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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atezolizumab | Drug | Participants will receive atezolizumab as per the schedule described in individual cohort. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope | Duarte | California | 91010 | United States | ||
| Stanford University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34932793 | Derived | 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. |
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| 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. |
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| 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. |
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| 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. |
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| Azacitidine | Drug | Participants will receive azacitidine as per the schedule described in individual cohort. |
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| 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) |
| Cohorts C1 and C2: Cmax of Atezolizumab | Pre-infusion (0h), 30 min post 60-min infusion on Cy1D8; pre-infusion (0h) on Cy1D22, Cy2D8 & 22, Cy3D8, Cy7D8, every 8 Cy up to EOT (approximately 3.5 Yr); 90 days after EOT (approximately 3.5 Yr) (1 Cy = 21 or 28 days) |
| Cohorts A and A2: Minimum Serum Concentration (Cmin) 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: Cmin 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) |
| Cohorts C1 and C2: Cmin of Atezolizumab | Pre-infusion (0h), 30 min post 60-min infusion on Cy1D8; pre-infusion (0h) on Cy1D22, Cy2D8 & 22, Cy3D8, Cy7D8, every 8 Cy up to EOT (approximately 3.5 Yr); 90 days after EOT (approximately 3.5 Yr) (1 Cy = 21 or 28 days) |
| Percentage of Participants with Overall Response, According to 2006 International Working Group (IWG) Response Criteria for MDS | Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years) |
| Percentage of Participants with Overall Response After Induction Therapy, According to 2006 IWG Response Criteria for MDS | After end of induction up to disease progression or death, whichever occurs first (up to approximately 3.5 years) |
| Duration of Clinical Response, According to 2006 IWG Response Criteria for MDS | Time from the initial overall response to the time of disease progression or death, whichever occurs first (up to approximately 3.5 years) |
| Time to Acute Myeloid Leukemia (AML) Progression, According to 2006 IWG Response Criteria for MDS | Randomization up to the date of AML progression (up to approximately 3.5 years) |
| Progression Free Survival (PFS), According to 2006 IWG Response Criteria for MDS | Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years) |
| Cohorts A, A2, B, and B2: Overall Survival (OS) | Randomization up to death due to any cause (up to approximately 3.5 years) |
| Percentage of Participants With Change in Red Cell and Platelet Transfusion | Baseline up to approximately 3.5 years |
| Cohorts A2 or B2: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score | D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days) |
| Cohorts A2 and B2: Functional Assessment of Chronic Illness Therapy Fatigue Questionnaire (FACIT-Fatigue) Score | D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days) |
| Palo Alto |
| California |
| 94305 |
| United States |
| University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center | San Francisco | California | 94158 | United States |
| University of Colorado Hospital - Anschutz Cancer Pavilion | Aurora | Colorado | 80045 | United States |
| University of Kansas Medical Center | Westwood | Kansas | 66205 | United States |
| Dana Farber Cancer Institute | Boston | Massachusetts | 02215 | United States |
| University of Nebraska Medical Center; UNMC Oncology/Hematology | Omaha | Nebraska | 68198-7680 | United States |
| Roswell Park Cancer Institute; Grace Cancer Drug Center | Buffalo | New York | 14263 | United States |
| Montefiore Einstein Cancer Center | The Bronx | New York | 10461 | United States |
| Cleveland Clinic Foundation | Cleveland | Ohio | 44915 | United States |
| Medical University of South Carolina; Hollings Cancer Center | Charleston | South Carolina | 29425 | United States |
| Sarah Cannon Research Institute | Nashville | Tennessee | 37203 | United States |
| The University of Texas MD Anderson Cancer Center | Houston | Texas | 77030-4009 | United States |
| University of Virginia Health System; Hematology/Oncology Division | Charlottesville | Virginia | 22908 | United States |
| Fred Hutchinson Cancer Research Center | Seattle | Washington | 98109 | United States |
| ID | Term |
|---|---|
| D009190 | Myelodysplastic Syndromes |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C000594389 | atezolizumab |
| D001374 | Azacitidine |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
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