MedPath

A Study Of PF-04449913 In Japanese Patients With Select Hematologic Malignancies

Phase 1
Completed
Conditions
Acute Myeloid Leukemia
Interventions
Drug: LDAC
Drug: Low dose ARA-C (LDAC)
Registration Number
NCT02038777
Lead Sponsor
Pfizer
Brief Summary

This is an open-label, multi-center, Phase 1 study of PF-04449913 in Japanese patients. PF-04449913 will be administered orally as a single agent in patients with select advanced hematologic malignancies, or in combination with LDAC \[Low-Dose Ara-C\] or cytarabine and daunorubicin in previously untreated patients with AML \[Acute Myeloid Leukemia\] or high-risk MDS \[Myelodysplastic Syndrome\], or in combination with azacitidine in previously untreated patients with AML.

Detailed Description

Not available

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
48
Inclusion Criteria
  • Patients with select advanced hematologic malignancies who are refractory, resistant or intolerant to prior therapies for monotherapy cohort.
  • Patients with AML or High-Risk MDS who are newly diagnosed and previously untreated for combination cohort.
  • Patients with AML who are newly diagnosed and previously untreated for azacitidine combination cohort.
  • ECOG [Eastern Cooperative Oncology Group] performance status 0 to 2
  • Adequate organ function
Exclusion Criteria
  • Patients with active CNS disease
  • Patient with active malignancy with the exception of basal cell carcinoma, non melanoma skin cancer, carcinoma in situ cervical
  • Patient has an active, life threatening or clinically significant uncontrolled systemic infection

Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Expansion Cohort of LDAC Combination for EfficacyPF-04449913PF-04449913 in combination with LDAC to evaluate efficacy
Combination Cohort 1PF-04449913PF-04449913 in combination with low dose ARA-C (LDAC)
Continuation CohortPF-04449913PF-04449913 Monotherapy for one patient rolled-over from another trial in the same project.
Expansion Cohort of LDAC Combination for EfficacyLDACPF-04449913 in combination with LDAC to evaluate efficacy
Monotherapy CohortPF-04449913PF-04449913 Monotherapy
Azacitidine Combination CohortPF-04449913PF-04449913 in combination with azacitidine
Combination Cohort 1Low dose ARA-C (LDAC)PF-04449913 in combination with low dose ARA-C (LDAC)
Combination Cohort 2PF-04449913PF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy.
Combination Cohort 2CytarabinePF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy.
Combination Cohort 2DaunorubicinPF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy.
Azacitidine Combination CohortAzacitidinePF-04449913 in combination with azacitidine
Primary Outcome Measures
NameTimeMethod
Number of Participants With Dose-limiting Toxicities (DLTs): Monotherapy CohortDay -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 CohortDay 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 CohortFor 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 CohortFor 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 1Day 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 1Day 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 1Baseline 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 1Baseline 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 2Day -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 2Day 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 2Baseline 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 2Baseline 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 CohortBaseline 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 3Day 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 3Day 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 3Baseline 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 3Baseline 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'.

Secondary Outcome Measures
NameTimeMethod
Single Dose- Maximum Observed Plasma Concentration (Cmax) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1
Single Dose- Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1
Single Dose- Terminal Plasma Half-life (T1/2) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.

Single Dose- Area Under the Plasma Concentration Curve: From Time Zero to End of Dosing Interval (AUCtau), From Time Zero to Last Quantifiable Concentration (AUClast) and From Time Zero to Infinity (AUCinf) of PF-04449913 for Monotherapy CohortAUCtau: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day -5 of Cycle 1; AUClast and AUCinf: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours. AUClast = area under the curve from time zero to last quantifiable concentration. AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Single Dose- Clearance (CL/F) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

CL/F was defined as apparent total clearance of the drug from plasma after oral administration. CL/F of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Single Dose- Volume of Distribution (Vz/F) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.

Multiple Dose Cmax, Minimum Observed Plasma Concentration (Cmin), Average Observed Plasma Concentration (Cavg), Trough Plasma Concentration (Ctrough) of PF-04449913: Monotherapy CohortCmax, Cmin: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing on Day 21 of Cycle 1; Cavg: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day 21 of Cycle 1; Ctrough: Pre-dose on Day 21 of Cycle 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing on Day 21 of Cycle 1
Multiple Dose- AUCtau of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1

AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours. AUClast = area under the curve from time zero to last quantifiable concentration. AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Multiple Dose- Clearance (CL/F) of PF-04449913: Monotherapy CohortPre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1

CL/F was defined as apparent total clearance of the drug from plasma after oral administration. CL/F of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Multiple Dose- Accumulation Ratio (Rac) of PF-04449913: Monotherapy Cohort0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day -5 and Day 21 of Cycle 1

Rac was the observed accumulation ratio for AUCtau, determined as ratio of Day 21 AUCtau to Day -5 AUCtau. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Multiple Dose- Steady State Accumulation Ratio (Rss) of PF-04449913: Monotherapy CohortAUCtau: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day 21 of Cycle 1; AUCinf: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

Rss = Ratio of Day 21 AUCtau to Day -5 AUCinf. AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Monotherapy CohortBaseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

Biomarker assessments were used to understand the in vivo mechanism of action of PF-04449913, as well as potential mechanisms of resistance. In this outcome measure ratio of GLI1 levels (mRNA, fresh tissue) at baseline to day 21 cycle 1 is reported.

Number of Participants With Best Response: Monotherapy CohortDay 1 up to End of Treatment (25 mg: maximum up to 108 days; 50 mg: maximum up to 151 days; 100 mg: maximum up to 444 days)

Best response observed for: CR, Cri, MLFS, PR, PRi, CytogeneticCR(CRc), MolecularCR(CRm). For AML-CR:neutrophils(nt) \[mcL\]\>=1000, platelets(pt)\[mcL\]\>=10\^5, BMB\<5%. CRi:nt(mcL)\<1000/pt(mcL)\<10\^5, BMB\<5%. MLFS:nt(mcL)1000 and pt(mcL)\<10\^5, BMB\<5%. PR:nt(mcL)\>=1000, pt(mcL)\>=10\^5, decrease to 5-25 and \>=50% decrease from start. PRi: nt\<1000, \<10\^5. CRc: nt(mcL)\>1,000, pt(mcL)\>10\^5, BMB\<5%. CRm: nt(mcL)\>1,000, pt(uL)\>10\^5, BMB\<5%. For myelodysplasia-CR: hemoglobin(Hgb)\[gram per deciliter{g/dL}\]\>=11, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9, blasts0%, BMB\<=5%. mCR:\<=5% and decreased by \>=50% BMB. PR:decrease by\>=50% with \>5% BMB, CRc: disappearance of chromosomal abnormality, no new appearance, PRc:\>=50% reduced chromosomal abnormality. For myleofibrosis-CR: hgb(g/L)\>=110, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9, All \<=ULN, BMB \<=5%. PR: hgb\>=110, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9. CML- PR: 1-35% Philadelphia chromosome(PC) positive(+) cells, CR:0% PC+ cells. Responses with at least 1 participant were reported.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 1Cmax, Cmin: Pre-dose and 0.5, 1, 2, 4, 6 and 24 hours post PF-04449913 dose on Day 10 and 21 of Cycle 1; Cavg: 0 to 24 hours post PF-04449913 dose on Day 10 and 21 of Cycle; Ctrough: Pre-dose on Day 10 and 21 of Cycle 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of PF-04449913: Combination Cohort 1Pre-dose and 0.5, 1, 2, 4, 6 and 24 hours post PF-04449913 dose on Day 10 and Day 21 of Cycle 1
Multiple Dose- AUCtau of PF-04449913: Combination Cohort 10 to 24 hours post PF-04449913 dose on Day 10 and Day 21 of Cycle 1

AUCtau was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Multiple Dose- CL/F of PF-04449913: Combination Cohort 1Pre-dose and 0.5, 1, 2, 4, 6 and 24 hours post PF-04449913 dose on Day 10 and Day 21 of Cycle 1

CL/F was defined as apparent total clearance of the drug from plasma after oral administration. CL/F of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Cytarabine: Combination Cohort 1Cmax, Cmin: Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1; Cavg: 0 to 12 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1; Ctrough: Pre-LDAC dose on Day 2 and Day 10 of Cycle 1

LDAC= low dose ara-cytarabine/low dose cytarabine. Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours, dosing interval was of 12 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of Cytarabine: Combination Cohort 1Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1

LDAC= low dose ara-cytarabine/low dose cytarabine.

Multiple Dose- T1/2 of Cytarabine: Combination Cohort 1Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1

LDAC= low dose ara-cytarabine/low dose cytarabine. Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.

Multiple Dose- AUCinf and AUCtau of Cytarabine: Combination Cohort 1AUCinf: Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1; AUCtau: 0 to 12 hours post LDAC dosing on Day 2 and Day 10 of Cycle

LDAC= low dose ara-cytarabine/low dose cytarabine. AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 12 hours.

Multiple Dose- Cmax, Cmin, and Ctrough of Ara-uridine: Combination Cohort 1Cmax, Cmin: Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1; Cavg: 0 to 12 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1; Ctrough: Pre-LDAC dosing on Day 2 and Day 10 of Cycle 1

Ara-uridine was a metabolite of cytarabine. Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 12 hours. Ctrough = Pre-dose concentration, observed directly from data. Ara-uridine was a metabolite of cytarabine.

Multiple Dose- Tmax of Ara-uridine: Combination Cohort 1Pre-dose and 0.25, 0.5, 1, 2, 4 and 6 hours post LDAC dosing on Day 2 and Day 10 of Cycle 1

Ara-uridine was a metabolite of cytarabine.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 2Cmax, Cmin: Pre-dose, 0.5, 1, 6, and 24 hrs post dose on Day 3, 10 of induction Cycle (IC) 1 and 4 hrs post dose on Day 10 of IC 1; Cavg: 0 to 24 hrs post dose on Day 3 and Day 10 of IC 1; Ctrough: Pre dose on Day 3 and Day 10 of IC 1 (PF-04449913 Dose)

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of PF-04449913: Combination Cohort 2Pre-dose, 0.5, 1, 6, and 24 hours post PF-04449913 dosing on Day 3 of Induction Cycle 1 and pre-dose, 0.5, 1, 4, 6, and 24 hours post PF-04449913 dosing on Day 10 of Induction Cycle 1
Multiple Dose- AUCtau of PF-04449913: Combination Cohort 2Pre-dose, 0.5, 1, 6, and 24 hours post PF-04449913 dosing on Day 3 of induction Cycle 1 and pre-dose, 0.5, 1, 4, 6, and 24 hours post PF-04449913 dosing on Day 10 of induction Cycle 1

AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Multiple Dose- CL/F of PF-04449913: Combination Cohort 2Pre-dose, 0.5, 1, 6, and 24 hours post PF-04449913 dosing on Day 3 of induction Cycle 1 and pre-dose, 0.5, 1, 4, 6, and 24 hours post PF-04449913 dosing on Day 10 of induction Cycle 1

CL/F was defined as apparent total clearance of the drug from plasma after oral administration. CL/F of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Daunorubicin: Combination Cohort 2Cmax, Cmin: Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of induction Cycle (IC) 1; Cavg: 0 to 24 hours post dose on Day 3 of IC 1; Ctrough: Pre-dose on Day 3 of IC 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of Daunorubicin: Combination Cohort 2Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1
Multiple Dose- T1/2 of Daunorubicin: Combination Cohort 2Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of at induction Cycle 1

Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium

Multiple Dose- AUCinf and AUCtau of Daunorubicin: Combination Cohort 2AUCinf: Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1; AUCtau: 0 to 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1

AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Daunorubicinol: Combination Cohort 2Cmax, Cmin: Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of induction Cycle (IC) 1; Cavg: 0 to 24 hours post dose on Day 3 of IC 1; Ctrough: Pre-dose on Day 3 of IC 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval of 24 hours. Ctrough = Pre-dose concentration, observed directly from data. Daunorubicinol was a metabolite of daunorubicin.

Multiple Dose- Tmax of Daunorubicinol: Combination Cohort 2Pre-dose, 0.25 (mid-infusion), 0.5 (immediately prior to end of infusion), 1, 4, 6, 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1

Daunorubicinol was a metabolite of daunorubicin.

Multiple Dose- AUCtau of Daunorubicinol: Combination Cohort 20 to 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1

Daunorubicinol was a metabolite of daunorubicin. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Combination Cohort 1Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

Biomarker assessments were used to understand the in vivo mechanism of action of PF-04449913, as well as potential mechanisms of resistance. In this outcome measure ratio of GLI1 levels (mRNA, fresh tissue) at baseline to day 21 cycle 1 is reported.

Ratio of GLI1 Levels at Baseline to Day 21 Cycle1: Combination Cohort 2Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

Biomarker assessments were used to understand the in vivo mechanism of action of PF-04449913, as well as potential mechanisms of resistance. In this outcome measure ratio of GLI1 levels (mRNA, fresh tissue) at baseline to day 21 cycle 1 is reported.

Number of Participants With Best Response: Combination Cohort 1Day 1 up to end of treatment (maximum up to 486 days)

Best response observed for: CR, Cri, MLFS, PR, PRi, CRc, CRm. Response criteria for participants with AML- CR: neutrophils \[mcL\] \>=1000, platelets(pt)\[mcL\] \>=10\^5, BMB \<5%. CRi: neutrophils (mcL) \<1000 or pt (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and pt (mcL) \<10\^5, BMB \<5%. PR: neutrophils (mcL) \>=1000, pt (mcL) \>=100000, decrease to 5-25 and \>=50% decrease from start. PRi: neutrophils (mcL) \<1000 or pt (mcL) \<10\^5, BMB decrease to 5-25 and \>=50% decrease from start. Minor Response: BMB \>=25% decrease from start. CRc: neutrophils (mcL) \>1,000, pt (mcL) \>10\^6, BMB \<5%. CRm: neutrophils (mcL) \>1,000, pt (mcL) \>100,000, BMB \<5%. For participants with myelodysplastic syndrome (MDS), DMR- CR: \>=11 Hgb (g/dL), \>=1\*10\^9 neutrophils(L), \>=100\*10\^9 pt(L), 0% blasts, \<=5% BMB. mCR: HI response, \<=5% and decreased by \>=50% BMB. PR: decrease by \>=50% but still \>5% BMB. Only those responses which had at least 1 participant were reported.

Number of Participants With Best Response: Combination Cohort 2Day 1 up to end of treatment (maximum up to 343 days)

Best response observed for: CR, Cri, MLFS, PR, PRi, CRc, CRm. Response criteria for AML- CR:neutrophils(nt)\[mcL\] \>=1000, platelets (mcL) \>=100000, BMB \<5%. CRi: nt(mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: nt(mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: nt(mcL) \>=1000, platelets (mcL) \>=100000, decrease to 5-25 and \>=50% decrease from start. PRi: nt(mcL) \<1000 or platelets (mcL) \<100000, BMB decrease to 5-25 and \>=50% decrease from start. Minor Response: BMB \>=25% decrease from start. Cytogenetic CR (CRc): nt(mcL) \>1,000, platelets (mcL) \>100,000, BMB \<5%. CRm: nt(mcL) \>1,000, platelets (mcL) \>100,000, BMB \<5%. For participants with myelodysplastic syndrome (MDS), DMR was defined as - CR: \>=11 Hgb (g/dL), \>=1\*10\^9 nt(L), \>=100\*10\^9 platelets (L), 0% blasts, \<=5% BMB. mCR: HI response, \<=5% and decreased by \>=50% BMB. PR: decrease by \>=50% but still \>5% BMB. Only those responses which had at least 1 participant were reported.

Percentage of Participants With Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR: Combination Cohort 1Day 1 up to end of treatment (maximum up to 486 days)

CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Duration of Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 1Day 1 up to end of treatment (maximum up to 486 days)

Duration of response was the time from the date of first documentation of a CR/CRi and DMR to the date of first documentation of relapse after CR/CRi and DMR or death due to any cause. Duration of response data was censored on the date of the last adequate response assessment for participants who do not have an event (relapse or death). DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Time to Response: Combination Cohort 1Day 1 up to end of treatment (maximum up to 486 days)

The time from the date of first dose of study drug to the date of first documentation of a CR or CRi and DMR. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Overall Survival: Combination Cohort 1First dose of study drug up to death or date of last contact (maximum up to 514 days)

Overall survival was defined as the time from the date of first dose of study drug to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact.

Overall Survival (OS): Expansion CohortFirst dose of study drug up to death or date of last contact (maximum up to 1408 days)

OS was defined as the time from the date of first dose of study drug to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact.

Number of Participants With Best Response: Expansion CohortFrom first dose of study drug up to disease progression (maximum duration of 1408 days)

Best response observed for: CR, Cri, MLFS, PR, PRi, CytogeneticCR(CRc), MolecularCR(CRm). For AML-CR:neutrophils(nt) \[mcL\]\>=1000, platelets(pt)\[mcL\]\>=10\^5, BMB\<5%. CRi:nt(mcL)\<1000/pt(mcL)\<10\^5, BMB\<5%. MLFS:nt(mcL)1000 and pt(mcL)\<10\^5, BMB\<5%. PR:nt(mcL)\>=1000, pt(mcL)\>=10\^5, decrease to 5-25 and \>=50% decrease from start. PRi: nt\<1000, \<10\^5. CRc: nt(mcL)\>1,000, pt(mcL)\>10\^5, BMB\<5%. CRm: nt(mcL)\>1,000, pt(uL)\>10\^5, BMB\<5%. For myelodysplasia-CR: hemoglobin(Hgb)\[gram per deciliter{g/dL}\]\>=11, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9, blasts0%, BMB\<=5%. mCR:\<=5% and decreased by \>=50% BMB. PR:decrease by\>=50% with \>5% BMB, CRc: disappearance of chromosomal abnormality, no new appearance, PRc:\>=50% reduced chromosomal abnormality. For myleofibrosis-CR: hgb(g/L)\>=110, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9, All \<=ULN, BMB \<=5%. PR: hgb\>=110, nt(L)\>=1\*10\^9, pt(L)\>=100\*10\^9. CML- PR: 1-35% Philadelphia chromosome(PC) positive(+) cells, CR:0% PC+ cells. Responses with at least 1 participant were reported.

Percentage of Participants With CR/CRi and DMR: Expansion CohortDay 1 up to end of treatment (maximum up to 1408 days)

CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Duration of Response: Expansion CohortDay 1 up to end of treatment (maximum up to 1408 days)

Duration of response was the time from the date of first documentation of a CR/CRi and DMR to the date of first documentation of relapse after CR/CRi and DMR or death due to any cause. Duration of response data was censored on the date of the last adequate response assessment for participants who do not have an event (relapse or death). DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Time to Response: Expansion CohortDay 1 up to end of treatment (maximum up to 1408 days)

The time from the date of first dose of study drug to the date of first documentation of a CR or CRi and DMR. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Expansion CohortBaseline, Day 21 of Cycle 1(Predose)

Biomarker assessments were used to understand the in vivo mechanism of action of PF-04449913, as well as potential mechanisms of resistance. In this outcome measure ratio of GLI1 levels (Blood, mRNA) at baseline to day 21 cycle 1 is reported.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 3Cmax, Cmin: Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1; Cavg: 0 to 24 hors post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1; Ctrough: Pre PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval, dosing interval was of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of PF-04449913: Combination Cohort 3Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1
Multiple Dose- AUCtau of PF-04449913: Combination Cohort 30 to 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.

Multiple Dose- CL/F of PF-04449913: Combination Cohort 3Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

CL/F was defined as apparent total clearance of the drug from plasma after oral administration. CL/F of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Azacitidine: Combination Cohort 3Cmax: 0.25, 0.5, 1, 2, 6 hrs post azacitidine dose on Day 1/Cycle 1;Cmin: Pre-dose, 0.25, 0.5, 1, 2, 6 hrs post azacitidine dose on Day 7/Cycle 1;Cavg: 0 to 24 hrs post azacitidine dose on Day 7/Cycle 1;Ctrough:Pre azacitidine dose on Day 7/Cycle 1

Cmax = Maximum plasma concentration, observed directly from data. Cmin = Minimum plasma concentration observed directly from data. Cavg = Average plasma concentration over the dosing interval of 24 hours. Ctrough = Pre-dose concentration, observed directly from data.

Multiple Dose- Tmax of Azacitidine: Combination Cohort 30.25, 0.5, 1, 2, and 6 hours post azacitidine dosing on Day 1 of Cycle 1 and pre-dose, 0.25, 0.5, 1, 2, and 6 hours post azacitidine dosing on Day 7 of Cycle 1
Multiple Dose- AUCtau and AUCinf of Azacitidine: Combination Cohort 3AUCinf: 0.25, 0.5, 1, 2, and 6 hours post azacitidine dosing at Day 1 of Cycle 1 and pre-dose, 0.25, 0.5, 1, 2, and 6 hours post azacitidine dosing at 7 of Cycle 1; AUCtau: 0 to 24 hours post azacitidine dosing on Day 1 and 7 of Cycle 1

AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours. AUCinf = AUClast + (Clast/kel), where Clast = predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and where kel = terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Overall Survival: Combination Cohort 3First dose of study drug up to death or date of last contact (maximum up to 841 days)

Overall survival was defined as the time from the date of first dose of study drug to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact.

Ratio of GLI1 Levels at Baseline to End of Treatment: Combination Cohort 3Baseline, at the end of treatment (hours unspecified, any day maximum up to 841 days)

Biomarker assessments were used to understand the in vivo mechanism of action of PF-04449913, as well as potential mechanisms of resistance. In this outcome measure ratio of GLI1 levels (Blood, mRNA) to end of treatment is reported.

Number of Participants With Best Response: Combination Cohort 3Day 1 up to end of treatment (maximum up to 841 days)

Best response observed for: CR, Cri, MLFS, PR, PRi, CRc, CRm. Response criteria for participants with AML- CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, decrease to 5-25 and \>=50% decrease from start. PRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB decrease to 5-25 and \>=50% decrease from start. Minor Response: BMB \>=25% decrease from start. CRc: neutrophils (mcL) \>1,000, platelets (mcL) \>100,000, BMB \<5%. CRm: neutrophils (mcL) \>1,000, platelets (mcL) \>100,000, BMB \<5%. Only those responses which had at least 1 participant were reported.

Percentage of Participants With CR/CRi and DMR: Combination Cohort 3Day 1 up to end of treatment (maximum up to 841 days)

CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Duration of Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 3Day 1 up to end of treatment (maximum up to 841 days)

Duration of response was the time from the date of first documentation of a CR/CRi and DMR to the date of first documentation of relapse after CR/CRi and DMR or death due to any cause. Duration of response data was censored on the date of the last adequate response assessment for participants who do not have an event (relapse or death). DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Time to Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 3Day 1 up to end of treatment (maximum up to 841 days)

The time from the date of first dose of study drug to the date of first documentation of a CR or CRi and DMR. DMR included CR, CRi, MLFS, mCR and PR. CR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, bone marrow blasts (BMB) \<5%. CRi: neutrophils (mcL) \<1000 or platelets (mcL) \<100000, BMB \<5%. MLFS: neutrophils (mcL) 1000 and platelets (mcL) \<100000, BMB \<5%. PR: neutrophils (mcL) \>=1000, platelets (mcL) \>=100000, BMB decrease to 5-25 and \>=50% decrease from start.

Number of Participants With Laboratory Test Abnormalities: Continuation CohortBaseline up to maximum 1146 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), blood urea nitrogen (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 TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Expansion CohortDay 1 up to 28 days after last dose of study drug (Maximum up to 1436 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 Vital Signs: Expansion CohortBaseline up to maximum 1436 days

Vital signs included blood pressure (sitting or supine) and heart rate. Vital sign criteria included: Systolic BP: \<90 millimeter of mercury \[mmHg\]; Systolic BP change from baseline: maximum increase and decrease \>=30 mmHg; Diastolic BP minimum \< 50 mmHg; Diastolic BP change from baseline: maximum decrease and increase \>=20 mmHg; heart rate \<40 and \>120 beats per minute. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With Clinically Significant Vital Signs: Continuation CohortBaseline up to maximum 1146 days

Vital signs included blood pressure (sitting or supine) and heart rate. Vital sign criteria included: Systolic BP: \<90 millimeter of mercury \[mmHg\]; Systolic BP change from baseline: maximum increase and decrease \>=30 mmHg; Diastolic BP minimum \< 50 mmHg; Diastolic BP change from baseline: maximum decrease and increase \>=20 mmHg; heart rate \<40 and \>120 beats per minute. Clinically significant changes in vital signs were determined by the investigator's discretion.

Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Continuation CohortDay 1 up to 28 days after last dose of study drug (Maximum up to 1146 days)

AE: any untoward medical occurrence in participant who received study drug or medical device without regard to possibility of causal relationship with the treatment or usage. 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 Laboratory Test Abnormalities: Expansion CohortBaseline up to maximum 1436 months

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), blood urea nitrogen (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'.

Trial Locations

Locations (9)

Japanese Red Cross Nagoya First Hospital

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Nagoya, Aichi, Japan

Kobe University Hospital

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Kobe-shi, Hyogo, Japan

Akita University Hospital

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Akita, Japan

National Cancer Center Hospital

🇯🇵

Chuo-ku, Tokyo, Japan

Yamagata University Hospital

🇯🇵

Yamagata-Shi, Yamagata, Japan

Tohoku University Hospital

🇯🇵

Sendai, Miyagi, Japan

Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital

🇯🇵

Bunkyo-ku, Tokyo, Japan

Kyushu University Hospital

🇯🇵

Fukuoka, Japan

Tokyo Medical University Hospital

🇯🇵

Tokyo, Japan

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