Bendamustine + Pomalidomide + Dex in R/R Multiple Myeloma
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT01754402
- Lead Sponsor
- Cristina Gasparetto
- Brief Summary
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.
- Detailed Description
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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 56
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Expansion Bendamustine * 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 Cohort 1: benda 120mg + pom 3mg Bendamustine * 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 Cohort 1: benda 120mg + pom 3mg Pomalidomide * 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 Cohort 1: benda 120mg + pom 3mg Dexamethasone * 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 Cohort 2: benda 120mg + pom 4mg Bendamustine * 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 Cohort 2: benda 120mg + pom 4mg Pomalidomide * 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 Cohort 2: benda 120mg + pom 4mg Dexamethasone * 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 Expansion Dexamethasone * 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 Expansion Pomalidomide * 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
- Primary Outcome Measures
Name Time Method Initial Response Rate 2 cycles (approximately 2 months) 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 nMaximum Tolerated Dose of Pomalidomide and Bendamustine 2 cycles (approximately 2 months) 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).
- Secondary Outcome Measures
Name Time Method Overall Response Rate 2 years after last dose of study drug 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 diseaseTime to Next Therapy 2 years after last dose of study drug Time to next Therapy - defined as the time elapsed for patients from initiation of study therapy until initiation of next therapy
Time to Progression 2 years after last dose of study drug Time to progression - defined as time elapsed in patients between achievement of response and disease progression
Progression Free Survival 2 years after last dose of study drug The time elapsed for patients between initiation of study therapy and either disease progression or death
Trial Locations
- Locations (1)
Duke University Medical Center
🇺🇸Durham, North Carolina, United States