Phase II Study of V-BEAM Conditioning Regimen Prior to Second Autologous Stem Cell Transplantation

Study Overview
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Brief Summary
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BEAM regimen (BCNU, etoposide, cytarabine, and melphalan) is the most commonly used conditioning regimen for relapsed/refractory lymphoma patients needing autologous stem cell transplantation. Since these components are all effective in myeloma and bortezomib has shown promising results in the transplant setting, here the investigators propose a phase II study to investigate the combination of bortezomib and BEAM as a new conditioning regimen for patients who relapse or progress after the first autologous transplantation and for whom a second autologous transplant is considered.

Official Title
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A Phase II Study of V-BEAM (Bortezomib, Carmustine, Etoposide, Cytarabine, and Melphalan) as Conditioning Regimen Prior to Second Autologous Stem Cell Transplantation for Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Carmustine
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Melphalan
* Procedure: Stem cell infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have a histologically confirmed diagnosis of multiple myeloma. Patient must have received a prior autologous stem cell transplantation with melphalan conditioning for multiple myeloma with subsequent disease progression and repeat autologous stem cell transplantation is deemed appropriate by the treating physicians. Patient must receive induction chemotherapy including 2 to 4 cycles of anti-myeloma therapy including bortezomib, with or without immune modulating agents and/or corticosteroids, Completion of induction therapy will occur within 30 days of first study drug dose. Patient must have ≥ 2x106/kg CD34+ autologous stem cells available for transplantation. Patient must be ≥ 18 years of age. Patient must have life expectancy of greater than 6 months. Patient must have an ECOG performance status ≤ 2 or Karnofsky performance status ≥ 60% (see Appendices A and B) Patient must have normal bone marrow and organ function as defined below within 14 days prior to first study drug dose (conditioning regimen): Absolute neutrophil count ≥500/mm3 Platelets ≥ 50,000/mm3 Hemoglobin ≥ 8 g/dl Total bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Creatinine clearance (Appendix C) ≥30 mL/min/1.73m2 Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry through Day +100 visit. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Patient must be able to understand and willing to sign an IRB approved written informed consent document. Exclusion Criteria: Patient must not be refractory to induction therapy. Refractory is defined as disease progression while on therapy or within 30 days following completion of therapy. Patient must not have had disease progression requiring active treatment within 12 months of previous autologous stem cell transplant. Maintenance therapy is not considered active treatment. Patient must not have peripheral neuropathy ≥ grade 3 based on NCI CTCAE v 4.0 (Appendix D). Patient must not be receiving renal replacement therapy, hemodialysis, or peritoneal dialysis. Patient must not have another concurrent malignancy requiring treatment. Patient must not be receiving any other investigational agents within 14 days prior to the first dose of study drug. Patient must not have known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib, carmustine, etoposide, cytarabine, and melphalan, or other agents used in the study. Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patient must not be pregnant and/or breastfeeding. Inclusion of Women and Minorities -Both men and women and members of all races and ethnic groups are eligible for this trial.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V-BEAM + Stem Cell Infusion<br>Bortezomib IV or SC (1.3mg/m2) on Days -6, -3, +1 and +4 Carmustine IV (300mg/m2) on Day -7 Etoposide IV twice daily (100 mg/m2) on Days -6, -5, -4, and -3 Cytarabine IV twice daily (100 mg/m2) on Days -6, -5, -4, and -3 Melphalan IV (140 mg/m2) on Day-2 Stem cell infusion on Day 0 | Drug: Bortezomib<br> <br> * Other names: Velcade;Drug: Carmustine<br> <br> * Other names: BCNU, BiCNU®;Drug: Etoposide<br> <br> * Other names: Vepesid, VP-16;Drug: Cytarabine<br> <br> * Other names: Ara-C, Cytosar-U, 1-β-Arabinofuranosylcytosine, Arabinosylcytosine, Cytosine arabinoside;Drug: Melphalan<br> <br> * Other names: Alkeran®, L-PAM;Procedure: Stem cell infusion<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (Complete Response + Stringent Complete Response) | Defined by the International Myeloma Working Group (IMWG) criteria | Day +100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-free Survival (PFS) | PFS is defined as the duration from transplant to time of first progression, death, relapse after CR, or the date the patient was last known to be in remission. Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. | Median follow-up of 6 months (range: 6.0-12.0 months) | 
| Overall Response Rate (ORR) | ORR includes Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR) Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. | 3 months following Day +100 visit | 
| Very Good Partial Response Rate (VGPR+nCR+sCR+CR) | Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. | Day +100 | 
| Toxicity of V-BEAM | Graded per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients are evaluated from first receiving study treatment until a 30-day follow-up after the conclusion of treatment for adverse events not resulting in death. Adverse events resulting in death will be evaluated through Day +100. This outcomes measures the common toxicities observed. Please refer to the Serious Adverse Event and Other Adverse Event sections of the results for further details. | 30 days after end of treatment / Day +100 | 
| Time to Neutrophil Engraftment After V-BEAM. | Time to neutrophil engraftment is defined as duration between Day 0 to the first day of ANC > 0.5x109/L post transplant when it is sustained for more than three consecutive days. | Day +100 | 
| Number of Participants With Overall Survival (OS) | OS is defined as the duration from the time of transplant to death or last follow-up. | Median follow-up of 6 months (range: 6-12 months) | 
| Treatment Related Mortality (TRM) of V-BEAM |  | Day +100 | 
| Time to Platelet Engraftment After V-BEAM. | Time to platelet engraftment is defined as the duration between Day 0 to the first day of platelet count sustained at > 20x109/L without transfusion. The median time to neutrophil and platelet engraftment will be reported. | Day +100 |