A Study to Determine the Safety and Efficacy for the Combination of Durvalumab and Daratumumab in Relapsed and Refractory Multiple Myeloma (FUSIONMM-003)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: Durvalumab; Drug: Pomalidomide; Drug: Daratumumab

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • AZ St-Jan Brugge Oostende AV
  • Leuven, Belgium, B-3000
    • Universitaire Ziekenhuizen Leuven Univeristy Hospitals Leuven
  • Yvoir, Belgium, 5530
    • Cliniques Universitaires UCL de Mont-Godine
• Canada
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 3L6
      • Saint John Regional Hospital
    • Saint John, New Brunswick, Canada, E2L 3L6
      • Local Institution - 103
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution - 104
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, H1T 2M4
      • Local Institution - 101
    • Montreal, Quebec, Canada, H4A 3J1
      • Muhc Glen Site
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet University Hospital
  • Copenhagen, Denmark, 2100
    • Local Institution - 552
  • Odense, Denmark, DK-5000
    • Odense University Hospital
  • Odense, Denmark, DK-5000
    • Local Institution - 553
  • Vejle, Denmark, 7100
    • Vejle Hospital
  • Vejle, Denmark, 7100
    • Local Institution - 551
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus an der TU Dresden
  • Heidelberg, Germany, 69115
    • UniversitatsKlinikum Heidelberg
  • Heidelberg, Germany, 69115
    • Local Institution - 203
  • Tubingen, Germany, 72076
    • University Hospital Tübingen
  • Wuerzburg, Germany, 97080
    • Universitätsklinikum Wuerzburg
  • Wuerzburg, Germany, 97080
    • Local Institution - 201
• Italy
  • Bologna, Italy, 40138
    • Policlinico S. Orsola - Malpighi
  • Bologna, Italy, 40138
    • Local Institution - 354
  • Novara, Italy, 28100
    • A.O.U. Maggiore della Carita
  • Novara, Italy, 28100
    • Local Institution - 353
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Padova, Italy, 35128
    • Local Institution - 355
  • Palermo, Italy, 90146
    • Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
  • Pisa, Italy, 56126
    • A.O. Universitaria Ospedale S.Chiara Dip.Oncologia, Div. Ematologia
• Spain
  • Barcelona, Spain, 08907
    • Hospital Durán i Reynals - Instituto Catalàn de Oncologìa ICO
  • Barcelona, Spain, 08907
    • Local Institution - 453
  • Gijon, Spain, 33394
    • Hospital de Cabuenes
  • Gijon, Spain, 33394
    • Local Institution - 451
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Madrid, Spain, 28040
    • Local Institution - 452
• Sweden
  • Gothenburg, Sweden, 60 Gothenburg
    • Sahlgrenska University Hospital
  • Lund, Sweden, 221 85
    • Local Institution - 501
  • Lund, Sweden, 221 85
    • Skånes Universitetssjukhus Malmö
  • Stockholm, Sweden, SE-141 86
    • Local Institution - 502
  • Stockholm, Sweden, SE-14186
    • Karolinska universitetssjukhuset - Huddinge
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • St. Bartholomew's and The Royal London Hospital
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital
  • Oxford, United Kingdom, 0X3 7LE
    • Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
  • Oxford, United Kingdom, 0X3 7LE
    • Local Institution - 252
  • Sutton (Surrey), United Kingdom, SM2 5PT
    • Royal Marsden Hospital
  • Sutton (Surrey), United Kingdom, SM2 5PT
    • Local Institution - 253
  • Wolverhampton, United Kingdom, WV10 0QP
    • The Royal Wolverhampton Hospital NHS Trust
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90095-1752
      • UCLA Division of Hematology Oncology
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
    • Denver, Colorado, United States, 80218
      • Local Institution - 007
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Partners Cancer Care, Inc.
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Perelman Center for Advanced Medicine
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania - Perelman Center for Advanced Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Nashville Drug Development Unit
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Durvalumab; Drug: Daratumumab
Experimental: 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	Drug: Dexamethasone; Drug: Durvalumab; Drug: Pomalidomide; Drug: Daratumumab

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Celgene

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2016
• Primary Completion (Actual): January 3, 2022
• Study Completion (Actual): January 3, 2022

Study Registration Dates

• First Submitted: June 17, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimate): June 21, 2016

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Daratumumab; PD-L1; Durvalumab; Phase 2; Open-Label; Relapsed and Refractory (RRMM); FUSION MM-003
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Pomalidomide; Daratumumab; Durvalumab
• Other Study ID Numbers: MEDI4736-MM-003