A Phase 2, Multicenter, Open-label, Study to Determine the Safety and Efficacy for the Combination of Durvalumab (DURVA) and Daratumumab (DARA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)
Overview
- Phase
- Phase 2
- Intervention
- Daratumumab
- Conditions
- Multiple Myeloma
- Sponsor
- Celgene
- Enrollment
- 37
- Locations
- 64
- Primary Endpoint
- Overall Response Rate (ORR)
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an open-label, multicenter study to confirm the safety and efficacy of durvalumab + daratumumab (D2) in subjects with relapsed and refractory multiple myeloma. This study will also explore the safety and efficacy of the addition of pomalidomide + dexamethasone to durvalumab + daratumumab (PD3).
On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the United States (US) Food and Drug Administration (FDA). The decision by the FDA was based on data related to risks of anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in combination with IMiDs® immunomodulatory drugs in patients with multiple myeloma. As a result, enrollment into this study has been discontinued. Subjects who are receiving clinical benefit, based on the discretion of the investigator, may remain on study treatment after being reconsented.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must have measurable disease as defined by m-protein or serum free light chain.
- •Must have failed last line of treatment (refractory to last line of treatment).
- •Must have achieved at least a minimal response (MR) to at least 1 prior anti-myeloma regimen before developing PD (relapsed)
- •Has performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
- •Must be at least 18 years of age
Exclusion Criteria
- •Has non-secretory multiple myeloma
- •Has had prior anti-myeloma therapy within 2 weeks prior to study Day 1
- •Has received prior therapy with an anti-programmed cell death 1 receptor (anti-PD-1), antiprogrammed death-ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
- •Has received prior treatment with daratumumab or other anti-CD38 therapies previously
- •Has undergone prior organ or allogeneic hematopoetic stem cell transplantation
- •Has received autologous stem cell transplantation (ASCT) within 12 weeks before the date of randomization.
- •Has received prior treatment with a monoclonal antibody within 5 half-lives of Study Day 1
- •Has received investigational agents within 28 days or 5 half-lives (whichever is longer) of Study Day 1
- •Has received live, attenuated vaccine within 30 days prior to Study Day 1
- •Has chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal
Arms & Interventions
Daratumumab Plus Durvalumab Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward
Intervention: Daratumumab
Daratumumab Plus Durvalumab Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward
Intervention: Durvalumab
Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward * oral POM at 4mg/day on days 1 to 21 * oral/IV dex at 40mg/day (\>75 years old) or 20mg/day (\>75 years old) on days 1, 8, 15 and 22
Intervention: Daratumumab
Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward * oral POM at 4mg/day on days 1 to 21 * oral/IV dex at 40mg/day (\>75 years old) or 20mg/day (\>75 years old) on days 1, 8, 15 and 22
Intervention: Durvalumab
Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward * oral POM at 4mg/day on days 1 to 21 * oral/IV dex at 40mg/day (\>75 years old) or 20mg/day (\>75 years old) on days 1, 8, 15 and 22
Intervention: Pomalidomide
Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment
* Intravenous (IV) durvalumab at 1500mg on Day 1 or 2 of a 28-day cycle * IV daratumumab at 16mg/kg on days 1, 8, 15 and 22 at cycles 1-2; on days 1 and 15 at cycles 3-6; and on day 1 from cycle 7 onward * oral POM at 4mg/day on days 1 to 21 * oral/IV dex at 40mg/day (\>75 years old) or 20mg/day (\>75 years old) on days 1, 8, 15 and 22
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Overall Response Rate (ORR)
Time Frame: From first dose to up to approximately 66 months
Tumor response of partial response (PR) or better was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. ORR was calculated as the percent of responders (multiplied by 100). Partial response required ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M protein by ≥ 90% or to \< 200 mg per 24 hours.
Number of Participants With Adverse Events (AEs)
Time Frame: From first dose to 90 days after last dose (up to approximately 58 months)
Number of participants who experienced at least one adverse event. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition should be considered an AE.
Number of Participants With Serious Adverse Events (SAEs)
Time Frame: From first dose to 90 days after last dose (up to approximately 58 months)
Number of participants who experienced at least one serious adverse event. An SAE is any AE occurring at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, constitutes an important medical event.
Secondary Outcomes
- Kaplan-Meier Estimate of Duration of Response (DOR) - Simon Stage 1: D2 Arm(From the earliest date of documented response (PR or better) to earliest date of progressive disease (up to approximately 66 months))
- Time of Maximum Observed Concentration (Tmax) - Simon Stage 1: D2 Arm(Cycle 1 - Days 2, 8, 15, 22)
- Kaplan-Meier Estimate of Duration of Response (DOR) - PD3 Arm(From the earliest date of documented response (PR or better) to earliest date of progressive disease (up to approximately 66 months))
- Kaplan-Meier Estimate of Progression-Free Survival (PFS) - Simon Stage 1: D2 Arm(From enrollment to first documentation of progressive disease or death from any cause during study, whichever occurs earlier (up to approximately 66 months))
- Kaplan-Meier Estimate of Progression-Free Survival (PFS) - PD3 Arm(From enrollment to first documentation of progressive disease or death from any cause during study, whichever occurs earlier (up to approximately 66 months))
- Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Simon Stage 1: D2 Arm(Cycle 1 - Days 2, 8, 15, 22)
- Time-To-Response (TTR)(From enrollment to earliest documented response (up to approximately 66 months))
- Maximum Observed Plasma Concentration (Cmax) - Simon Stage 1: D2 Arm(Cycle 1 - Days 2, 8, 15, 22)
- Area Under the Plasma Concentration-Time Curve to the Last Measurable Plasma Concentration [AUC(0-Last)] - Simon Stage 1: D2 Arm(Cycle 1 - Days 2, 8, 15, 22)