Conditioning Regimen of Bendamustine and Melphalan Followed by Transplant in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of Bendamustine (TREANDA™), in combination with Melphalan in subjects with multiple myeloma who are undergoing an Autologous Stem Cell Transplant.

Detailed Description
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Bendamustine (TREANDA™) has been used in clinical trials to treat multiple myeloma. The results from these trials suggest that it may be beneficial in the treatment of multiple myeloma in a different treatment context. Researchers aim to determine if there may be an improved benefit in the context of bone marrow transplant. This initial clinical trial is intended to help determine how safe it is to use bendamustine as a conditioning regimen for bone marrow transplant, and to look for any initial evidence of benefit. Bendamustine (TREANDA™) is approved by the Food and Drug Administration (FDA) for the treatment of Chronic Lymphocytic Leukemia and Melphalan is a type of chemotherapy drug. The use of Melphalan alone as a conditioning regimen for Autologous Stem Cell Transplant is considered Standard of Care, that is, the treatment or process that your doctor would normally follow to treat your disease. Although Bendamustine (TREANDA™) has been used in multiple myeloma research studies, the combination of Bendamustine (TREANDA™) and Melphalan as treatment for Multiple Myeloma is not approved by the FDA, thus the combination therapy used in this research study is considered investigational.

Official Title
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A Phase 1-2 Study of a Novel Conditioning Regimen of Bendamustine and Melphalan Followed by Autologous Stem Cell Transplant for Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Melphalan
* Drug: Bendamustine
* Drug: Bendamustine
* Drug: Bendamustine
* Drug: Bendamustine
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with multiple myeloma who have received induction therapy and have had stem cells mobilized in preparation for autologous transplantation will be eligible for this study. Patients are also eligible with relapsed or refractory disease, after attempts at more standard approaches, and with the availability of stem cells. Patients must be age 18 or older. Patients must have a life expectancy of at least 12 weeks. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Patients must provide written informed consent. Exclusion Criteria: Impaired renal function with a measured or calculated creatinine clearance of less than 25 ml/min. Impaired hepatic function defined as a bilirubin greater than 1.5 x upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 x ULN. Serious active or uncontrolled infection or medical condition. Women who are pregnant or breast feeding. Women of childbearing age must use adequate contraception and have a negative pregnancy test. Impaired pulmonary function with a diffusing capacity of the lung for carbon monoxide (DLCO) less than 45% predicted. Impaired cardiac function with an ejection fraction less than 40% of predicted. Other systemic anticancer therapy or ongoing toxicities from such therapy.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>Dose Level 1; Bendamustine 30 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Bendamustine<br>* 30 mg/m^2 given on day 2 of melphalan<br>* Other names: Treanda;Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;|
| Experimental: Dose Level 2<br>Dose Level 2; Bendamustine 60 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 60 mg/m^2 given on the 2nd day of melphalan<br>* Other names: Treanda;|
| Experimental: Dose Level 3<br>Dose Level 3; Bendamustine 90 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 90 mg/m^2 given on the 2nd day of melphalan<br>* Other names: Treanda;|
| Experimental: Dose Level 4<br>Dose Level 4; Bendamustine 120 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 60 mg/m^2 given on the 1st and 2nd day of melphalan<br>* Other names: Treanda;|
| Experimental: Dose Level 5<br>Dose Level 5; Bendamustine 150 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 90 mg/m^2 given on the 1st day of melphalan and 60 mg/m^2 given on the 2nd day of melphalan<br>* Other names: Treanda;|
| Experimental: Dose Level 6<br>Dose Level 6; Bendamustine 225 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 125 mg/m^2 given on the 1st day of melphalan and 100mg/m^2 given on the 2nd day of melphalan<br>* Other names: Treanda;|
| Experimental: Phase 2<br>Bendamustine 225 mg/m^2 total, Melphalan 200 mg/m^2 total (140 mg/m^2 total for patients with Creatinine Clearance <70 ml/min) | Drug: Melphalan<br>* 100 mg/m^2 for 2 days (70 mg/m^2 for patients with Creatinine Clearance <70 ml/min)<br>* Other names: Alkeran;Drug: Bendamustine<br>* 125 mg/m^2 given on the 1st day of melphalan and 100mg/m^2 given on the 2nd day of melphalan<br>* Other names: Treanda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (Phase 1) | The Maximum Tolerated Dose was not met in Phase 1 of the study. Phase 2 participants were enrolled at the highest dose administered in Phase 1 (Dose Level 6) and this Outcome Measure is the reported number of dose-limiting toxicities experienced by Phase 1 participants. DLTs were defined as any grade 3 non-hematologic adverse even that did not resolve within 72 hours, any occurrence of a grade 4 non-hematologic adverse event, or failure to engraft with an absolute neutrophil count of 500/mm^3 and platelet count of 20,000/mm^3 untransfused by Day 35 post-transplant. | 35 days post-transplant | 
| Overall Response Rate (Phase 2) - Number of Participants Achieving at Least a Partial Response or Better in Disease Status at Day 100 Post-transplant | Number of patients achieving at least a partial response or better in disease status at Day 100 post-transplant, as defined by the International Myeloma Working Group (IMWG) disease response criteria. Partial response in disease status is defined by the IMWG as ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 hours; If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required | 100 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (Phase 1) | Time elapsed between Day 0 and disease progression, as defined by the International Myeloma Working Group (IMWG) disease response criteria. Disease progression is defined as an increase of >25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL) Urine M-component and/or (the absolute increase must be > 200 mg/24 h) Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved free light chain levels. The absolute increase must be > 10 mg/dL Bone marrow plasma cell percentage; the absolute percentage must be > 10% Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder | From Day 0 to first incidence of disease progression, up to 1,128 days | 
| Progression-Free Survival (Phase 2) | Time elapsed between Day 0 and disease progression, as defined by the International Myeloma Working Group (IMWG) disease response criteria. Disease progression is defined as an increase of >25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL) Urine M-component and/or (the absolute increase must be > 200 mg/24 h) Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved free light chain levels. The absolute increase must be > 10 mg/dL Bone marrow plasma cell percentage; the absolute percentage must be > 10% Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder | From Day 0 to first incidence of disease progression, up to 86 months | 
| Overall Survival at 2 Years (Phase 1) | Time elapsed between Day 0 and death from any cause, whichever came first, assessed up to 2 years. | From Day 0 until time of death, assessed up to 2 years. | 
| Overall Survival at 3 Years (Phase 2) | Time elapsed between Day 0 and death from any cause, whichever came first, assessed up to 3 years. | From Day 0 until time of death, assessed up to 3 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MM, Multiple Myeloma, Autologous Stem Cell Transplant, ASCT