A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients

Study Overview
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Brief Summary
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This multi center open label Phase 1b study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF-04449913) when combined with azacitidine in patients with previously untreated Higher Risk Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). This clinical study includes two components: (a) a safety lead in cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS cohort.

Official Title
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An Open-label Phase 1b Study of PF-04449913 (Glasdegib) in Combination With Azacitidine in Patients With Previously Untreated Higher-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia

Conditions
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Myelodysplastic Syndrome, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: PF-04449913 (Glasdegib)
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients must have previously untreated MDS, AML, or CMML according to the WHO 2016 classification. MDS patients must have Intermediate (>3 to 4.5 points), High Risk (>4.5 - 6) or Very High Risk (>6 points) disease according to the Revised International Prognostic Scoring System 2012 (IPSS-R). Clinical indication for treatment with azacitidine for MDS or AML. Exclusion criteria: Patients with AML who are candidates for standard induction chemotherapy as first line treatment. Patients with known active CNS leukemia. Prior treatment with a smoothened inhibitor (SMOi) and/or hypomethylating agent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2 | Drug: PF-04449913 (Glasdegib)<br>* Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles<br>Drug: Azacitidine<br>* 75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle<br>|
| Experimental: Arm B<br>AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2 | Drug: PF-04449913 (Glasdegib)<br>* Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles<br>Drug: Azacitidine<br>* 75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAEs were AEs that occurred after initiation of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. Grades of AEs were defined by NCI CTCAE version 4.03. | Cycle 1 Day 1 up to 28 days after last dose of study drug or beginning of new anti-cancer therapy (assessed up to 16 months) | 
| Number of Participants With Serious Adverse Events (SAEs) in the LIC | An serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator. Grades of AEs were defined by NCI CTCAE version 4.03. | Cycle 1 Day 1 up to 28 days after last dose of study drug or beginning of new anti-cancer therapy (assessed up to 16 months) | 
| Number of Participants With Laboratory Abnormalities in the LIC | Laboratory parameters included: hematology parameters (activated partial thromboplastin time, hemoglobin, INR, lymphocyte count, neutrophil count, platelet count, white blood cell), chemistry parameters (alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, CPK, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate). Grades of laboratory abnormalities were defined by NCI CTCAE version 4.03. | Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 17 months) | 
| Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts | Percentage of participants achieving CR as defined by the 2017 European Leukemia Net (ELN) Response Criteria for all participants with AML and modified International Working Group (IWG) criteria (2006) for all participants with MDS in the expansion cohorts. For AML cohort, CR was defined as neutrophils ≥ 1 x 10^9/L, platelets ≥ 1 x 10^11/L, percentage of bone marrow blasts (BMB) <5% with no peripheral blasts and no blasts with Auer rods, no extramedullary disease (EMD), and transfusion independent. For MDS cohort, CR was defined as having responses of hemoglobin ≥11 g/dL, neutrophils ≥1 x 10^9/L, platelets ≥1 x 10^11/L, percentage of blasts = 0%, percentage of BMB≤5%, and normal maturation of all cell lines (note if has persistent dysplasia), and all responses must last at least 4 weeks. | Cycle 1 Day 1 to End of Treatment (EoT) visit (within 14 days after last dose) (assessed up to 22 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC | RR (Percentage of participants achieving CR+PR among all the enrolled and treated patients as defined by modified International Working Group (IWG) criteria (2006)) in the LIC. CR was defined as having responses of hemoglobin ≥11 g/dL, neutrophils ≥1 x 10^9/L, platelets ≥1 x 10^11/L, percentage of blasts = 0%, percentage of BMB≤5%, and normal maturation of all cell lines (note if has persistent dysplasia), and all responses must last at least 4 weeks. PR was defined as meeting all CR criteria if abnormal before treatment except BMB, percentage of BMB decreased by ≥50% but still >5% for at least 4 weeks. | Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 18 months) | 
| Number of Participants With Efficacy Measures Other Than CR in the LIC | Number of participants with efficacy measures other than CR as defined by modified IWG criteria (2006) in LIC, including marrow CR(mCR), stable disease(SD), hematologic improvement(HI). CR: hemoglobin≥11 g/dL, neutrophils≥1 x 10^9/L, platelets≥1 x 10^11/L, percentage of blasts=0%, percentage of BMB≤5%, normal maturation of all cell lines (note if has persistent dysplasia), all responses last at least 4 weeks. mCR: BMB≤5% & decreased by≥50%. SD: failure to achieve PR, no evidence of progression. HI: erythroid response (pretreatment<11g/dL): hemoglobin increase by≥1.5 g/dL, relevant reduction of units of red blood cell transfusions by at least 4 transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks; platelet response (pretreatment<1x10^11/L): increase of≥30x10^9/L if starting with >20x10^9/L, and increase from <20x10^9/L to >20x10^9/L and by at least 100%; neutrophil response (pretreatment<1x10^9/L): at least a 100% increase, absolute increase >0.5x10^9/L | Cycle 1 Day 1 to last follow up visit (at least 28 days after discontinuation of treatment) (assessed up to 18 months) | 
| Number of Participants With TEAEs in the AML and MDS Cohorts | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. TEAEs were AEs that occurred after initiation of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. AEs were graded by NCI CTCAE version 4.03. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) | 
| Number of Participants With SAEs in the AML and MDS Cohorts | A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator. AEs were graded by NCI CTCAE version 4.03. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) | 
| Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Laboratory parameters included: hematology parameters (activated partial thromboplastin time, hemoglobin, INR, lymphocyte count, neutrophil count, platelet count, white blood cell), chemistry parameters (alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, CPK, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate). Laboratory abnormalities were graded by NCI CTCAE version 4.03. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) | 
| Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | Number of participants with CR with partial hematologic recovery (CRh), CR with incomplete blood count recovery (CRi), partial remission (PR), stable disease (SD), and morphologic leukemia free state (MLFS). CRh: neutrophils>5x10^8/L, platelets>5x10^10/L, BMB<5%, no peripheral blasts, no blasts with Auer rods, no extramedullary disease (EMD), not qualifying for CR. CRi: neutrophils <1x10^9/L or platelets<1x10^11/L; BMB <5%, no peripheral blasts, no blasts with Auer rods; no EMD; neutrophils or platelets not recovered; not qualifying for CRh. PR: neutrophils ≥1x10^9/L; platelets ≥1x10^11/L; blasts decreased to 5-25% and ≥50% decrease from pretreatment; blasts≤5% if Auer rod positive. SD: ≥3 months of absence of CR without minimal residual disease (CRMRD-), CR, CRh, CRi, PR, and MLFS, criteria for PD not met. MLFS: neutrophils <1x10^9/L and platelets<1x10^11/L, BMB<5%, no blasts with Auer rods; no EMD; neutrophils and platelets not recovered; not qualifying for CRi | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 20 months) | 
| Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | Number of participants with PR, marrow CR (mCR), SD, complete or partial cytogenetic response, and hematologic improvement (HI). PR: BMB >5% and decreased by ≥50% (at least 4 weeks), meeting all CR criteria if abnormal before treatment except BMB. mCR: BMB ≤5% and decreased by ≥50%. SD: failure to achieve PR, no evidence of progression. Complete or partial cytogenic response: disappearance of chromosomal abnormality without new ones, or ≥ 50% reduction of chromosomal abnormality. HI: erythroid response (pretreatment <11g/dL): hemoglobin increase by≥1.5 g/dL, relevant reduction of units of red blood cell transfusions by at least 4 transfusions/8 weeks compared to pretreatment transfusion number in previous 8 weeks; platelet response (pretreatment <1x10^11/L): increase of ≥30x10^9/L if starting with >20x10^9/L, and increase from <20x10^9/L to >20x10^9/L and by at least 100%; neutrophil response (pretreatment <1x10^9/L): at least a 100% increase, absolute increase >0.5x10^9/L. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 22 months) | 
| Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts | Overall survival (OS) was defined as the time from date of first study treatment to date of death from any cause. Patients last known to be alive were to be censored at the date of last contact. OS was analyzed and displayed graphically for each expansion cohort separately using the Kaplan-Meier method. The median event time and corresponding two-sided 95%CI were provided for each cohort. OS was first analyzed when the primary endpoint of CR was analyzed in the respective expansion cohort. | Cycle 1 Day 1 to date of death from any cause (assessed up to 24 months) | 
| Duration of CR in the AML and MDS Cohorts | Duration of CR was defined as the duration from date of first achieving CR to the date of disease progression (relapse) after CR, or death due to any cause. Participants last known to be alive who were free from disease progression or relapse after CR were censored at the date of the last assessment that verified their disease status. Duration of CR was analyzed using the Kaplan-Meier method. Disease progression was defined as: percentage of bone marrow blasts increased by ≥50% to >5% (for participants with <5% blasts at screening), >10% (for participants with 5-10% blasts at screening), >20% (for participants with 11-20% blasts at screening) or >30% (for participants with 21-30% blasts at screening), and with any of the following condition: at least 50% decrease from maximum remission/response in granulocytes or platelets; reduction in hemoglobin by ≥2 g/dL; transfusion dependence. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) | 
| Time to CR in the AML and MDS Cohorts | Time to CR was defined for participants in the expansion cohorts who had achieved response on study as the time from date of the first dose of study drug to date of the first documentation of response. Time to CR was analyzed using the Kaplan-Meier method. | Cycle 1 Day 1 to EoT visit (within 14 days after last dose) (assessed up to 24 months) | 
| Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | Maximum plasma concentration of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis. | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Day 15 | 
| Area Under the Plasma Concentration Curve From Time Zero to End of Dosing Interval (AUCtau) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | Area under the plasma concentration curve from time zero to end of dosing interval (AUCtau) of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis. | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Day 15 | 
| Time to First Occurrence of Maximum Plasma Concentration (Tmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | Time to first occurrence of maximum plasma concentration of glasdegib dosed in combination with azacitidine (C1D7) and when dosed alone (C1D15) in the Lead-in Cohort was estimated using non-compartmental analysis. | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Day 15 | 
| Maximum Plasma Concentration (Cmax) of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | Maximum plasma concentration of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis. | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 7. | 
| Area Under the Plasma Concentration Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | Area under the plasma concentration curve from time zero to extrapolated infinite time (AUCinf) of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis. | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 7. | 
| Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | Time to first occurrence of maximum plasma concentration of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis. | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1; pre-dose and 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 7. | 
| Trough Plasma Concentration (Ctrough) of Glasdegib on C1D15 and C2D1 in the AML and MDS Cohorts | Trough plasma concentration was defined as the estimated lowest concentration before next dose administration. | Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 and Cycle 2 Day 1. | 
| Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Number of participants that met categorical criteria of QTcF values in LIC, AML and MDS cohorts | Cycle 1 Day 1 to EoT visit (assessed up to 16 months in the LIC cohort and 24 months in the AML and MDS cohorts) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, AML, CMML