A PHASE 1 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF PF-04449913 (GLASDEGIB), AN ORAL HEDGEHOG INHIBITOR, ADMINISTERED AS A SINGLE AGENT IN JAPANESE PATIENTS WITH SELECT HEMATOLOGIC MALIGNANCIES AND IN COMBINATION WITH INTENSIVE CHEMOTHERAPY, LOW-DOSE ARA-C, OR AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR HIGH-RISK MYELODYSPLASTIC SYNDROME

Number of Participants With Dose-limiting Toxicities (DLTs): Monotherapy Cohort

时间窗: Day -5 up to Day 28 of Cycle 1 (33 days)

Criteria: Grade \>=3 non-hematologic toxicity (nht), except Grade \>=3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities, alanine aminotransferase (AT)/aspartate AT elevation that returned to Grade \<=1/baseline within 7 days, allergic reactions possibly related to PF-04449913 that led to discontinuation of study drug; Prolonged myelosuppression lasted \>42 days from point of detection = absolute neutrophil count \< 500/microliter or platelet count \<10\*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); Inability to deliver \>=80% of the planned study doses for all agents in a combination due to nht; Delay of \>28 days in receiving next scheduled cycle due to persisting nht; Asymptomatic participant with Grade \>=3 QTc prolongation required repeat testing, re-evaluation by qualified person, and correction of reversible causes for confirmation. Post-correction, if Grade 3 prolongation persisted, event was a DLT.

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Monotherapy Cohort

时间窗: Day 1 up to 28 days after last dose of study drug (For 25 mg: maximum up to 136 days; For 50 mg: maximum up to 179 days; For 100 mg: maximum up to 472 days)

AE:any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Serious AE: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. TEAEs:events absent before treatment or that worsened relative to pretreatment state. Treatment-related TEAE:any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to drug was assessed by the Investigator. National cancer institute common terminology criteria (NCI-CTCAE) Grade(G) v4.0:G 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G 4:life-threatening consequence, urgent intervention indicated.

Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Monotherapy Cohort

时间窗: For 25 mg: Baseline up to maximum 108 days; For 50 mg: Baseline up to maximum 151 days; For 100 mg: Baseline up to maximum 444 days

Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With Worst On-study Laboratory Abnormalities: Monotherapy Cohort

时间窗: For 25 mg: Baseline up to maximum 136 days; For 50 mg: Baseline up to maximum 179 days; For 100 mg: Baseline up to maximum 472 days

Laboratory parameters included- hematology: lymphocytes/leukocytes percentage (%), neutrophils/leukocytes, basophils/leukocytes, eosinophils/leukocytes and monocytes/leukocytes (%), prothrombin time second (sec), blasts/leukocytes (%); clinical chemistry: lactate dehydrogenase units per liter (u/l), protein gram/liter (g/l), blood urea nitrogen (BUN) millimoles per liter (mmol/l), urate, chloride, calcium (mmol/l); urinalysis: specific gravity, pH, urine glucose and ketones (scalar), nitrite, leukocyte esterase, urine erythrocytes (scalar), urine leukocytes (scalar). In this outcome measure participants for each laboratory parameter were evaluated as normal, abnormal low, abnormal high or abnormal low and an abnormal high. Laboratory values were as per laboratory normal ranges. Values above normal range = abnormal high and below range = abnormal low. Participants with both an abnormal low and high value while on study were reported as 'Abnormal low and Abnormal high'.

Number of Participants With DLTs: Combination Cohort 1

时间窗: Day 1 up to Day 28 of Cycle 1 (28 days)

Criteria: Grade \>=3 non-hematologic toxicity (nht), except Grade \>=3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities, alanine aminotransferase (AT)/aspartate AT elevation that returned to Grade \<=1/baseline within 7 days, allergic reactions possibly related to PF-04449913 that led to discontinuation of study drug; Prolonged myelosuppression lasted \>42 days from point of detection = absolute neutrophil count \< 500/microliter or platelet count \<10\*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); Inability to deliver \>=80% of the planned study doses for all agents in a combination due to nht; Delay of \>28 days in receiving next scheduled cycle due to persisting nht; Asymptomatic participant with Grade \>=3 QTc prolongation required repeat testing, re-evaluation by qualified person, and correction of reversible causes for confirmation. Post-correction, if Grade 3 prolongation persisted, event was a DLT.

Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 1

时间窗: Day 1 up to 28 days after last dose of study drug (maximum up to 514 days)

AE: any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Serious AE: 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. TEAEs: events absent before treatment or that worsened relative to pretreatment state. Treatment-related TEAE: any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to drug was assessed by the Investigator. NCI-CTCAE Grade: Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated.

Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 1

时间窗: Baseline up to maximum 486 days

Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 1

时间窗: Baseline up to maximum 514 days

Laboratory parameters included- hematology: lymphocytes/leukocytes (%), neutrophils/leukocytes (%), basophils/leukocytes (%), eosinophils/leukocytes (%), monocytes/leukocytes (%), prothrombin time (sec), blasts/leukocytes (%); clinical chemistry: lactate dehydrogenase (u/l), protein (g/l), BUN (mmol/l), urate (mmol/l), chloride (mmol/l), calcium (mmol/l); urinalysis: specific gravity (scalar), pH (scalar), urine glucose (scalar), ketones (scalar), nitrite, leukocyte esterase, urine erythrocytes (scalar), urine leukocytes (scalar). In this outcome measure participants for each laboratory parameter were evaluated as normal, abnormal low only, abnormal high only or abnormal low and an abnormal high. Laboratory values were as per laboratory normal ranges. Values above normal range = abnormal high and below range = abnormal low. Participants with both an abnormal low and an abnormal high value while on study were reported as 'Abnormal low and Abnormal high'.

Number of Participants With DLTs: Combination Cohort 2

时间窗: Day -3 up to anytime between Day 21 and Day 28 of first induction cycle (24 to 31 days)

Criteria: Grade \>=3 non-hematologic toxicity (nht), except Grade \>=3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities, alanine aminotransferase (AT)/aspartate AT elevation that returned to Grade \<=1/baseline within 7 days, allergic reactions possibly related to PF-04449913 that led to discontinuation of study drug; Prolonged myelosuppression lasted \>42 days from point of detection = absolute neutrophil count \< 500/microliter or platelet count \<10\*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); Inability to deliver \>=80% of the planned study doses for all agents in a combination due to nht; Delay of \>28 days in receiving next scheduled cycle due to persisting nht; Asymptomatic participant with Grade \>=3 QTc prolongation required repeat testing, re-evaluation by qualified person, and correction of reversible causes for confirmation. Post-correction, if Grade 3 prolongation persisted, event was a DLT.

Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 2

时间窗: Day 1 up to 28 days after last dose of study drug (maximum up to 371 days)

AE: any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Serious AE: 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. TEAEs: events absent before treatment or that worsened relative to pretreatment state. Treatment-related TEAE: any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to drug was assessed by the Investigator. NCI-CTCAE Grade: Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated.

Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 2

时间窗: Baseline up to maximum 343 days

Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 2

时间窗: Baseline up to maximum 371 days

Laboratory parameters included- hematology: lymphocytes/leukocytes (%), neutrophils/leukocytes (%), basophils/leukocytes (%), eosinophils/leukocytes (%), monocytes/leukocytes (%), prothrombin time (sec), blasts/leukocytes (%); clinical chemistry: lactate dehydrogenase (u/l), protein (g/l), BUN (mmol/l), urate (mmol/l), chloride (mmol/l), calcium (mmol/l); urinalysis: specific gravity (scalar), pH (scalar), urine glucose (scalar), ketones (scalar), urine erythrocytes (scalar), urine leukocytes (scalar). In this outcome measure participants for each laboratory parameter were evaluated as normal, abnormal low only, abnormal high only or abnormal low and an abnormal high. Participants that had both an abnormal low and an abnormal high value while on study were reported as 'Abnormal low and Abnormal high'.

Percentage of Participants Achieving Disease Modifying Response (DMR): Expansion Cohort

时间窗: Baseline up to maximum 736 days

DMR included complete remission (CR), CR with incomplete blood count recovery (Cri), morphologic leukemia-free state (MLFS), marrow CR (mCR) and partial remission (PR). CR: \>=11 gram per deciliter (g/dL) hemoglobin (Hgb), \>=1\*10\^9 neutrophils (L), \>=100\*10\^9 platelets (L), 0% blasts, \<=5% bone marrow blasts (BMB), normal maturation of all cell lines, if had persistent dysplasia. . CRi: \<1000 neutrophils (mcL), \<100000 platelets (mcL), \<5% BMB, either neutrophils or platelets not recovered, no extramedullary disease (EMD). MLFS: 1000 neutrophils (mcL) and \<100000 platelets (mcL), \<5% BMB, neutrophils and platelets not recovered, flow cytometry negative, no EMD. PR: \>=1000 neutrophils (mcL), \>=100000 platelets (mcL), decrease to 5-25 and \>=50% decrease from start, Blasts \<=5% if Auer rod positive. mCR: hematologic improvement (HI) response, \<=5% and decreased by \>=50% BMB. PR: decrease by \>=50% but still \>5% BMB.

Number of Participants With DLTs: Combination Cohort 3

时间窗: Day 1 up to Day 28 of Cycle 1 (28 days)

Criteria: Grade \>=3 non-hematologic toxicity (nht), except Grade \>=3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities, alanine aminotransferase (AT)/aspartate AT elevation that returned to Grade \<=1/baseline within 7 days, allergic reactions possibly related to PF-04449913 that led to discontinuation of study drug; Prolonged myelosuppression lasted \>42 days from point of detection = absolute neutrophil count \< 500/microliter or platelet count \<10\*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); Inability to deliver \>=80% of the planned study doses for all agents in a combination due to nht; Delay of \>28 days in receiving next scheduled cycle due to persisting nht; Asymptomatic participant with Grade \>=3 QTc prolongation required repeat testing, re-evaluation by qualified person, and correction of reversible causes for confirmation. Post-correction, if Grade 3 prolongation persisted, event was a DLT.

Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 3

时间窗: Day 1 up to 28 days after last dose of study drug (maximum up to 869 days)

AE: any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Serious AE: 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. TEAEs: events absent before treatment or that worsened relative to pretreatment state. Treatment-related TEAE: any untoward medical occurrence attributed to study drug in a participant who received study drug. Relatedness to drug was assessed by the Investigator. NCI-CTCAE Grade: Grade 3=severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated.

Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 3

时间窗: Baseline up to maximum 841 days

Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 3

时间窗: Baseline up to maximum 869 days

Laboratory parameters included- hematology: lymphocytes/leukocytes (%), neutrophils/leukocytes (%), basophils/leukocytes (%), eosinophils/leukocytes (%), monocytes/leukocytes (%), blasts/leukocytes (%); clinical chemistry: lactate dehydrogenase (u/l), protein (g/l), BUN (mmol/l), urate (mmol/l), chloride (mmol/l), calcium (mmol/l); urinalysis: specific gravity (scalar), pH (scalar), urine glucose (scalar), ketones (scalar), nitrite, leukocyte esterase, urine erythrocytes (scalar), urine leukocytes (scalar). In this outcome measure participants for each laboratory parameter were evaluated as normal, abnormal low only, abnormal high only or abnormal low and an abnormal high. Participants that had both an abnormal low and an abnormal high value while on study were reported as 'Abnormal low and Abnormal high'.