Clinical trial NCT02431208: 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)
Official title: A Phase Ib Study of the Safety and Pharmacokinetics of Atezolizumab (Anti-PD-L1 Antibody) Alone or in Combination With an Immunomodulatory Drug and/or Daratumumab in Patients With Multiple Myeloma (Relapsed/Refractory and Post-Autologous Stem Cell Transplantation)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-04-30
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

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)

Primary outcomes:
measure: Percentage of Participants by Best Overall Response According to International Myeloma Working Group (IMWG) Criteria
timeFrame: From Day 1 of Cycle 2 (cycle = 21 or 28 days) until progression, withdrawal, or study end (up to 36 months overall)
measure: Recommended Phase II Dose (RP2D) of Lenalidomide in the Combinations Tested
timeFrame: From start of treatment until 30 days after last dose (up to approximately 36 months)
measure: RP2D of Pomalidomide in the Combinations Tested
timeFrame: From start of treatment until 30 days after last dose (up to approximately 36 months)
measure: Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: From start of treatment until 30 days after last dose (up to approximately 36 months)
Secondary outcomes:
measure: Duration of Response (DOR) According to IMWG Criteria
timeFrame: From first observed response until the date of first recorded progression or death from any cause (up to 36 months overall)
measure: Progression-Free Survival (PFS) According to IMWG Criteria
timeFrame: From start of treatment until the date of first recorded progression or death from any cause (up to 36 months overall)
measure: Percentage of Participants with Objective Response According to IMWG Criteria
timeFrame: 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.
measure: Overall Survival
timeFrame: From start of treatment until death from any cause (up to 36 months overall)
measure: Maximum Observed Serum Concentration (Cmax) of Atezolizumab
timeFrame: 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
measure: Minimum Observed Serum Concentration (Cmin) of Atezolizumab
timeFrame: 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)
measure: Cmax of Lenalidomide
timeFrame: 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
measure: Cmin of Lenalidomide
timeFrame: Predose (0 h) on Day 1 of Cycles 1, 4 (cycle = 21 days) and Day 15 of Cycles 1, 2, 3, 4, 8
measure: Cmax of Pomalidomide
timeFrame: 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
measure: Cmin of Pomalidomide
timeFrame: Predose (0 h) on Day 15 of Cycles 1, 2, 3, 4, 8 (cycle = 28 days)
measure: Cmax of Daratumumab
timeFrame: From predose (0 h) on Day 1 of Cycle 1 until treatment discontinuation (up to 36 months overall); see Outcome Measure Description for details
measure: Cmin of Daratumumab
timeFrame: 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)
measure: Change in Number of Participants With Anti-Drug Antibody (ADA) Response to Atezolizumab from Baseline to End of Study
timeFrame: From treatment start until study end (up to 36 months overall); see Outcome Measure Description for details
measure: Change in Number of Participants With ADA Response to Daratumumab from Baseline to End of Study
timeFrame: 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)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: University Of Arkansas
state: Arkansas
city: La Jolla
country: United States
facility: Scripps Clinic Torrey Pines
state: California
city: Sacramento
country: United States
facility: UC Davis; Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Hospital - Florida
state: Florida
city: Atlanta
country: United States
facility: Emory Univ Winship Cancer Inst
state: Georgia
city: Maywood
country: United States
facility: Loyola University Med Center
state: Illinois
city: Goshen
country: United States
facility: Indiana University Health; Goshen Center for Cancer Care
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Department of Medicine; IU Simon Cancer Center
state: Indiana
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr; Hem/Onc
state: Massachusetts
city: Ann Arbor
country: United States
facility: Univ of Michigan Medical Ctr
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute.
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital; Hematology Oncology
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: Mount SInai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center; Stephenson Cancer Center
state: Oklahoma
city: Providence
country: United States
facility: Lifespan Cancer Institute
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina; Hollings Cancer Center
state: South Carolina
city: Dallas
country: United States
facility: Texas Oncology-Baylor Sammons Cancer Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern MC at Dallas
state: Texas
city: Houston
country: United States
facility: Houston Methodist Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: