Phase I: Melphalan, Bendamustine and Carfilzomib for Autologous Transplant in Multiple Myeloma

Study Overview
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Brief Summary
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This is a phase I clinical trial. Patients with a diagnosis of multiple myeloma undergoing autologous transplantation will receive a preparative regimen of melphalan, bendamustine, and carfilzomib. We hypothesize that the addition of carfilzomib to a conditioning regimen of melphalan and bendamustine in the setting of autologous transplantation for multiple myeloma is feasible and safe.

Official Title
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A Phase I Study of Melphalan, Bendamustine, and Carfilzomib for Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Cohort 1: Carfilzomib 15 mg/m2
* Drug: Cohort 2: Carfilzomib 20 mg/m2
* Drug: Cohort 2b: Carfilzomib 20 mg/m2
* Drug: Cohort 3b: Carfilzomib 27 mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple myeloma At least 2 x 106 CD34+ cells/kg have been collected from the patient and cryopreserved for ASCT Greater than 18 years Karnofsky score greater than 70% No evidence of progressive bacterial, viral, or fungal infection Absolute neutrophil count above 1000 Platelet count above 50,000 Hemoglobin above 8 g/dL Creatinine clearance greater than 50 mL/min Total bilirubin, ALT, and AST less than 2 x the upper limit of normal Alkaline phosphatase less than or equal to 250 IU/L Left Ventricular Ejection Fraction (LVEF) greater than or equal to 45% Adjusted Carbon Monoxide Diffusing Capacity (DLCO) greater than or equal to 60% Negative HIV serology Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and hematological toxicity) Patients with a pre-transplant disease status consistent with a very good partial response (VGPR), partial response (PR), stable disease (SD), progressive disease (PD), or relapse from complete remission (CR). Exclusion Criteria: Patients who are refractory to carfilzomib. Refractory is defined as disease progression while on carfilzomib therapy after receiving at least two cycles of treatment. Patients with a complete response (CR) (including near CR and stringent CR) to conventional induction therapy and proceeding to transplantation. Pregnant or nursing females or women of reproductive capability who are unwilling to use effective contraception. A woman of reproductive capability is one who has not undergone a hysterectomy (removal of the womb), has not had both ovaries removed, or has not been post-menopausal (stopped menstrual periods) for more than 24 months in a row. Male subjects who refuse to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse. This must be done even if they are surgically sterilized (ie, post-vasectomy). Patient with Grade 2 peripheral neuropathy Inability to provide informed consent Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. Known allergies to any of the components of the investigational treatment regimen or required ancillary treatments. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Diagnosed or treated for another malignancy within 3 years of enrollment (with the exception of non-melanoma skin cancer). Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial. Prisoner

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1: Carfilzomib 15 mg/m2<br>Carfilzomib 15 mg/m2 on days -2, -1, +5, and +6 IV over 10 minutes. | Drug: Cohort 1: Carfilzomib 15 mg/m2<br>* Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 15 mg/m2 on day -2, -1, + 5 and +6<br>* Other names: Melphalan - Alkeran;|
| Active Comparator: Cohort 2: Carfilzomib 20 mg/m2<br>Carfilzomib 20 mg/m2 on days -2, -1, +5, and +6 IV over 10 minutes. | Drug: Cohort 2: Carfilzomib 20 mg/m2<br>* Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 100 mg/m2 on day -2 and day -1 Carfilzomib 20 mg/m2 on day -2, -1, + 5 and +6<br>* Other names: Melphalan - Alkeran;|
| Active Comparator: Cohort 2b: Carfilzomib 20 mg/m2<br>Carfilzomib 20 mg/m2 on days -2, -1 and +5 IV over 10 minutes. | Drug: Cohort 2b: Carfilzomib 20 mg/m2<br>* Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 20 mg/m2 on day -2, -1 and + 5<br>* Other names: Melphalan - Alkeran;|
| Active Comparator: Cohort 3: Carfilzomib 27mgm2<br>Carfilzomib 27 mg/m2 on days -2, -1 and +5 IV over 10 minutes. | Drug: Cohort 3b: Carfilzomib 27 mg/m2<br>* Carfilzomib 20 mg/m2 on days -29, -28, -22, -21, -15, and -14 Bendamustine 120 mg/m2 on day -2 and 100 mg/m2 day -1 Melphalan 140 mg/m2 on day -1 Carfilzomib 27 mg/m2 on day -2, -1 and + 5<br>* Other names: Melphalan - Alkeran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | An absence of neutrophil engraftment by Day +22, absence of platelet engraftment by Day +35, and any grade 4 GI toxicity or any >/= grade 3 non-hematologic toxicity as defined by the common toxicity criteria, which is deemed by the DSMB as probably related to the study protocol. | Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | Engraftment of Neutrophils: ANC recovery is defined as an absolute neutrophil count (ANC) of ≥ 0.5 x 109/L for three consecutive laboratory values obtained on different days. The day used as neutrophil engraftment is the date of the first of three laboratory values. Engraftment of Platelets: Platelet engraftment is defined as a platelet count ≥ 20 x 109/L for 3 consecutive measurements obtained on different days. The patient must not have received a platelet infusion for seven consecutive days prior to the first day being considered. The day used as platelet engraftment is the date of the first of three laboratory values. Graft Failure: Graft failure includes failure to achieve neutrophil engraftment by day 22. | Assessed daily (while inpatient) through clinical and laboratory examinations up to 90 days. |