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

NCT02508870 | Completed Phase 1

• 1 other identifier: GO29754
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 15

Brief Summary

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.

Conditions

Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants with DLTs

  Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28

• Recommended Phase 2 Dose (RP2D) of Atezolizumab in Combination with Azacitidine

  Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28

• Percentage of Participants with Adverse Events (AEs)

  Baseline up to approximately 3.5 years

Secondary Outcomes (18)

• Cohorts A and A2: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab

  Pre-infusion (0 hour [0h]) on Day 1 (D1) of Cycles (Cy) 1, 2, 3, 4, 8, 12, and 16, end of treatment (EOT) (up to approximately 3.5 years [Yr]), and 90 days after last dose (up to approximately 3.5 Yr) (Cy length = 21 days)

• Cohorts B and B2: Percentage of Participants with ADAs to Atezolizumab

  Pre-infusion (0h) on Cy1, 2 Days 8 (D8) & 22 (D22) & Cy3 D8; pre-infusion (0h) on Cy7 D1 & then every 8 Cy up to EOT (approximately 3.5 Yr) and 90 days after last dose (approximately 3.5 Yr) (Cy length = 21 or 28 days)

• Cohorts C1 and C2: Percentage of Participants with ADAs to Atezolizumab

  Pre-infusion (0h) on Cy1, 2 D8 & D22 & Cy3 D8; pre-infusion (0h) on Cy7 D8 & then every 8 Cy up to EOT (approximately 3.5 Yr) and 90 days after last dose (approximately 3.5 Yr) (Cy length = 21 or 28 days)

• Cohorts A and A2: Maximum Serum Concentration (Cmax) of Atezolizumab

  Pre-infusion (0h), 30 minutes (min) post 60-min infusion on Cy 1 D1; pre-infusion (0h) on D1 of Cy 2, 3, 4, 8, 12, & 16, EOT (approximately 3.5 Yr); 90 days after EOT (approximately 3.5 Yr) (Cy length = 21 days)

• Cohorts B and B2: Cmax of Atezolizumab

  Pre-infusion (0h), 30 min post 60-min infusion on Cy1D8; pre-infusion (0h) on Cy1D22, Cy2D8 & 22, Cy3D8, Cy7D1, every 8 Cy up to EOT (approximately 3.5 Yr); 90 days after EOT (approximately 3.5 Yr) (1 Cy = 21 or 28 days)

Study Arms (6)

Cohort A: Atezolizumab - HMA R/R MDS

EXPERIMENTAL

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.

Drug: Atezolizumab

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Azacitidine

Cohort C1: Atezolizumab+Azacitidine - HMA-Naive MDS

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Azacitidine

Cohort C2: Atezolizumab+Azacitidine - HMA-Naive MDS

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Azacitidine

Cohort A2: Atezolizumab - HMA R/R MDS

EXPERIMENTAL

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.

Drug: Atezolizumab

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

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Azacitidine

Interventions

Atezolizumab DRUG

Participants will receive atezolizumab as per the schedule described in individual cohort.

Also known as: Tecentriq, MPDL3280A, RO5541267

Cohort A2: Atezolizumab - HMA R/R MDS; Cohort A: Atezolizumab - HMA R/R MDS; Cohort B2: Atezolizumab+Azacitidine - HMA R/R MDS; Cohort B: Atezolizumab+Azacitidine - HMA R/R MDS; Cohort C1: Atezolizumab+Azacitidine - HMA-Naive MDS; Cohort C2: Atezolizumab+Azacitidine - HMA-Naive MDS

Azacitidine DRUG

Participants will receive azacitidine as per the schedule described in individual cohort.

Also known as: Vidaza

Cohort B2: Atezolizumab+Azacitidine - HMA R/R MDS; Cohort B: Atezolizumab+Azacitidine - HMA R/R MDS; Cohort C1: Atezolizumab+Azacitidine - HMA-Naive MDS; Cohort C2: Atezolizumab+Azacitidine - HMA-Naive MDS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (15)

City of Hope

Duarte, California, 91010, United States

Location

Stanford University

Palo Alto, California, 94305, United States

Location

University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94158, United States

Location

University of Colorado Hospital - Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

University of Kansas Medical Center

Westwood, Kansas, 66205, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Nebraska Medical Center; UNMC Oncology/Hematology

Omaha, Nebraska, 68198-7680, United States

Location

Roswell Park Cancer Institute; Grace Cancer Drug Center

Buffalo, New York, 14263, United States

Location

Montefiore Einstein Cancer Center

The Bronx, New York, 10461, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44915, United States

Location

Medical University of South Carolina; Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

University of Virginia Health System; Hematology/Oncology Division

Charlottesville, Virginia, 22908, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• Gerds AT, Scott BL, Greenberg P, Lin TL, Pollyea DA, Verma A, Dail M, Feng Y, Green C, Ma C, Medeiros BC, Yan M, Yousefi K, Donnellan W. Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Blood Adv. 2022 Feb 22;6(4):1152-1161. doi: 10.1182/bloodadvances.2021005240.

  PMID: 34932793 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

atezolizumab; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2015
• First Posted: July 27, 2015
• Study Start: September 30, 2015
• Primary Completion: June 10, 2019
• Study Completion: June 10, 2019
• Last Updated: August 19, 2019

Record last verified: 2019-08

Locations

US (15)