Bendamustine + Pomalidomide + Dex in R/R Multiple Myeloma

A Phase I-II Study of the Combination of Bendamustine and Pomalidomide With Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

This study is designed as a phase I-II, open label, dose finding study. Study treatment will be as follows, in 28 day cycles: Pomalidomide: once daily orally (PO) dosing on days 1-21, every 28 days Bendamustine: once intravenously (IV) dosing on day 1, every 28 days Dexamethasone: weekly PO or IV dosing on days 1, 8, 15, and 22. After completing 6 cycles of treatment, dexamethasone may be decreased to 20mg per investigator discretion. After completing 12 cycles of treatment, patients will proceed to the maintenance phase of the study. Patients will receive Pomalidomide on day 1-21, every 28 days and dexamethasone on days 1, 8, 15, and 22 every 28 days until time of progression.

PRIMARY ENDPOINTS: Phase I • Determination of the MTD of the combination therapy Phase II: • Response rate (CR+PR) SECONDARY ENDPOINTS: Overall Response Rate (ORR) Progression Free Survival (PFS) Time to Progression (TTP) Time to next therapy A total of 56 patients may be enrolled in this study: Dose escalation phase: Up to 24 subjects; Dose expansion phase: Up to a maximum of 38 patients treated at the maximum tolerated dose (MTD). Study treatment will be administered starting at Cohort 1 for up to four sequential cohorts, with 3-6 patients in each cohort. A standard 3+ 3 dose escalation schedule will be used. A minimum of 3 patients will be entered within each cohort, to be expanded to 6 patients if dose limiting toxicities (DLTs) are observed, to determine the MTD. Once the MTD is reached, any additional patients will be enrolled at the MTD level. Dose Escalation Cohort -1: bendamustine 120 mg/m2; pomalidomide 2mg; dexamethasone 40mg** Cohort 1 (initial dose): bendamustine 120/mg/m2; pomalidomide 3 mg; dexamethasone 40 mg** Cohort 2: bendamustine 120 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg** Cohort 3: bendamustine 150 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg** Cohort 4: bendamustine 180 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg** EVALUATION: For toxicity: 1 cycle (All patients will be considered evaluable for toxicity unless they cannot complete the first cycle of therapy due to withdrawal of consent or disease progression.) For efficacy: 2 cycles Intended treatment duration: Patients will continue on protocol as long as they are receiving clinical benefit and will be removed for disease progression (at the investigator's discretion the patient may be treated up to one cycle after progression noted to confirm progression), adverse event/unacceptable toxicity or side effect, or withdrawal of consent. A DLT is defined as any of the following occurring during the first treatment cycle (28 days) that are judged by the investigator to be at least possibly related to the study therapy: Hematologic: Febrile neutropenia (ANC <1.0x109/L) with fever of 38.5 C. Subjects who enter the study with lower counts (ANC <1.0x109/L) due to >5030%* marrow involvement will not be evaluated for this portion of the DLT definition. Grade 4 neutropenia (ANC < 0.5x109/L) for more than 7 days despite GCSF support. Subjects who enter the study with lower counts (ANC <1.0x109/L) due to >5030%* marrow involvement will not be evaluated for this portion of the DLT definition. Grade 4 thrombocytopenia (platelets count <25.0x109/L) lasting >7 days despite dose delay. Subjects who enter the study with lower counts (platelets <50.0x109/L) due to >5030%* marrow involvement will not be evaluated for this portion of the DLT definition. Grade 3-4 thrombocytopenia associated with bleeding Any hematologic toxicity requiring a dose reduction within Cycle 1 Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from Cycle 1 greater than 14 days Non-hematologic: Any > Grade 3 toxicity determined by the Investigator to be related to pomalidomide or bendamustine (with the exception of thrombotic events and as noted below). > Grade 3 nausea, vomiting, or diarrhea, despite the use of maximal antiemetic/antidiarrheal therapy > Grade 3 neuropathy with pain >Grade 3 venous thromboembolic events. Any Grade 4 rash related to the agents will be considered a DLT. A Grade 3 rash related to the agents that has not resolved to < Grade 2 within a 10 day period despite steroids therapy will be considered a DLT. If an event is attributed to progressive disease, it will not be counted as a DLT. Any non-hematologic toxicity requiring a dose reduction within Cycle 1 Delay in ability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from Cycle 1 greater than 14 days

Pomalidomide: once daily oral (PO) dosing on days 1-21, every 28 days Bendamustine: once intravenous (IV) dosing on day 1, every 28 days Dexamethasone: weekly PO or IV dosing on days 1, 8, 15, and 22 every 28 days

Pomalidomide: once daily oral (PO) dosing on days 1-21, every 28 days Bendamustine: once intravenous (IV) dosing on day 1, every 28 days Dexamethasone: weekly PO or IV dosing on days 1, 8, 15, and 22 every 28 days

Pomalidomide 3mg: once daily oral (PO) dosing on days 1-21, every 28 days Bendamustine 120 mg: once intravenous (IV) dosing on day 1, every 28 days Dexamethasone: weekly PO or IV dosing on days 1, 8, 15, and 22 every 28 days

Bendamustine will be administered intravenously over 1 hour (if using Treanda) or over 10 minutes (if using Bendeka) on day 1, every 28 days for 12 cycles.

Pomalidomide will be administered once daily orally (PO) on days 1-21, every 28 days until disease progression or death.

Dexamethasone will be administered weekly orally or intravenously on days 1, 8, 15, and 22 every 28 days until disease progression or death. After 6 cycles of treatment, the dose may be reduced to 20mg at investigator's discretion. For subjects ≥ 75 years of age, the starting dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each 28-day treatment cycle.

In the phase I dose escalation portion, patients will be sequentially enrolled in 4 cohorts at dose levels in a standard 3+3 design until the maximum tolerated dose (MTD) is reached. Cohort 1 (bendamustine 120mg/m2 + pomalidomide 3mg); Cohort 2 (bendamustine 120mg/m2 + pomalidomide 4mg); Cohort 3 (bendamustine 150mg/m2 + pomalidomide 4mg); Cohort 4 (bendamustine 180mg/m2 + pomalidomide 4mg) If dose limiting toxicity (DLT) is observed in 2 or more of the six patients at the same dosing level while DLT is observed in only 1 or none of the 6 patients at the dosing level immediately below it, then the lower dosing level will be defined as the maximum tolerated dose (MTD).

The number of patients achieving a complete response (CR) or partial response (PR). Response is defined by the International Myeloma Working Group as: CR- Negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and < 5% plasma cells in bone marrow PR- > 50% reduction of serum M-protein and urine M-protein by >90% or to < 200 mg/24 h In addition, if present at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required VGPR - Serum and urine M-protein detectable by immunofixation but n

The number of patients achieving stable disease (SD), partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) sCR = CR as defined in Primary Outcome measure 2 plus normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence VGPR = Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h SD = Not meeting criteria for CR, VGPR, PR, or progressive disease

Time to progression - defined as time elapsed in patients between achievement of response and disease progression

Time to next Therapy - defined as the time elapsed for patients from initiation of study therapy until initiation of next therapy

The time elapsed for patients between initiation of study therapy and either disease progression or death

INCLUSION CRITERIA: Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. Cytopathologically or histologically confirmed diagnosis of multiple myeloma Relapsed or refractory to most recent therapy (i.e. < 25% response, progression during therapy or within 60 days after completion). Refractory to prior lenalidomide therapy (i.e. history of progression on therapy using full or maximally tolerated dose of lenalidomide for >/= two cycles). Measurable disease: Serum M protein > 0.5 g/dL or Urine Bence Jones protein >200 mg/24 hr or Elevated Free Light Chain per International Myeloma Working Group (IMWG) criteria, and abnormal ratio Evidence of progression/relapse Over 18 Life expectancy of more than 3 months Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Total bilirubin < 2 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN Serum creatinine <3 mg/dL • Absolute neutrophil count (ANC) >1.0 x 109/L or <1.0 x 109/L but > 0.75 due to >30%* marrow involvement (without granulocyte and granulocyte/macrophage colony stimulating factor (GCSF and GMCSF) for >1 week and of pegylated GCSF for >2 weeks) Hemoglobin >8 g/dL Platelet count >75.0 x 109/L or < 75.0 x 109/L but >50.0 x 109/L due to >30%* marrow involvement (without platelet transfusions for >1 week) Transfusions allowed if clinically indicated Agree to take enteric coated aspirin 81 mg daily Consent Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test and abstain from sex or begin TWO acceptable methods of birth control >28 days before pomalidomide dose, and agree to ongoing pregnancy testing. Male patients must abstain from sex or use a latex condom and not donate sperm while taking pomalidomide and for 1 week after stopping drug. Register with POMALYST REMS™ and comply with their requirements. EXCLUSION CRITERIA: Patients with known sensitivity to immunomodulatory drugs (IMiDs) Use of experimental drugs or therapy within 21 days of study-related drug therapy. Exposure to chemotherapy or steroids within 14 days of study-related drug therapy. Prior use of pomalidomide. Radiation therapy within 14 days of screening. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). Plasma cell leukemia. Waldenström's macroglobulinemia. Major surgery within 21 days prior to first dose. Pregnant or lactating females. Congestive heart failure, symptomatic ischemia, conduction abnormalities uncontrolled or myocardial infarction in the last six months. Uncontrolled hypertension Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose. Active treatment or intervention for other malignancy or need active treatment within 8 months of starting study treatment. Serious psychiatric or medical conditions that interfere with treatment Significant neuropathy (Grade 3, Grade 4) at first dose and/or within 14 days before enrollment Contraindication to required concomitant drugs Patients with primary systemic amyloidosis