Myelodysplastic Syndromes
Conditions
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.
Interventions
DRUGAtezolizumab
Participants will receive atezolizumab as per the schedule described in individual cohort.
DRUGAzacitidine
Participants will receive azacitidine as per the schedule described in individual cohort.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | 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 |
Secondary
| Measure | Time frame |
|---|---|
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
Countries
United States
Outcome results
None listed