Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
MDS, AML, CMML
Brief summary
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.
Interventions
DRUGPF-04449913 (Glasdegib)
Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles
DRUGAzacitidine
75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) | maximum of approximately 15 months | 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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. |
| Number of Participants With Serious Adverse Events (SAEs) in the LIC | maximum of approximately 15 months | 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. |
| Number of Participants With Laboratory Abnormalities in the LIC | maximum of approximately 16 months | Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported. |
| Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts | maximum of 23 months in AML cohort and 34 months in MDS cohort | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | maximum of around 23 months in AML cohort and 40 months in MDS cohort | Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported. |
| 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 | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 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 was estimated using non-compartmental analysis. |
| Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | maximum of 23 months | Number of participants 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 |
| Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | maximum of 34 months | Number of participants with PR, mCR, SD, complete or partial cytogenetic response, and 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. |
| Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts | maximum of approximately 32 months in AML cohort and 32 months in MDS cohort | 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. |
| Duration of CR in the AML and MDS Cohorts | maximum of 23 months in AML cohort and 34 months in MDS cohort | 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. |
| Time to CR in the AML and MDS Cohorts | maximum of 23 months in AML cohort and 34 months in MDS cohort | 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. |
| Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC | maximum of approximately 16 months | Response rate (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. |
| 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 | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15 | 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. |
| Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7 | 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. |
| 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 | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7 | Area under the plasma concentration curve from time zero to extrapolated infinite time of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis. |
| Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7 | 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. |
| Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts | Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 (C1D15) and Cycle 2 Day 1 (C2D1) | Trough plasma concentration was defined as the estimated lowest concentration before next dose administration. |
| Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | maximum of approximately 15 months in the LIC cohort, 23 months in AML cohort, and 40 months in MDS cohort | Number of participants that met categorical criteria of QTcF values in LIC, AML and MDS cohorts |
| Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15 | 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. |
| Number of Participants With Efficacy Measures Other Than CR in the LIC | maximum of approximately 16 months | 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 |
| Number of Participants With TEAEs in the AML and MDS Cohorts | maximum of around 23 months in AML cohort and 40 months in MDS cohort | An 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.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. |
| Number of Participants With SAEs in the AML and MDS Cohorts | maximum of around 23 months in AML cohort and 40 months in MDS cohort | An 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. |
Countries
Belgium, Canada, France, Germany, United Kingdom, United States
Participant flow
Pre-assignment details
12 participants were enrolled and received combination therapy of glasdegib and azacitidine in the Lead-in Cohort (LIC). 31 participants were enrolled in the acute myeloid leukemia (AML) cohort, and 30 received glasdegib + azacitidine (1 participant withdrew consent before receiving treatment). 30 participants were enrolled and received glasdegib + azacitidine in the myelodysplastic syndrome (MDS) cohort.
Participants by arm
| Arm | Count |
|---|---|
| Lead-in Cohort Participants received SC administration of azacitidine daily at a dose of 75 mg/m2/day on Days 1-7 of every 28 days, and received oral self-administration of glasdegib daily and continuously at home with a starting dose of 100 mg QD. In Cycle 1 only, administration of glasdegib commenced on Day 2 of the cycle (C1D2) to permit DDI evaluation. | 12 |
| AML Cohort Participants received SC or IV administration of azacitidine at the starting dose of 75 mg/m2/day for 7 days every 28 days, and received oral self-administration of glasdegib daily and continuously at home with a starting dose of 100 mg QD. | 30 |
| MDS Cohort Participants received SC or IV administration of azacitidine at the starting dose of 75 mg/m2/day for 7 days every 28 days, and received oral self-administration of glasdegib daily and continuously at home with a starting dose of 100 mg QD. | 30 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 8 | 24 | 17 |
| Overall Study | Lost to Follow-up | 1 | 3 | 1 |
| Overall Study | Other reason | 3 | 3 | 9 |
| Overall Study | Study Participation Terminated by Sponsor | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Lead-in Cohort | AML Cohort | MDS Cohort | Total |
|---|---|---|---|---|
| Age, Customized 18-44 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 45-64 years | 3 Participants | 3 Participants | 7 Participants | 13 Participants |
| Age, Customized >=65 years | 9 Participants | 27 Participants | 23 Participants | 59 Participants |
| Age, Customized <75 years | 7 Participants | 16 Participants | 22 Participants | 45 Participants |
| Age, Customized >=75 years | 5 Participants | 14 Participants | 8 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 23 Participants | 23 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 22 Participants | 24 Participants | 57 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 6 Participants | 23 Participants |
| Sex: Female, Male Male | 7 Participants | 18 Participants | 24 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 12 | 25 / 30 | 17 / 30 |
| other Total, other adverse events | 12 / 12 | 29 / 30 | 29 / 30 |
| serious Total, serious adverse events | 9 / 12 | 24 / 30 | 19 / 30 |
Outcome results
Primary
Number of Participants With Laboratory Abnormalities in the LIC
Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported.
Time frame: maximum of approximately 16 months
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment. Number of participants analyzed = number of participants evaluable for this outcome measure (OM). Number analyzed = number of participants evaluable for this OM with at least 1 result of the specified laboratory parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | creatine phosphokinase increased | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Activated partial thromboplastin time prolonged | 5 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Anemia | 12 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hemoglobin increased | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | international normalized ratio increased | 8 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Lymphocyte count decreased | 9 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Lymphocyte count increased | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Neutrophil count decreased | 10 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Platelet count decreased | 12 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypophosphatemia | 4 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | White blood cell decreased | 11 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Alanine aminotransferase increased | 4 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Alkaline phosphatase increase | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Aspartate aminotransferase increased | 2 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Blood bilirubin increased | 6 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Creatinine increased | 11 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypercalcemia | 1 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hyperglycemia | 1 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hyperkalemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypermagnesemia | 2 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypernatremia | 1 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypoalbuminemia | 5 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypocalcemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypoglycemia | 1 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypokalemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hypomagnesemia | 2 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the LIC | Hyponatremia | 6 Participants |
Primary
Number of Participants With Serious Adverse Events (SAEs) in the LIC
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.
Time frame: maximum of approximately 15 months
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Serious Adverse Events (SAEs) in the LIC | All-causality SAEs | 9 Participants |
| Lead-in Cohort | Number of Participants With Serious Adverse Events (SAEs) in the LIC | Treatment-related SAEs | 7 Participants |
Primary
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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE.
Time frame: maximum of approximately 15 months
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) | All-causality TEAEs | 12 Participants |
| Lead-in Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) | Treatment-related TEAEs | 12 Participants |
| Lead-in Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Lead-in Cohort (LIC) | Maximum Grade 3 or 4 TEAEs | 8 Participants |
Primary
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.
Time frame: maximum of 23 months in AML cohort and 34 months in MDS cohort
Population: The full analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Cohort | Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts | 20.0 Percentage of participants |
| MDS Cohort | Percentage of Participants Achieving Complete Remission (CR) in the AML and MDS Cohorts | 13.3 Percentage of participants |
Secondary
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.
Time frame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Population: The PK parameter analysis set included all participants who received study treatment and had at least 1 of the PK parameters of interest. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = number of participants with evaluable results at the specific timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 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 | C1D7 | 13230 nanogram * hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 49 |
| 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 | C1D15 | 14350 nanogram * hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 61 |
Secondary
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 of azacitidine dosed in combination with glasdegib (C1D7) and when dosed alone (C1D1) in the Lead-in Cohort was estimated using non-compartmental analysis.
Time frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7
Population: The PK parameter analysis set included all participants who received study treatment and had at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 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 | C1D1 | 1319 ng*hr/mL | Geometric Coefficient of Variation 19 |
| 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 | C1D7 | 1260 ng*hr/mL | Geometric Coefficient of Variation 21 |
Secondary
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.
Time frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7
Population: The PK concentration analysis set included all participants who received treatment and had at least 1 value of analyte concentration of glasdegib or azacitidine available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Cohort | Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | C1D1 | 778.5 ng/mL | Geometric Coefficient of Variation 23 |
| Lead-in Cohort | Cmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | C1D7 | 716.9 ng/mL | Geometric Coefficient of Variation 32 |
Secondary
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.
Time frame: maximum of 23 months in AML cohort and 34 months in MDS cohort
Population: The analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Cohort | Duration of CR in the AML and MDS Cohorts | 5.78 Months |
| MDS Cohort | Duration of CR in the AML and MDS Cohorts | 6.18 Months |
Secondary
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.
Time frame: maximum of approximately 32 months in AML cohort and 32 months in MDS cohort
Population: The full analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Cohort | Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts | 9.2 Months |
| MDS Cohort | Kaplan-Meier Estimate of Median Overall Survival (OS) in the AML and MDS Cohorts | 17.8 Months |
Secondary
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.
Time frame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Population: The PK concentration analysis set included all participants who received treatment and had at least 1 value of analyte concentration of glasdegib or azacitidine available. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = number of participants with evaluable results at the specific timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Cohort | Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | C1D7 | 1013 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58 |
| Lead-in Cohort | Maximum Plasma Concentration (Cmax) of Glasdegib Dosed in Combination With Azacitidine (C1D7) and When Dosed Alone (C1D15) in the Lead-in Cohort | C1D15 | 991.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 57 |
Secondary
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
Time frame: maximum of approximately 15 months in the LIC cohort, 23 months in AML cohort, and 40 months in MDS cohort
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 450 ms <=Maximum QTcF interval <480 ms | 2 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline <30 ms | 3 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval ≥500 ms | 1 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval <450 ms | 5 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline >=60 ms | 2 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 30 ms <= QTcF maximum increase from baseline <60 ms | 7 Participants |
| Lead-in Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 480 ms <=Maximum QTcF interval <500 ms | 4 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval ≥500 ms | 3 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval <450 ms | 16 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 450 ms <=Maximum QTcF interval <480 ms | 6 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 480 ms <=Maximum QTcF interval <500 ms | 5 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline <30 ms | 18 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 30 ms <= QTcF maximum increase from baseline <60 ms | 10 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline >=60 ms | 2 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline <30 ms | 21 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 450 ms <=Maximum QTcF interval <480 ms | 7 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | QTcF maximum increase from baseline >=60 ms | 2 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 30 ms <= QTcF maximum increase from baseline <60 ms | 7 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval ≥500 ms | 2 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | 480 ms <=Maximum QTcF interval <500 ms | 4 Participants |
| MDS Cohort | Number of Participants Meeting Categorical Criteria of QTcF Values in LIC, AML and MDS Cohorts | Maximum QTcF interval <450 ms | 17 Participants |
Secondary
Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort
Number of participants 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
Time frame: maximum of 23 months
Population: The full analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | partial hematologic recovery (CRh) | 0 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | CR with incomplete blood count recovery (CRi) | 1 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | partial remission (PR) | 2 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | morphologic leukemia free state (MLFS) | 1 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the AML Cohort | stable disease (SD) | 6 Participants |
Secondary
Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort
Number of participants with PR, mCR, SD, complete or partial cytogenetic response, and 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.
Time frame: maximum of 34 months
Population: The full analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | HI of at least 1 lineage | 9 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | PR | 3 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | mCR | 5 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | SD | 8 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | Complete cytogenetic response | 5 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | Partial cytogenetic response | 1 Participants |
| Lead-in Cohort | Number of Participants With Disease-Specific Efficacy Measures in the MDS Cohort | HI of at least 1 lineage without CR or PR | 3 Participants |
Secondary
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
Time frame: maximum of approximately 16 months
Population: The full analysis set was defined as all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Efficacy Measures Other Than CR in the LIC | marrow CR | 2 Participants |
| Lead-in Cohort | Number of Participants With Efficacy Measures Other Than CR in the LIC | stable disease | 4 Participants |
| Lead-in Cohort | Number of Participants With Efficacy Measures Other Than CR in the LIC | hematologic improvement of at least 1 lineage | 6 Participants |
Secondary
Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts
Hematology lab parameters included activated partial thromboplastin time, hemoglobin, prothrombin international normalized ratio, lymphocyte, neutrophil, platelet, white blood cell; chemistry parameters included alanine aminotransferase, aspartate aminotransferase, alkaline aminotransferase, blood bilirubin, creatine phosphokinase, creatinine, calcium, blood glucose, potassium, magnesium, sodium, albumin, phosphate. Grades of lab abnormalities were defined by NCI CTCAE version 4.03. Grade 1(mild)=asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2(moderate)=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=life-threatening consequences, urgent intervention indicated. Grade 1-4 results are reported.
Time frame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment. Number of Participants Analyzed = number of participants evaluable for this outcome measure. Number Analyzed = number of participants with at least 1 observation of the given lab test.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | creatine phosphokinase increased | 5 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Anemia | 30 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | creatinine increased | 29 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Platelet count decreased | 29 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypercalcemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | international normalized ratio increased | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyperglycemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | White blood cell decreased | 22 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyperkalemia | 6 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Activated partial thromboplastin time prolonged | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypermagnesemia | 1 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Alanine aminotransferase increased | 13 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypernatremia | 2 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Leukocytosis | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypoalbuminemia | 22 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Alkaline phosphatase increased | 7 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypocalcemia | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hemoglobin increased | 0 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypoglycemia | 4 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Aspartate aminotransferase increased | 11 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypokalemia | 8 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Lymphocyte count increased | 6 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypomagnesemia | 12 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Blood bilirubin increased | 3 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyponatremia | 18 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Neutrophil count decreased | 25 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypophosphatemia | 13 Participants |
| Lead-in Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Lymphocyte count decreased | 23 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypophosphatemia | 7 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Lymphocyte count decreased | 24 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Lymphocyte count increased | 2 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Activated partial thromboplastin time prolonged | 0 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Anemia | 29 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hemoglobin increased | 0 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | international normalized ratio increased | 2 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Leukocytosis | 1 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Neutrophil count decreased | 25 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Platelet count decreased | 26 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | White blood cell decreased | 27 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Alanine aminotransferase increased | 12 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Alkaline phosphatase increased | 8 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Aspartate aminotransferase increased | 9 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Blood bilirubin increased | 10 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | creatine phosphokinase increased | 4 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | creatinine increased | 28 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypercalcemia | 0 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyperglycemia | 4 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyperkalemia | 6 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypermagnesemia | 2 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypernatremia | 1 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypoalbuminemia | 19 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypocalcemia | 11 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypoglycemia | 3 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypokalemia | 3 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hypomagnesemia | 10 Participants |
| MDS Cohort | Number of Participants With Laboratory Abnormalities in the AML and MDS Cohorts | Hyponatremia | 12 Participants |
Secondary
Number of Participants With SAEs in the AML and MDS Cohorts
An 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.
Time frame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
Population: The safety analysis population included all participants who received at least 1 dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With SAEs in the AML and MDS Cohorts | All-causality SAEs | 24 Participants |
| Lead-in Cohort | Number of Participants With SAEs in the AML and MDS Cohorts | Treatment-related SAEs | 8 Participants |
| MDS Cohort | Number of Participants With SAEs in the AML and MDS Cohorts | All-causality SAEs | 19 Participants |
| MDS Cohort | Number of Participants With SAEs in the AML and MDS Cohorts | Treatment-related SAEs | 9 Participants |
Secondary
Number of Participants With TEAEs in the AML and MDS Cohorts
An 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.Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE.
Time frame: maximum of around 23 months in AML cohort and 40 months in MDS cohort
Population: The safety analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lead-in Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | All-causality TEAEs | 30 Participants |
| Lead-in Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | Treatment-related TEAEs | 29 Participants |
| Lead-in Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | Maximum Grade 3 or 4 TEAEs | 20 Participants |
| MDS Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | All-causality TEAEs | 30 Participants |
| MDS Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | Treatment-related TEAEs | 29 Participants |
| MDS Cohort | Number of Participants With TEAEs in the AML and MDS Cohorts | Maximum Grade 3 or 4 TEAEs | 25 Participants |
Secondary
Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC
Response rate (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.
Time frame: maximum of approximately 16 months
Population: The safety analysis population included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Cohort | Percentage of Participants Achieving Complete Remission (CR) + Partial Remission (PR) in the LIC | 25.0 Percentage of participants |
Secondary
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.
Time frame: maximum of 23 months in AML cohort and 34 months in MDS cohort
Population: The analysis population included all participants who received at least 1 dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Cohort | Time to CR in the AML and MDS Cohorts | 5.54 Months |
| MDS Cohort | Time to CR in the AML and MDS Cohorts | 4.39 Months |
Secondary
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.
Time frame: Pre-dose and 0.25, 1, 4, 6, 24 hours post-dose on Cycle 1 Day 7 and Cycle 1 Day 15
Population: The PK parameter analysis set included all participants who received study treatment and had at least 1 of the PK parameters of interest. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = number of participants with evaluable results at the specific timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lead-in Cohort | 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 | C1D7 | 1.050 hour |
| Lead-in Cohort | 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 | C1D15 | 1.500 hour |
Secondary
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.
Time frame: 0.25, 0.5, 1, 2, 6 hours post-dose on Cycle 1 Day 1, predose and 0.25, 0.5, 1, 2, 6 hours postdose on Cycle 1 Day 7
Population: The PK parameter analysis set included all participants who received study treatment and had at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lead-in Cohort | Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | C1D1 | 0.5000 hour |
| Lead-in Cohort | Tmax of Azacitidine Dosed in Combination With Glasdegib (C1D7) and When Dosed Alone (C1D1) in the Lead-in Cohort | C1D7 | 0.5000 hour |
Secondary
Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts
Trough plasma concentration was defined as the estimated lowest concentration before next dose administration.
Time frame: Pre-dose and 1 and 4 hours post-dose on Cycle 1 Day 15 (C1D15) and Cycle 2 Day 1 (C2D1)
Population: The PK concentration analysis set included all participants who received treatment and had at least 1 value of analyte concentration of glasdegib or azacitidine available. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = number of participants with evaluable results at the specific timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lead-in Cohort | Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts | C1D15 | 468.440 ng/mL | Geometric Coefficient of Variation 88 |
| Lead-in Cohort | Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts | C2D1 | 462.806 ng/mL | Geometric Coefficient of Variation 110 |
| MDS Cohort | Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts | C1D15 | 308.144 ng/mL | Geometric Coefficient of Variation 95 |
| MDS Cohort | Trough Plasma Concentration (Ctrough) of Glasdegib on Cycle 1 Day 15 and Cycle 2 Day 1 in the AML and MDS Cohorts | C2D1 | 167.483 ng/mL | Geometric Coefficient of Variation 52 |