A Study of Atezolizumab Administered Alone or in Combination With Azacitidine in Participants With Myelodysplastic Syndromes

Roche

Status and phase: Completed; Phase 1

Conditions: Myelodysplastic Syndromes

Treatments: Drug: Azacitidine; Drug: Atezolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT02508870

GO29754

Details and patient eligibility

About

This is a multicenter, open-label, Phase 1b study of atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1] monoclonal antibody) in participants who have hypomethylating agent (HMA)-naïve myelodysplastic syndromes (MDS) and are International Prognostic Scoring System-Revised (IPSS-R) intermediate/high/very high-risk, or have MDS relapsed or are refractory (R/R) to prior HMA therapy. The primary objectives of this study are to determine the safety and tolerability of atezolizumab therapy in these participant populations, including treatment in combination with azacitidine.

Enrollment: 46 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Diagnosis of MDS (participants with therapy-related MDS are eligible)
• Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to (</=) 2
• Adequate end-organ function, as determined by laboratory tests obtained within 28 days prior to the first dose of study drug
• Willing and able to undergo a pre-treatment bone marrow biopsy and subsequent on-treatment bone marrow biopsies
• Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 28 days prior to initiation of study drug
• For women of childbearing potential and men: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures

For participants in Cohorts A, A2, B, and B2:

• Progression at any time after initiation of azacitidine or decitabine treatment OR
• Failure to achieve complete or partial response or hematological improvement after at least six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine OR
• Relapse after initial complete or partial response or hematological improvement after six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine administered within the past 2 years

For participants in Cohorts C1 and C2:

• Must not have received prior treatment for MDS with any hypomethylating agent
• IPSS-R risk category of Intermediate, High, or Very High assessed at screening

Exclusion criteria

• Participants with a diagnosis of MDS secondary to paroxysmal nocturnal hemoglobinuria (PNH), aplastic anemia, or another inherited bone marrow failure disorder
• Prior allogeneic stem cell transplant or solid organ transplant
• Pregnant or lactating, or intending to become pregnant during the study
• Investigational therapy within 28 days prior to initiation of study treatment
• Immunosuppressive therapy within 6 weeks of Cycle 1, Day 1
• Prior treatment with immune checkpoint blockade therapies (anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], anti-programmed death-1 [PD-1] or anti-PD-L1) or immune agonists (anti-cluster of differentiation [CD] 137, anti-CD40, anti-OX40)
• Any other therapy or serious medical condition, as specified in the protocol, or abnormality in clinical laboratory tests that, in the investigator's judgement, precludes the participant's safe participation in and completion of the study
• Left ventricular ejection fraction (LVEF) </= 40 percent (%) at screening
• Planned major surgery during the study or within 4 weeks of Cycle 1, Day 1
• History of idiopathic pulmonary fibrosis, organizing pneumonitis, drug-induced pneumonitis, or idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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46 participants in 6 patient groups

Cohort A: Atezolizumab - HMA R/R MDS

Experimental group

Description:

Participants with MDS who are HMA R/R will receive atezolizumab 1200 milligrams (mg) intravenous (IV) infusion every 3 weeks (Q3W) (21-day cycle). Treatment will continue for up to 17 cycles or until loss of clinical benefit, evidence of unacceptable toxicity, non-compliance with the protocol, voluntary withdrawal from the study, or study termination, whichever occurs first. Participants who achieve/maintain a partial response (PR) or hematological improvement (HI) after receiving 17 cycles of therapy may continue on study treatment beyond Cycle 17 until loss of clinical benefit.

Treatment:

Drug: Atezolizumab

Cohort B: Atezolizumab+Azacitidine - HMA R/R MDS

Experimental group

Description:

Induction: Participants with MDS who are HMA R/R will receive atezolizumab 840 mg IV infusion on Days 8 and 22 of each 28-day cycle along with azacitidine 75 milligrams per square meter (mg/m\^2) subcutaneously (SC) on Days 1 to 7 of 28-day cycle, for 6 cycles. Maintenance: Participants who complete induction treatment will receive atezolizumab 1200 mg IV infusion Q3W (21-day cycle) for up to 8 additional cycles. Participants who achieve/maintain a PR or HI after completing the 8 cycles of atezolizumab maintenance therapy, may continue on study treatment until loss of clinical benefit.

Treatment:

Drug: Atezolizumab

Drug: Azacitidine

Cohort C1: Atezolizumab+Azacitidine - HMA-Naive MDS

Experimental group

Description:

Participants with MDS who are HMA-naive will receive atezolizumab 840 mg IV infusion on Days 8 and 22 of each 28-day cycle along with azacitidine 75 mg/m\^2 SC on Days 1 to 7 of 28-day cycle, until loss of clinical benefit, evidence of unacceptable toxicity, non-compliance with the protocol, voluntary withdrawal from the study, or study termination, whichever occurs first.

Treatment:

Drug: Atezolizumab

Drug: Azacitidine

Cohort C2: Atezolizumab+Azacitidine - HMA-Naive MDS

Experimental group

Description:

If the participants enrolled in Cohort C1 fulfil the dose limiting toxicity (DLT) criteria, then additional participants with MDS who are HMA-naïve will receive atezolizumab 840 mg IV infusion on Days 8 and 22 of each 28-day cycle along with azacitidine 75 mg/m\^2 SC on Days 1 to 7 of 28-day cycle, until loss of clinical benefit, evidence of unacceptable toxicity, non-compliance with the protocol, voluntary withdrawal from the study, or study termination, whichever occurs first.

Treatment:

Drug: Atezolizumab

Drug: Azacitidine

Cohort A2: Atezolizumab - HMA R/R MDS

Experimental group

Description:

If atezolizumab alone or in combination with azacitidine is found to be initially safe and tolerable in participants with HMA R/R MDS in both Cohorts A and B, then additional randomly assigned participants will receive atezolizumab 1200 mg IV infusion Q3W (21-day cycle). Treatment will continue for up to 17 cycles or until loss of clinical benefit, evidence of unacceptable toxicity, non-compliance with the protocol, voluntary withdrawal from the study, or study termination, whichever occurs first. Participants who achieve/maintain a PR or HI after receiving 17 cycles of therapy may continue on study treatment beyond Cycle 17 until loss of clinical benefit.

Treatment:

Drug: Atezolizumab

Cohort B2: Atezolizumab+Azacitidine - HMA R/R MDS

Experimental group

Description:

If atezolizumab alone or in combination with azacitidine is found to be initially safe and tolerable in participants with HMA R/R MDS in both Cohorts A and B, then additional randomly assigned participants will receive atezolizumab 840 mg IV infusion on Days 8 and 22 of each 28-day cycle along with azacitidine 75 mg/m\^2 SC on Days 1 to 7 of 28-day cycle, for 6 cycles during induction. Participants who complete induction treatment will receive maintenance atezolizumab 1200 mg IV infusion Q3W (21-day cycle) for up to 8 additional cycles. Participants who achieve/maintain a PR or HI after completing the 8 cycles of atezolizumab maintenance therapy, may continue on study treatment until loss of clinical benefit.

Treatment:

Drug: Atezolizumab

Drug: Azacitidine