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)

Roche

Status and phase: Completed; Phase 1

Conditions: Multiple Myeloma

Treatments: Drug: Daratumumab; Drug: Pomalidomide; Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody; Drug: Lenalidomide; Drug: Dexamethasone

Study type: Interventional

Funder types: Industry

Identifiers

NCT02431208

GO29695

Details and patient eligibility

About

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.

Enrollment: 85 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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85 participants in 11 patient groups

Cohort A: ATZ (Run-In)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Cohort B1: ATZ + LEN (Dose Escalation)

Experimental group

Description:

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.

Treatment:

Drug: Lenalidomide

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Cohort C: ATZ + LEN (Post-ASCT):

Experimental group

Description:

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.

Treatment:

Drug: Lenalidomide

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Cohort D1: ATZ + DAR (Run-in)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Daratumumab

Cohort D2: ATZ + DAR (Expansion)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Daratumumab

Cohort D3: ATZ + DAR (Progressed)

Experimental group

Description:

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).

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Daratumumab

Cohort E1: ATZ + DAR + LEN (Dose Escalation)

Experimental group

Description:

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.

Treatment:

Drug: Lenalidomide

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Daratumumab

Cohort E2: ATZ + DAR + LEN (Expansion)

Experimental group

Description:

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.

Treatment:

Drug: Lenalidomide

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Daratumumab

Cohort F1: ATZ + DAR + POM (Dose Escalation)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Pomalidomide

Drug: Daratumumab

Cohort F2: ATZ + DAR + POM (Expansion)

Active Comparator group

Description:

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.

Treatment:

Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody

Drug: Pomalidomide

Drug: Daratumumab

Cohort F3: DAR + POM + Dexamethasone

Active Comparator group

Description:

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.

Treatment:

Drug: Dexamethasone

Drug: Pomalidomide

Drug: Daratumumab