Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin for Multiple Myeloma

Study Overview
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Brief Summary
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This is an open label phase I/II trial to determine the safety and the biologic activity of the bendamustine, bortezomib and pegylated liposomal doxorubicin combination.

Detailed Description
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Phase I component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine escalating cohorts IV over 1 hour, Days 1 and 4 1 Cycle = 28 days Phase II component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine at MTD IV over 1 hour, Days 1 and 4 Filgrastim (if defined in MTD) 5 µg/kg/day SC, Starting day 6 until neutrophil recovery to ANC >1000 1 Cycle = 28 days; Patients will continue treatment for a total of up to 8 cycles. ECOG Performance Status: 0-2 Hematopoietic: Absolute neutrophil count (ANC) ≥ 1.2 x K/mm3 Platelets ≥ 75 x K/mm3 Hepatic: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) AST ≤ 2.5 x ULN ALT ≤ 2.5 x ULN Renal: Serum creatinine < 3.0 mg/dL Cardiovascular: LVEF >45% corrected by MUGA scan or echocardiogram. No unstable angina pectoris or recent myocardial infarction (within 6 months)

Official Title
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A Phase I/II Trial of Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin in Patients With Relapsed or Refractory Multiple Myeloma: Hoosier Cancer Research Network MM08-141

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Doxorubicin
* Drug: Bortezomib
* Drug: Bendamustine
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A histologically established diagnosis of multiple myeloma with evidence of relapse or refractory disease. Must have a detectable serum or urine M-Protein by protein electrophoresis that is at least 500 mg/dL (serum) or 1 gm/24 hours (urine), respectively, or serum free light chain level >100 mg/l for the involved free light chain. Must have received at least one (1) prior line of systemic treatment that has included either lenalidomide or thalidomide. Must be willing to provide correlative blood samples. Exclusion Criteria: Must not have received an excessive cumulative dose of anthracycline No ≥ grade 2 peripheral neuropathy. No cytotoxic chemotherapy within 30 days prior to registration for protocol therapy. No autologous stem cell transplant within 6 months prior to registration for protocol therapy No prior radiation therapy to > 25% of bone marrow forming bones (i.e., pelvis) within 30 days prior to registration for protocol therapy. See Study Procedures Manual to calculate percent of prior radiation. No current corticosteroid therapy in doses greater than 10 mg daily of prednisone (or equivalent) if given for management of co-morbid conditions. No known central nervous system involvement by myeloma. No poorly controlled intercurrent illness including, but not limited to, ongoing or active infection, poorly controlled diabetes, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social climate that in the opinion of the investigator would limit compliance with study requirements. No patients known to be positive for HIV, or active Hepatitis A, B, or C. No major surgery within 30 days prior to registration for protocol therapy. Placement of a venous access device within 30 days prior to registration for protocol therapy is allowed.

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: Arm 1<br>Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin. | Drug: Bendamustine<br>* Phase I component: Bendamustine escalating cohorts to determine MTD, IV over 1 hour, Days 1 and 4<br>Drug: Doxorubicin<br>* Phase I and II components: Pegylated liposomal doxorubicin, 30 mg/m2 IV over 1 hour, Day 4<br>Drug: Bortezomib<br>* Phase I and II components: Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11<br>Drug: Bendamustine<br>* Phase II component: Bendamustine at at MTD IV over 1 hour, Days 1 and 4<br>Drug: Filgrastim<br>* Phase II component: Filgrastim (if defined in MTD) 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC >1000<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin. | In the first phase, MTD of bendamustine was determined in combination with bortezomib and pegylated liposomal doxorubicin to gain a better idea of safe dosing before proceeding with the second phase to assess efficacy. Assuming myelosuppression being a dose-limiting effect that could have been overcome with growth factor support, MTD of the combination with myeloid growth factor support was also tested. | From C1D1 up to a maximum of 7 months or until death | 
| Phase II : Overall Response Rate | Overall response rate (CR+PR) of bendamustine in association with bortezomib and pegylated liposomal doxorubicin was assessed in patients with relapsed or refractory Multiple Myeloma. Per modified International Myeloma Working Group criteria: Complete Response (CR) : Negative for monoclonal protein by immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow ; PR : 50% or more reduction in serum M-protein and 90% or more reduction in urine M-protein or to <200 mg/24hours or a 50% or more reduction in free light chain level ; Overall Response (OR) = CR +PR. | From C1D1 up to a maximum of 52 months or until death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I & Phase II : Toxicity of Treatment Regimen | Toxicity profile (for all patients) were presented by rate of overall toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined. | From C1D1 until death or up to a maximum of 54 months | 
| Phase II : Time to Progression | The time from the start of treatment (i.e., first dose) of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin to disease progression, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date for patient without progression/death or date of death due to other diseases for patients' deaths due to other causes.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; 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 hyperc. | From C1D1 up to a maximum of 54 months or until death | 
| Phase II: Progression-free Survival (PFS) | The time from the start of treatment of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. to disease progression or death (regardless of cause of death), whichever comes first. Censoring date will be the last disease evaluation date.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; 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 hyperc. | From C1D1 up to a maximum of 54 months until death | 
| Phase II: Duration of Survival | Duration of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. from first date of at least partial response to the time of progression or death due to disease progression as events, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date or date of death due to other causes as appropriate. | From C1D1 up to a maximum of 52 months | 
| Phase II: Overall Survival | The time from the start of treatment to death from any cause with last date known alive as censoring date. | From C1D1 up to a maximum of 54 months or until death |