Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Carfilzomib; Melphalan
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Melphalan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment