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)

Multiple Myeloma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02431208
• Other study ID #: GO29695
• Status: Completed
• Phase: Phase 1
• Start date: July 22, 2015
• Est. completion date: March 19, 2021

Study information

• Verified date: March 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: March 19, 2021
• Est. primary completion date: March 19, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
Participants will receive intravenous (IV) atezolizumab until loss of clinical benefit, withdrawal, or study end. Cohorts A to C will receive 1200 milligrams (mg) on Day 1 of each 21-day cycle. Cohorts D to F (combination with daratumumab) will receive 840 mg on Days 2 and 16 of Cycle 1 and on Days 1 and 15 of each 28-day cycle thereafter.
• Daratumumab
Participants will receive 16 milligrams per kilogram (mg/kg) IV daratumumab until loss of clinical benefit, withdrawal, or study end. Treatment will be per the U.S. Package Insert and given on Days 1, 8, 15, 22 of Cycles 1 and 2; on Days 1 and 15 of Cycles 3 to 6; and on Day 1 of each 28-day cycle thereafter.
• Lenalidomide
Lenalidomide will be administered orally (PO) until loss of clinical benefit, withdrawal, or study end. Cohort B1 will receive 10, 15, or 25 mg, ascending-dose lenalidomide, on Days 1-14 of each 21-day cycle. Cohort C will receive 10 mg on Days 1-14 of each 21-day cycle, beginning in Cycle 4. Cohort E (combination with daratumumab) will receive 10, 15, or 25 mg on Days 1-21 of each 28-day cycle. Participants in Cohort E1 will receive ascending-dose lenalidomide, and those in Cohort E2 will receive lenalidomide at the MTD as determined in Cohort E1.
• Pomalidomide
Pomalidomide will be administered PO until loss of clinical benefit, withdrawal, or study end. Cohort F (combination with daratumumab) will receive 2 or 4 mg on Days 1-21 of each 28-day cycle. Participants in Cohort F1 will receive ascending-dose pomalidomide, and those in Cohort F2 will receive pomalidomide at the MTD as determined in Cohort F1.
• Dexamethasone
Participants will receive either 20mg or 40mg of dexamethasone PO every 7 days from Day 1 of each cycle.

Locations

Country	Name	City	State
United States	Univ of Michigan Medical Ctr	Ann Arbor	Michigan
United States	Emory Univ Winship Cancer Inst	Atlanta	Georgia
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Med Ctr; Hem/Onc	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	UNC Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina; Hollings Cancer Center	Charleston	South Carolina
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Texas Oncology-Baylor Sammons Cancer Center	Dallas	Texas
United States	UT Southwestern MC at Dallas	Dallas	Texas
United States	Henry Ford Hospital; Hematology Oncology	Detroit	Michigan
United States	Karmanos Cancer Institute.	Detroit	Michigan
United States	Indiana University Health; Goshen Center for Cancer Care	Goshen	Indiana
United States	Comprehensive Cancer Centers of Nevada	Henderson	Nevada
United States	Houston Methodist Cancer Center	Houston	Texas
United States	Indiana University Department of Medicine; IU Simon Cancer Center	Indianapolis	Indiana
United States	Mayo Clinic Hospital - Florida	Jacksonville	Florida
United States	Scripps Clinic Torrey Pines	La Jolla	California
United States	University Of Arkansas	Little Rock	Arkansas
United States	University of Louisville	Louisville	Kentucky
United States	Loyola University Med Center	Maywood	Illinois
United States	Yale University	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount SInai Medical Center	New York	New York
United States	University of Oklahoma Health Sciences Center; Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Lifespan Cancer Institute	Providence	Rhode Island
United States	UC Davis; Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	RP2D of Pomalidomide in the Combinations Tested		From start of treatment until 30 days after last dose (up to approximately 36 months)
Primary	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)
Secondary	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)
Secondary	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)
Secondary	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.
Secondary	Overall Survival		From start of treatment until death from any cause (up to 36 months overall)
Secondary	Maximum Observed Serum Concentration (Cmax) of Atezolizumab	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)	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Cmin of Pomalidomide		Predose (0 h) on Day 15 of Cycles 1, 2, 3, 4, 8 (cycle = 28 days)
Secondary	Cmax of Daratumumab	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)	From predose (0 h) on Day 1 of Cycle 1 until treatment discontinuation (up to 36 months overall); see Outcome Measure Description for details
Secondary	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)
Secondary	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; 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)	From treatment start until study end (up to 36 months overall); see Outcome Measure Description for details
Secondary	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)