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.
Brief Title
A Study of Atezolizumab Administered Alone or in Combination With Azacitidine in Participants With Myelodysplastic Syndromes
Categories
Completion Date
Completion Date Type
Actual
Conditions
Myelodysplastic Syndromes
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.
* 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.
Inclusion 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
* 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02508870
Org Class
Industry
Org Full Name
Hoffmann-La Roche
Org Study Id
GO29754
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Measure
Percentage of Participants with DLTs
Outcome Time Frame
Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28
Outcome Measure
Recommended Phase 2 Dose (RP2D) of Atezolizumab in Combination with Azacitidine
Outcome Time Frame
Cohort A: Days 1 to 21; Cohorts B and C1: Days 1 to 28
Outcome Measure
Percentage of Participants with Adverse Events (AEs)
Outcome Time Frame
Baseline up to approximately 3.5 years
Secondary Outcomes
Outcome Time Frame
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)
Outcome Measure
Cohorts A and A2: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts B and B2: Percentage of Participants with ADAs to Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts C1 and C2: Percentage of Participants with ADAs to Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts A and A2: Maximum Serum Concentration (Cmax) of Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts B and B2: Cmax of Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts C1 and C2: Cmax of Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts A and A2: Minimum Serum Concentration (Cmin) of Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts B and B2: Cmin of Atezolizumab
Outcome Time Frame
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)
Outcome Measure
Cohorts C1 and C2: Cmin of Atezolizumab
Outcome Time Frame
Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
Outcome Measure
Percentage of Participants with Overall Response, According to 2006 International Working Group (IWG) Response Criteria for MDS
Outcome Time Frame
After end of induction up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
Outcome Measure
Percentage of Participants with Overall Response After Induction Therapy, According to 2006 IWG Response Criteria for MDS
Outcome Time Frame
Time from the initial overall response to the time of disease progression or death, whichever occurs first (up to approximately 3.5 years)
Outcome Measure
Duration of Clinical Response, According to 2006 IWG Response Criteria for MDS
Outcome Time Frame
Randomization up to the date of AML progression (up to approximately 3.5 years)
Outcome Measure
Time to Acute Myeloid Leukemia (AML) Progression, According to 2006 IWG Response Criteria for MDS
Outcome Time Frame
Randomization up to disease progression or death, whichever occurs first (up to approximately 3.5 years)
Outcome Measure
Progression Free Survival (PFS), According to 2006 IWG Response Criteria for MDS
Outcome Time Frame
Randomization up to death due to any cause (up to approximately 3.5 years)
Outcome Measure
Cohorts A, A2, B, and B2: Overall Survival (OS)
Outcome Time Frame
Baseline up to approximately 3.5 years
Outcome Measure
Percentage of Participants With Change in Red Cell and Platelet Transfusion
Outcome Time Frame
D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days)
Outcome Measure
Cohorts A2 or B2: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
Outcome Time Frame
D1 of every Cy up to study discontinuation (approximately 3.5 Yr) (1 Cy = 21 or 28 days)
Outcome Measure
Cohorts A2 and B2: Functional Assessment of Chronic Illness Therapy Fatigue Questionnaire (FACIT-Fatigue) Score
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Amit Verma
Investigator Email
amit.verma@einsteinmed.org
Investigator Phone
718-405-8505 / 718-904-2900
Categories Mesh Debug
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC SYNDROMES
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
MeSH Terms
MYELODYSPLASTIC SYNDROMES
BONE MARROW DISEASES
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
ATEZOLIZUMAB
AZACITIDINE
AZA COMPOUNDS
ORGANIC CHEMICALS
CYTIDINE
PYRIMIDINE NUCLEOSIDES
PYRIMIDINES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS
NUCLEOSIDES
NUCLEIC ACIDS, NUCLEOTIDES, AND NUCLEOSIDES
RIBONUCLEOSIDES