Phase 1/2A Study Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma
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, according to institutional standard operating procedure (SOP).
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 AEs. For the phase 1 component of the study, dose-limiting
toxicities will be captured during the first 30 days after transplantation (DLT period).
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the Maximum Tolerated Dose (MTD) of carfilzomib plus melphalans conditioning for AHSCT in patients with relapsed Multiple Myeloma(MM) [Phase I portion of study]
4 1/2 months
Luciano Costa, MD
Medical University of South Carolina
United States: Food and Drug Administration
|Medical University of South Carolina Hollings Cancer Center||Charleston, South Carolina 29425|
|Memorial Sloane Kettering Cancer Center||New York, New York 10065|