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

INCLUSION CRITERIA:

Patients must meet all of the following inclusion criteria to be eligible to enroll in this study.

1. Cytopathologically or histologically confirmed diagnosis of multiple myeloma

2. Relapsed or refractory to most recent therapy (i.e. < 25% response, progression during therapy or within 60 days after completion).

3. Refractory to prior lenalidomide therapy (i.e. history of progression on therapy using full or maximally tolerated dose of lenalidomide for >/= two cycles).

4. 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

5. Evidence of progression/relapse

6. Over 18

7. Life expectancy of more than 3 months

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

9. Total bilirubin < 2 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN

10. Serum creatinine <3 mg/dL

11. • 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

12. Agree to take enteric coated aspirin 81 mg daily

13. Consent

14. 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.

15. 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.

16. Register with POMALYST REMS™ and comply with their requirements.

EXCLUSION CRITERIA:

1. Patients with known sensitivity to immunomodulatory drugs (IMiDs)
2. Use of experimental drugs or therapy within 21 days of study-related drug therapy.
3. Exposure to chemotherapy or steroids within 14 days of study-related drug therapy.
4. Prior use of pomalidomide.
5. Radiation therapy within 14 days of screening.
6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
7. Plasma cell leukemia.
8. Waldenström's macroglobulinemia.
9. Major surgery within 21 days prior to first dose.
10. Pregnant or lactating females.
11. Congestive heart failure, symptomatic ischemia, conduction abnormalities uncontrolled or myocardial infarction in the last six months.
12. Uncontrolled hypertension
13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose.
14. Active treatment or intervention for other malignancy or need active treatment within 8 months of starting study treatment.
15. Serious psychiatric or medical conditions that interfere with treatment
16. Significant neuropathy (Grade 3, Grade 4) at first dose and/or within 14 days before enrollment
17. Contraindication to required concomitant drugs
18. Patients with primary systemic amyloidosis