A Study to Determine the Safety and Efficacy for the Combination of Durvalumab and Daratumumab in Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab
* Drug: Durvalumab
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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 Has moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C Has a prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years (with the exception Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental histologic finding of prostate cancer [T1a or T1b] or prostate cancer that is curative) Has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma Has clinically significant cardiac disease Is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab Plus Durvalumab Treatment<br>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 | Drug: Daratumumab<br> <br> Drug: Durvalumab<br> <br> |
| Experimental: Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment<br>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 | Drug: Daratumumab<br> <br> Drug: Durvalumab<br> <br> Drug: Pomalidomide<br> <br> Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | 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. | From first dose to up to approximately 66 months | 
| Number of Participants With Adverse Events (AEs) | 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. | From first dose to 90 days after last dose (up to approximately 58 months) | 
| Number of Participants With Serious Adverse Events (SAEs) | 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. | From first dose to 90 days after last dose (up to approximately 58 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-To-Response (TTR) | Time-to-response is calculated as the time from enrollment to the first date of documented response (partial response or better). Tumor response of partial response (PR) or better was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. 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. For those participants where POM + DEX were added, time-to-response was calculated from the date POM and DEX were added to the first date of documented response (PR or better). | From enrollment to earliest documented response (up to approximately 66 months) | 
| Kaplan-Meier Estimate of Duration of Response (DOR) - Simon Stage 1: D2 Arm | Duration of response was calculated as the time from the earliest date of documented response (PR or better) to the earliest date of disease progression as determined by the investigator. For those participants where POM + DEX was added, duration of response was calculated as the time from the earliest date of documented response after POM + DEX was added (PR or better) to the earliest date of disease. Tumor response of partial response (PR) or better was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. 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. Progressive Disease required increase of 25% from lowest response value in the serum M-component (absolute increase must be ≥ 0.5 g/dL) and/or urine M-component (absolute increase must be ≥ 200 mg/24 h). | 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 Duration of Response (DOR) - PD3 Arm | Duration of response was calculated as the time from the earliest date of documented response (PR or better) to the earliest date of disease progression as determined by the investigator. For those participants where POM + DEX was added, duration of response was calculated as the time from the earliest date of documented response after POM + DEX was added (PR or better) to the earliest date of disease progression as determined by the investigator. Participants who are alive or lost to follow-up will be censored on the last-known-to-be-alive date. Tumor response of partial response (PR) or better was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. 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. | 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 | Progression-free survival was calculated as the time between the enrollment to the first documentation of progressive disease or death from any cause during study, whichever occurs earlier using the International Myeloma Working Group (IMWG) Uniform Response Criteria. Progressive Disease required increase of 25% from lowest response value in the serum M-component (absolute increase must be ≥ 0.5 g/dL) and/or urine M-component (absolute increase must be ≥ 200 mg/24 h). | 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 | Progression-free survival was calculated as the time between the enrollment to the first documentation of progressive disease or death from any cause during study, whichever occurs earlier using the International Myeloma Working Group (IMWG) Uniform Response Criteria. Progressive Disease required increase of 25% from lowest response value in the serum M-component (absolute increase must be ≥ 0.5 g/dL) and/or urine M-component (absolute increase must be ≥ 200 mg/24 h). | From enrollment to first documentation of progressive disease or death from any cause during study, whichever occurs earlier (up to approximately 66 months) | 
| Maximum Observed Plasma Concentration (Cmax) - Simon Stage 1: D2 Arm | Pharmacokinetics of Durvalumab derived from serum concentration versus time data. | Cycle 1 - Days 2, 8, 15, 22 | 
| Time of Maximum Observed Concentration (Tmax) - Simon Stage 1: D2 Arm | Pharmacokinetics of Durvalumab derived from serum concentration versus time data. | 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 | Pharmacokinetics of Durvalumab derived from serum concentration versus time data. | Cycle 1 - Days 2, 8, 15, 22 | 
| Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Simon Stage 1: D2 Arm | Pharmacokinetics of Durvalumab derived from serum concentration versus time data. | Cycle 1 - Days 2, 8, 15, 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 2, Open-Label, Durvalumab, Daratumumab, Multiple Myeloma, Relapsed and Refractory (RRMM), FUSION MM-003, PD-L1