A Study to Determine the Safety and Efficacy for the Combination of Durvalumab and Daratumumab in Relapsed and Refractory Multiple Myeloma
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT02807454
- Lead Sponsor
- Celgene
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 37
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Daratumumab Plus Durvalumab Treatment Daratumumab * 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 Daratumumab Plus Durvalumab Treatment Durvalumab * 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 Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment Daratumumab * 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 Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment Durvalumab * 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 Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment Pomalidomide * 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 Pomalidomide+ Daratumumab+ Durvalumab+ Dexamethasone Treatment Dexamethasone * 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
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) 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) 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) 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 Outcome Measures
Name Time Method 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) 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).
Time of Maximum Observed Concentration (Tmax) - Simon Stage 1: D2 Arm Cycle 1 - Days 2, 8, 15, 22 Pharmacokinetics of Durvalumab derived from serum concentration versus time data.
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) 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.
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) 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).
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) 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).
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 Pharmacokinetics of Durvalumab derived from serum concentration versus time data.
Time-To-Response (TTR) From enrollment to earliest documented response (up to approximately 66 months) 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).
Maximum Observed Plasma Concentration (Cmax) - Simon Stage 1: D2 Arm Cycle 1 - Days 2, 8, 15, 22 Pharmacokinetics of Durvalumab derived from serum concentration versus time data.
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 Pharmacokinetics of Durvalumab derived from serum concentration versus time data.
Trial Locations
- Locations (64)
UCLA Division of Hematology Oncology
🇺🇸Los Angeles, California, United States
Local Institution - 103
🇨🇦Saint John, New Brunswick, Canada
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Cliniques Universitaires UCL de Mont-Godine
🇧🇪Yvoir, Belgium
MUHC Glen Site
🇨🇦Montreal, Quebec, Canada
Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Center For Cancer and Blood Disorders
🇺🇸Bethesda, Maryland, United States
AZ St-Jan Brugge Oostende AV
🇧🇪Brugge, Belgium
Skanes Universitetssjukhus Malmo
🇸🇪Lund, Sweden
Local Institution - 201
🇩🇪Wuerzburg, Germany
Local Institution - 502
🇸🇪Stockholm, Sweden
Karolinska Universitetssjukhuset - Huddinge
🇸🇪Stockholm, Sweden
Universitatsklinikum Wuerzburg
🇩🇪Wuerzburg, Germany
Local Institution - 453
🇪🇸Barcelona, Spain
Saint John Regional Hospital
🇨🇦Saint John, New Brunswick, Canada
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Local Institution - 203
🇩🇪Heidelberg, Germany
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
University of Pennsylvania - Perelman Center for Advanced Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Local Institution - 104
🇨🇦Toronto, Ontario, Canada
Sahlgrenska University Hospital
🇸🇪Gothenburg, Sweden
Local Institution - 501
🇸🇪Lund, Sweden
Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
🇬🇧Oxford, United Kingdom
St. Bartholomew's and The Royal London Hospital
🇬🇧London, United Kingdom
Local Institution - 253
🇬🇧Sutton (Surrey), United Kingdom
Local Institution - 451
🇪🇸Gijon, Spain
Universitatsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Washington University
🇺🇸Saint Louis, Missouri, United States
Hospital Durán i Reynals - Instituto Catalàn de Oncologìa ICO
🇪🇸Barcelona, Spain
The Royal Wolverhampton Hospital NHS Trust
🇬🇧Wolverhampton, United Kingdom
Hospital 12 de Octubre
🇪🇸Madrid, Spain
Universitatsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪Dresden, Germany
Local Institution - 452
🇪🇸Madrid, Spain
University Hospital Tubingen
🇩🇪Tubingen, Germany
Hospital de Cabuenes
🇪🇸Gijon, Spain
Local Institution - 252
🇬🇧Oxford, United Kingdom
Christie Hospital
🇬🇧Manchester, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton (Surrey), United Kingdom
Dana-Farber Partners Cancer Care, Inc.
🇺🇸Boston, Massachusetts, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Tennessee Oncology Nashville Drug Development Unit
🇺🇸Nashville, Tennessee, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Local Institution - 007
🇺🇸Denver, Colorado, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Local Institution - 552
🇩🇰Copenhagen, Denmark
Local Institution - 553
🇩🇰Odense, Denmark
Odense University Hospital
🇩🇰Odense, Denmark
Local Institution - 551
🇩🇰Vejle, Denmark
Vejle Hospital
🇩🇰Vejle, Denmark
Local Institution - 354
🇮🇹Bologna, Italy
Policlinico S. Orsola - Malpighi
🇮🇹Bologna, Italy
A.O.U. Maggiore della Carità
🇮🇹Novara, Italy
Local Institution - 353
🇮🇹Novara, Italy
Azienda Ospedaliera di Padova
🇮🇹Padova, Italy
Local Institution - 355
🇮🇹Padova, Italy
Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
🇮🇹Palermo, Italy
A.O. Universitaria Ospedale S.Chiara Dip.Oncologia, Div. Ematologia
🇮🇹Pisa, Italy
Rigshospitalet University Hospital
🇩🇰Copenhagen, Denmark
Universitaire Ziekenhuizen Leuven Univeristy Hospitals Leuven
🇧🇪Leuven, Belgium
Hopital Maisonneuve-Rosemont
🇨🇦Montreal, Quebec, Canada
Local Institution - 101
🇨🇦Montreal, Quebec, Canada