In this protocol, the investigators hypothesize that the combination of intravenous busulfan and melphalan with carfilzomib will be an effective preparative regimen with acceptable toxicity for participants with multiple myeloma who are candidates for autologous stem cell transplantation. To test this hypothesis, the investigators designed a phase I/II trial combining IV busulfan 130 mg/m2 plus melphalan 140 mg combined with escalating doses of carfilzomib ranging from 20 mg/m2 to 45 mg/m2. These results will be compared with the center's historical controls of participants treated with melphalan, busulfan and bortezomib.
Participants enrolled in this study protocol will receive daily intravenous (IV) infusions of carfilzomib for a total of 4 days (Day-9, -8 and Days -2, -1). The first two daily infusions will be given at a fixed dose of 20 mg/m2 and the final two doses will be escalated from the standard dose of 27 mg/m2 to 56 mg/m2 in a Phase I design, based on toxicity. The busulfan will be administered for 2 days over 3 hours from D-7, -6, at 130 mg/m2 . This dose was found to be safe and equivalent to the standard daily dose of 3.2 mg/kg. The 3rd and 4th daily doses of IV Busulfan will be adjusted in order to yield a systemic plasma drug exposure represented by a daily area under the plasma concentration versus time curve (AUC) of approximately 5,000 millimoles-minute per dose (mM-min). These targeted plasma concentration of IV busulfan will be based on pharmacokinetics studies performed during the first day of IV busulfan. Melphalan will be given at a dose of 140 mg/m2 on Day -3. Each cohort will start with a goal of accruing three patients to determine the dose limiting toxicity.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Carfilzomib is an anti-cancer drug acting as a selective proteasome inhibitor that is used to treat Multiple Myeloma.
Busulfan is an anti-cancer drug acting as a bifunctional alkylating agent that is used to treat Multiple Myeloma.
Melphalan is an anti-cancer drug acting as alkylating agent that is used to treat Multiple Myeloma.
Loyola University Medical Center
Maywood, Illinois, United States
RECRUITING36 participants evaluated for safety with treatment-related adverse events and grading by using CTCAE v4.0.
To determine the maximal tolerated dose of carfilzomib when added to busulfan and melphalan as a preparative regimen for high dose therapy with autologous hematopoietic transplantation for patients with multiply myeloma.
Time frame: 3 years
36 participants evaluated for tolerability with treatment-related adverse events and grading by using CTCAE v4.0.
To determine the maximal tolerated dose of carfilzomib when added to busulfan and melphalan as a preparative regimen for high dose therapy with autologous hematopoietic transplantation for patients with multiply myeloma.
Time frame: 3 years
36 participants evaluated for response to treatment by testing blood for multiple myeloma levels.
To evaluate complete, very good partial, partial and stable disease response rate for both clinical and biologic endpoints.
Time frame: 100 days
36 participants evaluated for progression by testing blood for multiple myeloma levels.
Progression Free Survival
Time frame: 3 years
36 participants evaluated for overall survival by clinical visit or contact by phone.
Overall Survival
Time frame: 3 years
36 participants evaluated for absolute neutrophil count by testing white blood cells levels.
Days to neutrophil engraftment: Absolute neutrophil count \> 500/microliter
Time frame: 100 days
36 participants evaluated for platelet engraftment by testing platelet count in blood cells.
Days to platelet engraftment: platelet count \> 20,000/microliter untransfused
Time frame: 100 days
36 participants evaluated by oral exam to assess mucositis events and grading levels by using CTCAE v4.0.
Mucositis: CTCAE v 4.0 grade and severity
Time frame: 100 days
36 participants evaluated by the liver to assess Veno-occlusive disease and grading levels by using CTCAE v4.0.
Veno-occlusive disease
Time frame: 100 days
36 participants evaluated by a physical exam to assess peripheral neuropathy and grading by using CTCAE v4.0.
Peripheral neuropathy greater than or equal to CTCAE V 4.0 Grade 3
Time frame: 3 years
36 participants evaluated for response to treatment by testing urine for multiple myeloma levels.
To evaluate complete, very good partial, partial no stable disease response rate for both clinical and biologic endpoints
Time frame: 100 days
36 participants evaluated for progression by testing urine for multiple myeloma levels.
Progression Free Survival
Time frame: 3 years
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