Phase 1b Study Evaluating OPomD in Relapsed or Refractory Multiple Myeloma
- Conditions
- Relapsed or Refractory Multiple Myeloma
- Interventions
- Drug: Immediate Release (IR) FormulationDrug: Gastro-Retentive (GR) Formulation
- Registration Number
- NCT02939183
- Lead Sponsor
- Amgen
- Brief Summary
A study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in patients with relapsed refractory multiple myeloma.
- Detailed Description
A multicenter, non-randomized, open-label, dose-exploration study evaluating two new formulations of oprozomib plus pomalidomide and dexamethasone in patients with relapsed refractory multiple myeloma. The study will be conducted in two parts. Part 1 will evaluate the formulations of oprozomib in combination with dexamethasone only. Part 2 will evaluate the formulations of oprozomib administered at increasing dose levels (dose escalation) in combination with pomalidomide and dexamethasone.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 61
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1 Oprozomib Immediate-release (IR) + Dexamethasone Immediate Release (IR) Formulation Oprozomib IR plus dexamethasone Part 1 Oprozomib Immediate-release (IR) + Dexamethasone Dexamethasone Oprozomib IR plus dexamethasone Part 1 Oprozomib Gastro-retentive (GR) + Dexamethasone Gastro-Retentive (GR) Formulation Oprozomib GR plus dexamethasone Part 1 Oprozomib Gastro-retentive (GR) + Dexamethasone Dexamethasone Oprozomib GR plus dexamethasone Part 2 Oprozomib IR + Pomalidomide + Dexamethasone Immediate Release (IR) Formulation Oprozomib IR plus pomalidomide and dexamethasone Part 2 Oprozomib IR + Pomalidomide + Dexamethasone Dexamethasone Oprozomib IR plus pomalidomide and dexamethasone Part 2 Oprozomib IR + Pomalidomide + Dexamethasone Pomalidomide Oprozomib IR plus pomalidomide and dexamethasone Part 2 Oprozomib GR + Pomalidomide + Dexamethasone Gastro-Retentive (GR) Formulation Oprozomib GR plus pomalidomide and dexamethasone Part 2 Oprozomib GR + Pomalidomide + Dexamethasone Dexamethasone Oprozomib GR plus pomalidomide and dexamethasone Part 2 Oprozomib GR + Pomalidomide + Dexamethasone Pomalidomide Oprozomib GR plus pomalidomide and dexamethasone Open-label Roll-over Gastro-Retentive (GR) Formulation Oprozomib GR monotherapy, or oprozomib GR plus dexamethasone Open-label Roll-over Dexamethasone Oprozomib GR monotherapy, or oprozomib GR plus dexamethasone
- Primary Outcome Measures
Name Time Method Number of Participants Who Experienced Dose-Limiting Toxcity (DLT) Day 1 to day 28 of cycle 1, where each cycle was 28 days DLTs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and included the below, if judged by the investigator/medical monitor to be possibly related to study treatment: Non-hematologic DLTs were any ≥ Grade 3 toxicity, except: Grade 3 asymptomatic electrolyte abnormalities (except hypophosphatemia \> 24 hours); Grade 3 nausea, vomiting and diarrhea \< 3 days; Grade 3 fatigue \< 14 days; ≥ Grade 3 hyperglycemia/toxicity due to dexamethasone; ≥ Grade 3 rash due to pomalidomide. Hematologic DLTs included: Grade 4 neutropenia if absolute neutrophil count \< 0.5 x 10\^9/L ≥ 7 days; febrile neutropenia; Grade 4 thrombocytopenia ≥ 7 days; Grade ≥ 3 with ≥ Grade 2 bleeding/requiring platelet transfusion.
Maximum Tolerated Dose (MTD) of Each Formulation of Oprozomib in Combination With Pomolidomide and Dexamethasone Day 1 to Day 28 of cycle 1, where each cycle was 28 days The MTD was the dose with the highest posterior probability of having a DLT rate within the target toxicity interval (15% to 25%), while the posterior probability of excessive/unacceptable toxicity (\>25% to 100%) is \<40%.
DLTs were graded using CTCAE version 4.03 and included the below, if judged by the investigator/medical monitor to be possibly related to study treatment: Non-hematologic DLTs were any ≥ Grade 3 toxicity, except: Grade 3 asymptomatic electrolyte abnormalities (except hypophosphatemia \> 24 hours); Grade 3 nausea, vomiting and diarrhea \< 3 days; Grade 3 fatigue \< 14 days; ≥ Grade 3 hyperglycemia/toxicity due to dexamethasone; ≥ Grade 3 rash due to pomalidomide. Hematologic DLTs included: Grade 4 neutropenia if absolute neutrophil count \< 0.5 x 10\^9/L ≥ 7 days; febrile neutropenia; Grade 4 thrombocytopenia ≥ 7 days; Grade ≥ 3 with ≥ Grade 2 bleeding/requiring platelet transfusion.Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Oprozomib in Combination With Dexamethasone and/or Pomalidomide) Day 1 of cycle 1 to 30 (+7) days after the last dose of study treatment or end of study date, whichever is earlier (where each cycle was 28 days). Median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that started on or after receiving the first dose of investigational product and up to and including 30 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered related to study treatment by the investigator. Any clinically significant changes in electrocardiograms, vital signs, physical examination with a neurological assessment and clinical laboratory tests were recorded as TEAEs.
Number of Participants With TEAEs and Treatment-emergent Serious AEs (Open-label Roll-over) Day 1 to 30 (+7) days after the last dose of study treatment or end of study date, whichever is earlier (where each cycle was 28 days). Median treatment duration for the open-label roll-over arm was 75.14 weeks TEAEs were any AE that started on or after receiving the first dose of investigational product and up to and including 30 days after the last dose of investigational product or the end of study date, whichever is earlier. Treatment-related TEAEs were those considered related to study treatment by the investigator. Serious TEAEs were any AE meeting at least 1 of the following criteria: fatal; life-threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event.
- Secondary Outcome Measures
Name Time Method Maximum Observed Concentration (Cmax) of Oprozomib Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose The mean Cmax of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.
Time to Cmax (Tmax) of Oprozomib Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose The median Tmax of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Oprozomib Cycle 1 days 8 and 22: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose. GR only: cycle 1 day 8: 8 hours post-dose The mean AUClast of oprozomib is presented following dosing on cycle 1 day 8 and cycle 1 day 22 for the IR and GR oprozomib formulations.
Best Overall Response (BOR) According to Revised International Myeloma Working Group Uniform Response Criteria (IMWG-URC) Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks BOR was the best response per IMWG-URC from best to worst: stringent complete response (sCR; complete response \[CR\], normal serum free light chain ratio, no clonal cells in bone marrow \[BM\]), CR (negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in BM), very good partial response (VGPR; serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein \[urine M-protein level \< 100 mg/24-h\]), partial response (PR; ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or \< 200 mg/24-h), minimal response (MR; 25-49% reduction of serum M-protein and 50-89% in 24-h urinary M-protein, exceeding 200 mg/24-h), stable disease (SD; not CR, VGPR, PR or progressive disease \[PD\]), and PD (≥ 25% increase in serum or urine M-component, development of new or increased size of existing bone lesions or soft tissue plasmacytomas, hypercalcemia attributed to the plasma cell proliferative disorder).
Overall Response Rate (ORR) According to IMWG-URC Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks The ORR was defined as the percentage of participants with a BOR of sCR, CR, VGPR, and PR per the IMWG-URC. Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to \< 200 mg/24-h. The 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.
Number of Participants With Progression Free Survival (PFS) Events Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks PFS was defined as the number of months from a participant's first dose of study treatment to the earlier of disease progression or death due to any cause. The number of participants who had a PFS event or who were censored are presented. PFS events were an assessment of progressive disease according to the IMWG-URC or death due to any cause. PFS data was censored: participants alive and no documented disease progression at time of analysis were censored at date of last disease assessment; participants alive with no disease assessment were censored at the first study dose date; participants alive without documented disease progression, with withdrawn consent were censored at date of last disease assessment before consent withdrawal; and for participants who started anti-cancer therapy other than study treatment prior to documentation of disease progression were censored at date of last disease assessment prior to starting new therapy.
Kaplan-Meier Estimate of PFS Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks PFS was defined as the number of months from a participant's first dose of study treatment to the earlier of disease progression or death due to any cause. Median PFS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. PFS data was censored: participants alive and no documented disease progression at time of analysis were censored at date of last disease assessment; participants alive with no disease assessment were censored at the first study dose date; participants alive without documented disease progression, with withdrawn consent were censored at date of last disease assessment before consent withdrawal; and for participants who started anti-cancer therapy other than study treatment prior to documentation of disease progression were censored at date of last disease assessment prior to starting new therapy.
Kaplan-Meier Estimate of Duration of Response (DOR) Day 1 of cycle 1 up to the end of study visit (where each cycle was 28 days); median treatment duration in Part 1 was 11.43 weeks and in Part 2 was 28 weeks DOR, presented in months, was defined as the number of days between the date of the first tumor assessment indicating an objective response (PR or better) through to the subsequent date of progression or death due to any cause, or where applicable date of censoring (date of first progressive disease assessment or death or date of censoring - date of the first objective response result + 1/30.4). Median PFS was estimated using the Kaplan-Meier method. 95% confidence intervals were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
Trial Locations
- Locations (1)
Research Site
🇪🇸Pamplona, Navarra, Spain