Clinical trial NCT02508870: A Study of Atezolizumab Administered Alone or in Combination With Azacitidine in Participants With Myelodysplastic Syndromes
Official title: A Phase Ib Study of the Safety and Pharmacology of Atezolizumab (Anti-PD-L1 Antibody) Administered Alone or in Combination With Azacitidine in Patients With Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-07-27
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with DLTs
timeFrame: Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28
measure: Recommended Phase 2 Dose (RP2D) of Atezolizumab in Combination with Azacitidine
timeFrame: Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Baseline up to approximately 3.5 years
Secondary outcomes:
measure: Cohorts A and A2: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: 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)
measure: Cohorts B and B2: Percentage of Participants with ADAs to Atezolizumab
timeFrame: 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)
measure: Cohorts C1 and C2: Percentage of Participants with ADAs to Atezolizumab
timeFrame: 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)
measure: Cohorts A and A2: Maximum Serum Concentration (Cmax) of Atezolizumab
timeFrame: 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)
measure: Cohorts B and B2: Cmax of Atezolizumab
timeFrame: 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)
measure: Cohorts C1 and C2: Cmax of Atezolizumab
timeFrame: 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)
measure: Cohorts A and A2: Minimum Serum Concentration (Cmin) of Atezolizumab
timeFrame: 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)
measure: Cohorts B and B2: Cmin of Atezolizumab
timeFrame: 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)
measure: Cohorts C1 and C2: Cmin of Atezolizumab
timeFrame: 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)
measure: Percentage of Participants with Overall Response, According to 2006 International Working Group (IWG) Response Criteria for MDS
timeFrame: Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
measure: Percentage of Participants with Overall Response After Induction Therapy, According to 2006 IWG Response Criteria for MDS
timeFrame: After end of induction up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
measure: Duration of Clinical Response, According to 2006 IWG Response Criteria for MDS
timeFrame: Time from the initial overall response to the time of disease progression or death, whichever occurs first (up to approximately 3.5 years)
measure: Time to Acute Myeloid Leukemia (AML) Progression, According to 2006 IWG Response Criteria for MDS
timeFrame: Randomization up to the date of AML progression (up to approximately 3.5 years)
measure: Progression Free Survival (PFS), According to 2006 IWG Response Criteria for MDS
timeFrame: Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
measure: Cohorts A, A2, B, and B2: Overall Survival (OS)
timeFrame: Randomization up to death due to any cause (up to approximately 3.5 years)
measure: Percentage of Participants With Change in Red Cell and Platelet Transfusion
timeFrame: Baseline up to approximately 3.5 years
measure: Cohorts A2 or B2: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
timeFrame: D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days)
measure: Cohorts A2 and B2: Functional Assessment of Chronic Illness Therapy Fatigue Questionnaire (FACIT-Fatigue) Score
timeFrame: D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion
state: Colorado
city: Westwood
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center; UNMC Oncology/Hematology
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Einstein Cancer Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute; Grace Cancer Drug Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina; Hollings Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System; Hematology/Oncology Division
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.