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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT02508870

Collaborator

(none)

Enrollment

Locations

Arms

44.3

Actual Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Atezolizumab Drug: Azacitidine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 30, 2015

Actual Primary Completion Date :

Jun 10, 2019

Actual Study Completion Date :

Jun 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Atezolizumab - HMA R/R MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267
Experimental: Cohort B: Atezolizumab+Azacitidine - HMA R/R MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267 Drug: Azacitidine Participants will receive azacitidine as per the schedule described in individual cohort. Other Names: Vidaza
Experimental: Cohort C1: Atezolizumab+Azacitidine - HMA-Naive MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267 Drug: Azacitidine Participants will receive azacitidine as per the schedule described in individual cohort. Other Names: Vidaza
Experimental: Cohort C2: Atezolizumab+Azacitidine - HMA-Naive MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267 Drug: Azacitidine Participants will receive azacitidine as per the schedule described in individual cohort. Other Names: Vidaza
Experimental: Cohort A2: Atezolizumab - HMA R/R MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267
Experimental: Cohort B2: Atezolizumab+Azacitidine - HMA R/R MDS 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 Participants will receive atezolizumab as per the schedule described in individual cohort. Other Names: Tecentriq MPDL3280A RO5541267 Drug: Azacitidine Participants will receive azacitidine as per the schedule described in individual cohort. Other Names: Vidaza

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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)]
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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Stanford University	Palo Alto	California	United States	94305
3	University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94158
4	University of Colorado Hospital - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
5	University of Kansas Medical Center	Westwood	Kansas	United States	66205
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	University of Nebraska Medical Center; UNMC Oncology/Hematology	Omaha	Nebraska	United States	68198-7680
8	Montefiore Einstein Cancer Center	Bronx	New York	United States	10461
9	Roswell Park Cancer Institute; Grace Cancer Drug Center	Buffalo	New York	United States	14263
10	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44915
11	Medical University of South Carolina; Hollings Cancer Center	Charleston	South Carolina	United States	29425
12	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
13	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
14	University of Virginia Health System; Hematology/Oncology Division	Charlottesville	Virginia	United States	22908
15	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109