A Study of Atezolizumab (Anti-Programmed Death-Ligand 1 [PD-L1] Antibody) Alone or in Combination With an Immunomodulatory Drug and/or Daratumumab in Participants With Multiple Myeloma (MM)
Phase 1
Completed
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT02431208
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This multicenter, open-label, Phase I study will evaluate the safety, efficacy, and pharmacokinetics of atezolizumab alone or in combination with daratumumab and/or various immunomodulatory agents in participants with MM who have relapsed or who have undergone autologous stem cell transplantation (ASCT). Cycle length will be 21 days in Cohorts A to C and 28 days in Cohorts D to F.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 85
Inclusion Criteria
- Previous diagnosis of MM with objective evidence of measurable disease
- Willing and able to undergo bone marrow aspiration and biopsy tissue sample collection during screening and on study
- Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to (</=) 2
- Left ventricular ejection fraction (LVEF) greater than or equal to (>/=) 40 percent (%)
- Total bilirubin </=2 times the ULN
- Creatinine </=2.0 milligrams per deciliter (mg/dL), with creatinine clearance (CrCl) using the Cockcroft-Gault formula >/=40 milliliters per minute (mL/min) or 60 mL/min for those who receive lenalidomide
- Corrected calcium at or below ULN
- Transaminase levels </=2.5 times the upper limit of normal (ULN)
- Receipt of >/=1 but not more than 3 prior lines of therapy (Cohorts A, B, C, D1, E)
- Receipt of 2, but not more that 3 prior lines of therapy that must have included a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) (alone or in combination, and are refractory to the last line of treatment(Cohort D2)
- Receipt of >/=2 prior lines of therapy and progressed on treatment with an anti-CD38 monoclonal antibody and are refractory to both a PI and IMiD (Cohort D3)
- Receipt of >/=4 lines of prior therapy and are refractory to the last line of treatment (Cohort F)
- Absolute neutrophil count (ANC) >/=1000 cells per microliter (cells/mcL) (Cohorts A, B, D, E, F)
- Platelet count >/=50,000 cells/mcL, or >/=30,000 cells/mcL if more than 50% bone marrow involvement (Cohorts A, B, D, E, F)
- All participants who are prescribed lenalidomide or pomalidomide must be counseled at a minimum of every 21-28 days about pregnancy precautions and risks of fetal exposure (Cohorts B, C, E, F)
- Agree to be registered in and comply with all requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program (Cohorts B, C, E)
- Agree to be registered in and comply with all requirements of the Pomalyst REMS program (Cohort F)
- Sufficient recovery from first or second ASCT within 60-120 days of transplant (Cohort C)
- Off antibiotic/antifungal therapy for >/=14 days (Cohort C)
- Completion of any prior radiotherapy (Cohort C)
- ANC >/=1500 cells/mcL (Cohort C)
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Exclusion Criteria
- Other malignancy within 2 years prior to screening, with some exceptions
- Prior therapy with atezolizumab or other immunotherapies including CD137 agonists, anti-programmed death (PD)-1, anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and anti-PD-L1 therapeutic antibodies
- Uncontrolled cancer pain
- Treatment with any investigational drug within 30 days or 5 half-lives of the investigational drug, whichever is longer
- Known hypersensitivity to study drug and/or drug class
- History of autoimmune disease except for controlled, treated thyroidism or Type 1 diabetes
- Prior systemic anti-myeloma therapy within 14 days of Cycle 1 Day 1
- Prior treatment with chimeric antigen receptor (CAR) T cells or other forms of adoptive cellular therapy, with the exception of autologous stem cell transplantation
- Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome
- Plasma cell leukemia (greater than 2,000 cells/mcL of circulating plasma cells by standard differential)
- Immunosuppressive therapy within 6 weeks of Cycle 1 Day 1
- Daily corticosteroid requirement within 2 weeks of Cycle 1 Day 1
- Prior allogeneic stem cell transplant or solid organ transplant
- Active hepatitis B, active hepatitis C, or positive for human immunodeficiency virus (HIV)
- Uncontrolled, clinically significant pulmonary disease (for example, chronic obstructive pulmonary disease, pulmonary hypertension, idiopathic pulmonary fibrosis) that in the opinion of the investigator would put the participant at significant risk for pulmonary complications during the study
- History of pneumonitis
- Uncontrolled intercurrent illness including but not limited to uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or breastfeeding females
- Inability to tolerate thromboprophylaxis (Cohorts B, C, E, F)
- Evidence of progressive MM compared to pretransplant evaluation (Cohort C)
- Prior treatment with anti-CD38 therapy including daratumumab (Cohorts D1, D2, E, F)
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Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort E1: ATZ + DAR + LEN (Dose Escalation) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort E1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose lenalidomide in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort F2: ATZ + DAR + POM (Expansion) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort F2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the MTD of pomalidomide determined in Cohort F1 in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort is randomized. Cohort C: ATZ + LEN (Post-ASCT): Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort C will evaluate atezolizumab administered in combination with lenalidomide in participants with MM who have measureable disease after ASCT. NOTE: This cohort is closed to enrollment. Cohort D2: ATZ + DAR (Expansion) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort D2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab in participants with relapsed or refractory MM who have received 2 but no more than 3 lines of prior treatment that must have included a PI and IMiD and are refractory to the last line of treatment. Cohort D3: ATZ + DAR (Progressed) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort D3 will involve an expansion to evaluate atezolizumab in combination with daratumumab in participants with relapsed or refractory MM who have received 2 or more lines of prior treatment and have progressed with an anti-cluster of differentiation (CD) 38 monoclonal antibody, either alone or in combination, and are refractory to both a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). Cohort B1: ATZ + LEN (Dose Escalation) Lenalidomide Cohort B1 will involve a dose escalation to evaluate atezolizumab administered in combination with ascending-dose lenalidomide in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort has been completed. Cohort A: ATZ (Run-In) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort A will involve a safety run-in to evaluate atezolizumab administered as a single agent in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort has been completed. Cohort B1: ATZ + LEN (Dose Escalation) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort B1 will involve a dose escalation to evaluate atezolizumab administered in combination with ascending-dose lenalidomide in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort has been completed. Cohort D1: ATZ + DAR (Run-in) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort D1 will involve a safety run-in to evaluate atezolizumab administered in combination with daratumumab in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. Cohort F1: ATZ + DAR + POM (Dose Escalation) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort F1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose pomalidomide in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort has been completed. Cohort E2: ATZ + DAR + LEN (Expansion) Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody Cohort E2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the maximum tolerated dose (MTD) of lenalidomide determined in Cohort E1 in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort C: ATZ + LEN (Post-ASCT): Lenalidomide Cohort C will evaluate atezolizumab administered in combination with lenalidomide in participants with MM who have measureable disease after ASCT. NOTE: This cohort is closed to enrollment. Cohort D1: ATZ + DAR (Run-in) Daratumumab Cohort D1 will involve a safety run-in to evaluate atezolizumab administered in combination with daratumumab in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. Cohort D3: ATZ + DAR (Progressed) Daratumumab Cohort D3 will involve an expansion to evaluate atezolizumab in combination with daratumumab in participants with relapsed or refractory MM who have received 2 or more lines of prior treatment and have progressed with an anti-cluster of differentiation (CD) 38 monoclonal antibody, either alone or in combination, and are refractory to both a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). Cohort D2: ATZ + DAR (Expansion) Daratumumab Cohort D2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab in participants with relapsed or refractory MM who have received 2 but no more than 3 lines of prior treatment that must have included a PI and IMiD and are refractory to the last line of treatment. Cohort E1: ATZ + DAR + LEN (Dose Escalation) Lenalidomide Cohort E1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose lenalidomide in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort E1: ATZ + DAR + LEN (Dose Escalation) Daratumumab Cohort E1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose lenalidomide in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort E2: ATZ + DAR + LEN (Expansion) Daratumumab Cohort E2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the maximum tolerated dose (MTD) of lenalidomide determined in Cohort E1 in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort E2: ATZ + DAR + LEN (Expansion) Lenalidomide Cohort E2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the maximum tolerated dose (MTD) of lenalidomide determined in Cohort E1 in participants with relapsed or refractory MM who have received up to 3 lines of prior treatment. NOTE: This cohort is closed to enrollment. Cohort F1: ATZ + DAR + POM (Dose Escalation) Daratumumab Cohort F1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose pomalidomide in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort has been completed. Cohort F1: ATZ + DAR + POM (Dose Escalation) Pomalidomide Cohort F1 will involve a dose escalation to evaluate atezolizumab administered in combination with daratumumab and ascending-dose pomalidomide in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort has been completed. Cohort F2: ATZ + DAR + POM (Expansion) Daratumumab Cohort F2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the MTD of pomalidomide determined in Cohort F1 in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort is randomized. Cohort F2: ATZ + DAR + POM (Expansion) Pomalidomide Cohort F2 will involve an expansion to evaluate atezolizumab administered in combination with daratumumab and the MTD of pomalidomide determined in Cohort F1 in participants with relapsed or refractory MM who have received 4 or more lines of prior treatment and are refractory to the last line of treatment. NOTE: This cohort is randomized. Cohort F3: DAR + POM + Dexamethasone Dexamethasone Cohort F3 is an expansion control arm for cohort F2. Participants will receive daratumumab in combination with pomalidomide at the MTD and dexamethasone. NOTE: This cohort is randomized. Cohort F3: DAR + POM + Dexamethasone Pomalidomide Cohort F3 is an expansion control arm for cohort F2. Participants will receive daratumumab in combination with pomalidomide at the MTD and dexamethasone. NOTE: This cohort is randomized. Cohort F3: DAR + POM + Dexamethasone Daratumumab Cohort F3 is an expansion control arm for cohort F2. Participants will receive daratumumab in combination with pomalidomide at the MTD and dexamethasone. NOTE: This cohort is randomized.
- Primary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) From start of treatment until 30 days after last dose (up to approximately 36 months) Recommended Phase II Dose (RP2D) of Lenalidomide in the Combinations Tested From start of treatment until 30 days after last dose (up to approximately 36 months) RP2D of Pomalidomide in the Combinations Tested From start of treatment until 30 days after last dose (up to approximately 36 months) Percentage of Participants by Best Overall Response According to International Myeloma Working Group (IMWG) Criteria From Day 1 of Cycle 2 (cycle = 21 or 28 days) until progression, withdrawal, or study end (up to 36 months overall)
- Secondary Outcome Measures
Name Time Method Progression-Free Survival (PFS) According to IMWG Criteria From start of treatment until the date of first recorded progression or death from any cause (up to 36 months overall) Overall Survival From start of treatment until death from any cause (up to 36 months overall) Minimum Observed Serum Concentration (Cmin) of Atezolizumab Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 (cycle = 21 or 28 days) and Day 2 of Cycle 1; then every 8 cycles until/at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall) Duration of Response (DOR) According to IMWG Criteria From first observed response until the date of first recorded progression or death from any cause (up to 36 months overall) Cmax of Daratumumab From predose (0 h) on Day 1 of Cycle 1 until treatment discontinuation (up to 36 months overall); see Outcome Measure Description for details Predose (0 h) and postdose (0.5 h) (infusion \~3-6 h) on Day 1 of Cycles 1, 3 (cycle = 28 days); predose (0 h) on Day 1 of Cycles 2, 4, 8; then every 8 cycles until/at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall)
Cmin of Daratumumab Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 (cycle = 28 days); then every 8 cycles until/at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall) Change in Number of Participants With ADA Response to Daratumumab from Baseline to End of Study From treatment start until study end; assessed predose (0 h) on Day 1 of Cycles 1, 3, 8 (cycle = 28 days); at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall) Percentage of Participants with Objective Response According to IMWG Criteria From Day 1 of Cycle 2 until progression, withdrawal, or study end (up to 36 months overall). For Cohort D3 Only: 6, 9, and 12 months. Maximum Observed Serum Concentration (Cmax) of Atezolizumab From predose (0 hours [h]) on Day 1 of Cycle 1 until treatment discontinuation (up to 36 months overall); see Outcome Measure Description for details Predose (0 h) and postdose (0.5 h) (infusion = 0.5-1 h) on Day 1 of Cycles 1, 3 (cycle = 21 or 28 days) and Day 2 of Cycle 1; predose (0 h) on Day 1 of Cycles 2, 4, 8; then every 8 cycles until/at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall)
Cmax of Lenalidomide Predose (0 h) and postdose (1 h) on Day 1 of Cycles 1, 4 (cycle = 21 days); predose (0 h) and postdose (0.5, 1, 2, 4, 8 h) on Day 15 of Cycles 1, 3; predose (0 h) and postdose (2 h) on Day 15 of Cycles 2, 4, 8 Cmin of Lenalidomide Predose (0 h) on Day 1 of Cycles 1, 4 (cycle = 21 days) and Day 15 of Cycles 1, 2, 3, 4, 8 Change in Number of Participants With Anti-Drug Antibody (ADA) Response to Atezolizumab from Baseline to End of Study From treatment start until study end (up to 36 months overall); see Outcome Measure Description for details From treatment start until study end; assessed predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 (cycle = 21 or 28 days) and Day 2 of Cycle 1; then every 8 cycles until/at treatment discontinuation (up to 36 months); and 90 days after last dose (up to 36 months overall)
Cmax of Pomalidomide Predose (0 h) and postdose (1, 2, 4, 6, 8 h) on Day 15 of Cycles 1, 3 (cycle = 28 days); predose (0 h) and postdose (4 h) on Day 15 of Cycles 2, 4, 8 Cmin of Pomalidomide Predose (0 h) on Day 15 of Cycles 1, 2, 3, 4, 8 (cycle = 28 days)
Trial Locations
- Locations (31)
University of Maryland School of Medicine
🇺🇸Baltimore, Maryland, United States
Mayo Clinic Hospital - Florida
🇺🇸Jacksonville, Florida, United States
Emory Univ Winship Cancer Inst
🇺🇸Atlanta, Georgia, United States
Loyola University Med Center
🇺🇸Maywood, Illinois, United States
Indiana University Health; Goshen Center for Cancer Care
🇺🇸Goshen, Indiana, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Henderson, Nevada, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mount SInai Medical Center
🇺🇸New York, New York, United States
UNC Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Lifespan Cancer Institute
🇺🇸Providence, Rhode Island, United States
Texas Oncology-Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
Medical University of South Carolina; Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
UT Southwestern MC at Dallas
🇺🇸Dallas, Texas, United States
University Of Arkansas
🇺🇸Little Rock, Arkansas, United States
Yale University
🇺🇸New Haven, Connecticut, United States
University of Louisville
🇺🇸Louisville, Kentucky, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
UC Davis; Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Indiana University Department of Medicine; IU Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Med Ctr; Hem/Onc
🇺🇸Boston, Massachusetts, United States
Univ of Michigan Medical Ctr
🇺🇸Ann Arbor, Michigan, United States
Karmanos Cancer Institute.
🇺🇸Detroit, Michigan, United States
Henry Ford Hospital; Hematology Oncology
🇺🇸Detroit, Michigan, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
University of Oklahoma Health Sciences Center; Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Houston Methodist Cancer Center
🇺🇸Houston, Texas, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
Scripps Clinic Torrey Pines
🇺🇸La Jolla, California, United States