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
Overview
- Phase
- Phase 1
- Intervention
- Bortezomib
- Conditions
- Multiple Myeloma
- Sponsor
- Sherif Farag, MB, BS
- Enrollment
- 32
- Locations
- 7
- Primary Endpoint
- Phase II : Overall Response Rate
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
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
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)
Investigators
Sherif Farag, MB, BS
Sponsor-Investigator
Hoosier Cancer Research Network
Eligibility Criteria
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.
Arms & Interventions
Arm 1
Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin.
Intervention: Bortezomib
Arm 1
Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin.
Intervention: Bendamustine
Arm 1
Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin.
Intervention: Doxorubicin
Arm 1
Bendamustine in combination with bortezomib and pegylated liposomal doxorubicin.
Intervention: Filgrastim
Outcomes
Primary Outcomes
Phase II : Overall Response Rate
Time Frame: From C1D1 up to a maximum of 52 months or until death
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.
Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin.
Time Frame: From C1D1 up to a maximum of 7 months or until death
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.
Secondary Outcomes
- Phase II: Overall Survival(From C1D1 up to a maximum of 54 months or until death)
- Phase I & Phase II : Toxicity of Treatment Regimen(From C1D1 until death or up to a maximum of 54 months)
- Phase II: Progression-free Survival (PFS)(From C1D1 up to a maximum of 54 months until death)
- Phase II: Duration of Survival(From C1D1 up to a maximum of 52 months)
- Phase II : Time to Progression(From C1D1 up to a maximum of 54 months or until death)