines the MTD. | Up to day 28 | 
| Phase II: Kaplan-Meier Estimate of the Percentage of Patients Who Are Alive and Have Not Developed Any Event | Kaplan-Meier estimate of the percentage of patients who are alive and have not developed relapse/progression of primary disease or clinical grade III-IV acute graft-versus- host disease (GVHD) or chronic GVHD requiring systemic treatment. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time | Time from day 0 to the date of the first progression/relapse. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | Up to 3 years | 
| Phase II: Kaplan-Meier Estimate for Overall Survival Time | The time from day 0 to the day of death from any cause. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | Up to 3 years | 
| Number of Regimen Related Toxicities (RRTs) | An RTT is defined as an adverse event (AE) that occurs within +37 days after transplant or 30 days after the last dose of carfilzomib (day +7), and is considered to be a direct consequence and a related event as a result of the combination of conditioning chemotherapy, GVHD prophylaxis regimen and carfilzomib. | Up to 30 days post treatment | 
| Phase II: Cumulative Incidence of Acute GVHD | The cumulative incidence of acute Graft Versus Host Disease (aGVHD). Events were assigned a severity grade using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0; lower values indicate least severe and higher values indicate most severe. Grades 2 - 4 and grades 3 - 4 events are reported. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | At day 180 post-transplant; data collected up to 3 years | 
| Phase II: Cumulative Incidence of Chronic GVHD | The cumulative incidence of chronic Graft Versus Host Disease (GVHD). Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | Up to 3 years | 
| Phase II: Cumulative Incidence of Non-relapse Mortality | The cumulative incidence of non-relapse mortality. Subjects who receive all 4 doses of carfilzomib at the maximum tolerated dose level will be considered evaluable for endpoint analysis. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Transplantation, Relapse, Graft-Versus-Host Disease, Multiple Myeloma, Lymphoma, Leukemia, Carfilzomib