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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02508870
• Other study ID #: GO29754
• Status: Completed
• Phase: Phase 1
• Start date: September 30, 2015
• Est. completion date: June 10, 2019

Study information

• Verified date: August 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: June 10, 2019
• Est. primary completion date: June 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Atezolizumab
Participants will receive atezolizumab as per the schedule described in individual cohort.
• Azacitidine
Participants will receive azacitidine as per the schedule described in individual cohort.

Locations

Country	Name	City	State
United States	University of Colorado Hospital - Anschutz Cancer Pavilion	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Einstein Cancer Center	Bronx	New York
United States	Roswell Park Cancer Institute; Grace Cancer Drug Center	Buffalo	New York
United States	Medical University of South Carolina; Hollings Cancer Center	Charleston	South Carolina
United States	University of Virginia Health System; Hematology/Oncology Division	Charlottesville	Virginia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	City of Hope	Duarte	California
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	University of Nebraska Medical Center; UNMC Oncology/Hematology	Omaha	Nebraska
United States	Stanford University	Palo Alto	California
United States	University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	University of Kansas Medical Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants with DLTs		Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28
Primary	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
Primary	Percentage of Participants with Adverse Events (AEs)		Baseline up to approximately 3.5 years
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Cohorts A, A2, B, and B2: Overall Survival (OS)		Randomization up to death due to any cause (up to approximately 3.5 years)
Secondary	Percentage of Participants With Change in Red Cell and Platelet Transfusion		Baseline up to approximately 3.5 years
Secondary	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)
Secondary	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)