Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation
This study is for patients that have multiple myeloma that has come back or relapsed and their condition indicates a procedure called an Autologous Hematopoietic Stem Cell Transplantation (AHSCT). AHSCT is a procedure when stem cells from bone marrow or blood are removed before high-dose chemotherapy. Afterwards, the removed stem cells are put back into the patient's body to form a new population of blood cells.
The high-dose chemotherapy administered before the AHSCT is called "Conditioning Therapy." The FDA has approved the use of the drug melphalan as a conditioning therapy. This research study will look at whether adding the study drug called carfilzomib will improve participant outcomes. Carfilzomib is considered investigational and is not approved by the FDA for the treatment of relapsed multiple myeloma.
This study is divided into two phases.
Phase I: Dose Escalation Phase:
The main purpose of Part I of this study is to examine the safety of the study drug, carfilzomib, and determine the safest amount of the study drug that can be given to subjects who have multiple myeloma. Subjects on this study will receive different dose levels of the study drug. If you are one of the first three subjects to receive the study drug, it will be at what is called the 'starting dose' for the study which is the lowest dose that is expected to be tolerated based on prior research. After the first set of participants receive the study drug, the study doctor will review their health to see how they are tolerating the treatment. This will decide if the study drug dosage will be increased or decreased for the next set of subjects who join the study. It is anticipated that 12- 18 participants will enroll in the Phase I portion of this study.
Phase II: Safety Confirmation Phase:
Once the study doctor has discovered the highest possible dose of study drug that subjects can tolerate, up to 28 more subjects may be enrolled at that dose level. The main purpose of the Phase II portion of the study is look at how effective the combination of carfilzomib and melphalan when given before your stem cell transplantation is in treating multiple myeloma. This expansion phase will also include evaluation of two single agent carfilzomib maintenance therapy regimens for patients without disease progression at day 100.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 1/2A Study Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma|
- To determine the Maximum Tolerated Dose (MTD) of carfilzomib plus melphalan as conditioning for AHSCT in patients with relapsed Multiple Myeloma(MM) [Phase I portion of study] [ Time Frame: Up to 4 1/2 months ] [ Designated as safety issue: Yes ]
- Very Good Partial Response (VGPR) Rate. [ Time Frame: Up to 17 months ] [ Designated as safety issue: No ]
VGPR defined as any one of the following:
≥ 90% reduction of serum M-protein; ≥ 90% reduction in 24-hour urinary M-protein or decrease to < 100 mg per 24 hour; ≥ 50% decrease in the difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio; ≥ 50% reduction in bone marrow plasma cells; ≥ 50% reduction in the size of soft tissue plasmacytomas.
- Complete Response (CR) Rate. [ Time Frame: Up to 17 months ] [ Designated as safety issue: No ]CR defined as the following: Negative immunofixation of the serum and urine. If only the measurable non-bone marrow parameter was FLC, normalization of FLC ratio. < 5% plasma cells in bone marrow. And, disappearance of any soft tissue plasmacytomas.
- Median time for neutrophil and platelet engraftment. [ Time Frame: Up to 1 month. ] [ Designated as safety issue: Yes ]Neutrophil engraftment is defined as the first of three consecutive days with absolute neutrophil count >500/mm3. Platelet engraftment is defined as the first of 3 consecutive days of platelets > 20,000/mm3 without platelet transfusion in the prior 7 days.
- Frequency and nature of grades 3 and 4 non-hematologic adverse events during the transplant component. [ Time Frame: Up to 4 1/2 months ] [ Designated as safety issue: Yes ]Grading of AE's is performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
- To investigate the pharmacodynamic effects of carfilzomib + high dose melphalan in terms of changes in expression of fanconi anemia/BRCA DNA repair genes and DNA fragmentation [ Time Frame: 4 1/2 months ] [ Designated as safety issue: No ]
|Study Start Date:||May 2012|
|Estimated Study Completion Date:||February 2018|
|Estimated Primary Completion Date:||November 2016 (Final data collection date for primary outcome measure)|
Experimental: Carfilzomib + high dose melphalan
Subjects will receive the appropriate dose of carfilzomib (according to assigned cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will be infused over 30 minutes. Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs.Drug: Melphalan
Subjects will receive 200 mg/m2 of intravenous melphalan on Day -2. Administered as an intravenous push or a fast infusion according to institutional standard operating procedure (SOP). Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs.
Hide Detailed Description
This is a phase 1/2a trial. Since this is an AHSCT conditioning regimen trial, only one cycle of therapy will be administered for each subject.
PHASE 1 The phase 1 component has a typical 3+3 design.
- Initially up to three subjects will be enrolled in each cohort starting at cohort 0 in the table below.
- If no dose limiting toxicity (DLT) is noted among the 3 initial subjects, 3 additional patients will be accrued at the subsequent cohort.
- If 1/3 subjects experience DLT, 3 additional subjects will be accrued at the cohort. If no additional DLT occur, accrual will continue at the subsequent cohort.
- If 2 or more subjects experience DLT in a given cohort, the dose will be considered higher than the maximum tolerated dose (MTD) and the immediately lower dose will be considered the MTD.
- If accrual is completed in cohort 4 with 0/3 or 1/6 DLT, the MTD will be considered "not reached" and cohort 4 will be expanded in the phase 2 of the trial.
- If 2 subjects experience DLTs in cohort 0, patients will be accrued in cohort -1, one subject at a time, with the subsequent subject only being accrued once the current subject has completed the DLT period (transplant day 30). The doses in cohort -1 will be considered the MTD if 0/3 or 1/6 subjects experience DLT.
- If ≥ 2 subjects experience DLT in cohort -1 the study will be interrupted without proceeding to phase 2a and the combination of carfilzomib and high dose melphalan will be considered too toxic.
PHASE 2 Once the MTD for the combination of carfilzomib and high dose melphalan with AHSCT is found, there will be expansion of the MTD cohort so that 28 individuals will be treated at the MTD of carfilzomib and high dose melphalan.
Screening - Subjects likely to meet eligibility criteria will be offered participation in the study after the investigator verifies with the registration system that there is a current available slot (phase 1). Subjects will sign informed consent prior to any protocol associated procedure. Screening procedures are outlined in Table 3 and will 1) ensure that subject meets all the eligibility criteria, 2) obtain disease assessment to allow efficacy measurements, 3) assess baseline toxicity and 4) provide initial biological samples for pharmacodynamic and correlative studies.
Treatment- Subjects will receive the appropriate dose of carfilzomib (according to assigned cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will be infused over 30 minutes. On day -2, with 60 to 120 minutes of the end of infusion of carfilzomib, subjects will receive 200 mg/m2 of intravenous melphalan as an intravenous push or a fast infusion. Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines.
Infusion of autologous cells- Infusion of autologous hematopoietic stem cells will occur on day 0 and follow institutional SOP.
Follow up phase - On day 1 following HSCT patients will receive pegfilgrastim 6 mg subcutaneously as per institutional standard of care aiming at faster engraftment. The follow up phase will last 100 days and will consist of standard post transplantation supportive care and monitoring of adverse events (AE's). For the phase 1 component of the study, dose-limiting toxicities will be captured during the first 30 days after transplantation (DLT period). Patients without progression may continue with carfilzomib maintenance therapy.
Patients will either be randomized in blocks of two to either maintenance therapy Arm 1= AB (two cycles of A followed by two cycles of B), or maintenance therapy Arm 2= BA (two cycles of B followed by two cycles of A). Maintenance regimen A will consist of carfilzomib 36 mg/m2 infused over 30 minutes on days 1,8,15. Maintenance regimen B will consist of carfilzomib 36 mg/m2 infused over 30 minutes on days 1, 2, 15 and 16. Each cycle will have 4 week duration. The first four maintenance therapy cycles will be dictated by a randomized assignment at time of study registration to maintenance therapy. For both maintenance therapy arms, a patient preference questionnaire will be administered to the patient upon completion of the 4th cycle. The remaining 8 cycles (cycles 5-12) will be administered according to the regimen schedule preferred by the patient as documented on the patient preference questionnaire.
Disease assessment- Disease assessment will occur at day 100 (+/- 7 days) and will consist of serum protein electrophoresis, serum and urine immunofixation, 24h urine protein electrophoresis, serum free light chains, bone marrow aspiration and biopsy, complete blood counts and metabolic panel.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01690143
|United States, Alabama|
|Birmingham, Alabama, United States, 35294|
|United States, New York|
|Memorial Sloan Kettering Cancer Center|
|New York, New York, United States, 10065|
|United States, South Carolina|
|Medical University of South Carolina Hollings Cancer Center|
|Charleston, South Carolina, United States, 29425|
|United States, Wisconsin|
|Medical College of Wisconsin|
|Milwaukee, Wisconsin, United States, 53226|
|Principal Investigator:||Luciano Costa, MD||University of Alabama at Birmingham|