Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Heart and Blood Diseases

Symptoms and General Pathology

Rare Diseases

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Leukemia

Hematologic Neoplasms

Graft vs Host Disease

Recurrence

Disease Attributes

Hematologic Diseases

Lymphosarcoma

Homologous Wasting Disease

All Drugs and Chemicals

Tacrolimus

Immunosuppressive Agents

Immunologic Factors

Calcineurin Inhibitors

Enzyme Inhibitors

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 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.

Carfilzomib

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.

Attaphol Pawarode, M.D.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

University of Michigan Rogel Cancer Center

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 1: Participants were administered 20 mg/m\^2 of Carfilzomib on days +6 and +7.

Dose Level 1 - Maximum Dose Carfilzomib 20 mg/m^2 IV

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 2: Participants were administered 27 mg/m\^2 of Carfilzomib on days +6 and +7.

Dose Level 2 - Maximum Dose Carfilzomib 27 mg/m^2 IV

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 3: Participants were administered 36 mg/m\^2 of Carfilzomib on days +6 and +7.

Dose Level 3 - Maximum Dose Carfilzomib 36 mg/m^2 IV

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 4: Participants were administered 45 mg/m\^2 of Carfilzomib on days +6 and +7.

Dose Level 4 - Maximum Dose Carfilzomib 45 mg/m^2 IV

Participants were administered 20 mg/m\^2 of Carfilzomib on days 1, 2, 6 and 7.

Dose Level 1 - Maximum Dose Carfilzomib 20 mg/m^2

Participants were administered 20 mg/m\^2 on days 1 and 2; 27 mg/m\^2 of Carfilzomib on days 6 and 7.

Dose Level 2 - Maximum Dose Carfilzomib 27 mg/m^2

Participants were administered 20 mg/m\^2 on days 1 and 2; 36 mg/m\^2 of Carfilzomib on days 6 and 7.

Dose Level 3 - Maximum Dose Carfilzomib 36 mg/m^2

Participants were administered 20 mg/m\^2 on days 1 and 2; 45 mg/m\^2 of Carfilzomib on days 6 and 7.

Dose Level 4 - Maximum Dose Carfilzomib 45 mg/m^2

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Dose Level 1, 2, 3, 4: Participants were administered 20, 27, 36, or 45 mg/m\^2 of Carfilzomib on days +6 and +7, respectively.

Participants in all cohorts were administered tacrolimus at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

Phase 1 Study Participants

Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib

Subjects who have received all 4 doses of carfilzomib at the maximum tolerated dose (MTD) level (dose level 3, 36 mg/m\^2): 39 subjects total. Note: three subjects who completed 4 doses of carfilzomib at the MTD during the phase 1 portion of the study were included in phase 2 analysis of the primary outcome measure.

Phase II: Kaplan-Meier Estimate of the Percentage of Patients Who Are Alive and Have Not Developed Any "Event"

1 year since transplant

3 years since transplant

Subjects who received all 4 doses of carfilzomib at the maximum tolerated dose (MTD) level (dose level 3, 36 mg/m\^2): 39 subjects total. Note: three subjects who completed 4 doses of carfilzomib at the MTD during the phase 1 portion of the study were included in phase 2 analysis.

Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time

Phase II: Kaplan-Meier Estimate for Overall Survival Time

Subjects who have received at least one dose of carfilzomib were evaluable for toxicities

Number of Regimen Related Toxicities (RRTs)

Acute GVHD grade 2-4

Acute GVHD grade 3-4

Phase II: Cumulative Incidence of Acute GVHD

cGVHD overall: Day 180

cGVHD overall: Day 365

cGVHD overall: Day 1095

cGVHD Moderate / Severe: Day 180

cGVHD Moderate / Severe: Day 365

cGVHD Moderate / Severe: Day 1095

cGVHD Requiring Systemic Therapy: Day 180

cGVHD Requiring Systemic Therapy: Day 365

cGVHD Requiring Systemic Therapy: Day 1095

Phase II: Cumulative Incidence of Chronic GVHD

Day 180

Day 365

Day 1095

Phase II: Cumulative Incidence of Non-relapse Mortality

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 1: Participants were administered 20 mg/m\^2 of Carfilzomib on days +6 and +7.

Participants in all cohorts were administered tacrolimus at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 2: Participants were administered 27 mg/m\^2 of Carfilzomib on days +6 and +7.

Participants in all cohorts were administered tacrolimus at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 3: Participants were administered 36 mg/m\^2 of Carfilzomib on days +6 and +7.

Participants in all cohorts were administered tacrolimus at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

"Participants in all cohorts were administered 20 mg/m\^2 of Carfilzomib on days +1 and +2, via intravenous catheter (IV) over 30 minutes.

Cohort 4: Participants were administered 45 mg/m\^2 of Carfilzomib on days +6 and +7.

Participants in all cohorts were administered tacrolimus at 0.03 mg/kg continuous infusion over 24 hours, starting on day -3 as standard graft-versus-host disease prophylaxis.

Spots Global Cancer Trial Database for Phase 1/2 Study of Carfilzomib for the Prevention of Relapse and GVHD in Allo-HCT for Hematologic Malignancies

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