Graft-Versus-Host Disease, Hematologic Malignancies, Relapse
Conditions
Keywords
Allogeneic Transplantation, Carfilzomib, Relapse, Graft-Versus-Host Disease, Multiple Myeloma, Lymphoma, Leukemia
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.
Interventions
DRUGCarfilzomib
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.
DRUGTacrolimus
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.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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: 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: 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. |
Countries
United States
Participant flow
Pre-assignment details
Two patients who consented never began treatment.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 - Maximum Dose Carfilzomib 20 mg/m^2 Participants were administered 20 mg/m\^2 of Carfilzomib on days 1, 2, 6 and 7. | 3 |
| Dose Level 2 - Maximum Dose Carfilzomib 27 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. | 3 |
| Dose Level 3 - Maximum Dose Carfilzomib 36 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. | 41 |
| Dose Level 4 - Maximum Dose Carfilzomib 45 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. | 4 |
| Total | 51 |
Baseline characteristics
| Characteristic | Dose Level 1 - Maximum Dose Carfilzomib 20 mg/m^2 | Dose Level 2 - Maximum Dose Carfilzomib 27 mg/m^2 | Dose Level 3 - Maximum Dose Carfilzomib 36 mg/m^2 | Dose Level 4 - Maximum Dose Carfilzomib 45 mg/m^2 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 32 years | 55 years | 58 years | 60 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 39 Participants | 4 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 22 Participants | 0 Participants | 24 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 19 Participants | 4 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 3 | 18 / 41 | 2 / 4 |
| other Total, other adverse events | 3 / 3 | 0 / 3 | 16 / 41 | 3 / 4 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 25 / 41 | 4 / 4 |
Outcome results
Primary
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.
Time frame: 1 year
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study Participants | Phase II: Kaplan-Meier Estimate of the Percentage of Patients Who Are Alive and Have Not Developed Any Event | 31 percentage of participants |
Primary
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.
Time frame: Up to day 28
Population: Phase 1 study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study Participants | Phase I: Maximum Tolerated Dose (MTD) of Carfilzomib | 36 milligrams per square meter (mg/m^2) |
Secondary
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.
Time frame: Up to 30 days post treatment
Population: Subjects who have received at least one dose of carfilzomib were evaluable for toxicities
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study Participants | Number of Regimen Related Toxicities (RRTs) | 4 Regimen related toxicities |
| Dose Level 2 - Maximum Dose Carfilzomib 27 mg/m^2 IV | Number of Regimen Related Toxicities (RRTs) | 1 Regimen related toxicities |
| Dose Level 3 - Maximum Dose Carfilzomib 36 mg/m^2 IV | Number of Regimen Related Toxicities (RRTs) | 15 Regimen related toxicities |
| Dose Level 4 - Maximum Dose Carfilzomib 45 mg/m^2 IV | Number of Regimen Related Toxicities (RRTs) | 6 Regimen related toxicities |
Secondary
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.
Time frame: At day 180 post-transplant; data collected up to 3 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Acute GVHD | Acute GVHD grade 2-4 | 32 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Acute GVHD | Acute GVHD grade 3-4 | 15 percentage of participants |
Secondary
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.
Time frame: Up to 3 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD overall: Day 365 | 15 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD overall: Day 1095 | 15 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Moderate / Severe: Day 180 | 2 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Moderate / Severe: Day 365 | 10 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Moderate / Severe: Day 1095 | 10 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Requiring Systemic Therapy: Day 180 | 2 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Requiring Systemic Therapy: Day 365 | 7 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD Requiring Systemic Therapy: Day 1095 | 7 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Chronic GVHD | cGVHD overall: Day 180 | 2 percentage of participants |
Secondary
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.
Time frame: Up to 3 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Non-relapse Mortality | Day 180 | 15 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Non-relapse Mortality | Day 365 | 17 percentage of participants |
| Phase 1 Study Participants | Phase II: Cumulative Incidence of Non-relapse Mortality | Day 1095 | 23 percentage of participants |
Secondary
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.
Time frame: Up to 3 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study Participants | Phase II: Kaplan-Meier Estimate for Overall Survival Time | 1 year since transplant | 72 percentage of participants |
| Phase 1 Study Participants | Phase II: Kaplan-Meier Estimate for Overall Survival Time | 3 years since transplant | 54 percentage of participants |
Secondary
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.
Time frame: Up to 3 years
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study Participants | Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time | 1 year since transplant | 72 percentage of participants |
| Phase 1 Study Participants | Phase II: Kaplan-Meier Estimate for Progression/Relapse-free Survival Time | 3 years since transplant | 40 percentage of participants |