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

Phase 1

Completed

Conditions: Hematologic Malignancies
Relapse
Graft-Versus-Host Disease

Interventions: Drug: Carfilzomib
Drug: Tacrolimus

Registration Number: NCT02145403

Lead Sponsor: University of Michigan Rogel Cancer Center

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Carfilzomib	Tacrolimus	Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7.
Carfilzomib	Carfilzomib	Carfilzomib will be administered IV over 30 minutes, starting at dose level 1 (20 mg/m2 IV) on Day +1, +2, +6 and +7.

Primary Outcome Measures

Name	Time	Method
Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib	Up to day 28	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.
Phase II: Kaplan-Meier Estimate of the Percentage of Patients Who Are Alive and Have Not Developed Any "Event"	1 year	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.

Secondary Outcome Measures

Name	Time	Method
Phase II: Kaplan-Meier Estimate for Overall Survival Time	Up to 3 years	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.
Number of Regimen Related Toxicities (RRTs)	Up to 30 days post treatment	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.
Phase II: Cumulative Incidence of Chronic GVHD	Up to 3 years	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.
Phase II: Cumulative Incidence of Non-relapse Mortality	Up to 3 years	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.
Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time	Up to 3 years	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.
Phase II: Cumulative Incidence of Acute GVHD	At day 180 post-transplant; data collected up to 3 years	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.