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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
PF-04449913 administered orally and continuously in 28 day cycles.
PF-04449913 administered orally and continuously in 28 day cycles.
Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.
Japanese Red Cross Nagoya First Hospital
Nagoya, Aichi-ken, Japan
Kobe University Hospital
Kobe, Hyōgo, Japan
Tohoku University Hospital
Sendai, Miyagi, Japan
Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital
Number of Participants With Dose-limiting Toxicities (DLTs): Monotherapy Cohort
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.
Time frame: Day -5 up to Day 28 of Cycle 1 (33 days)
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
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.
Time frame: 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)
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PF-04449913 administered orally and continuously in 28 day cycles.
Daunorubicin given using 60 mg/m2 for 3-days.
Cytarabine 100 mg/m2 on days 1 through 7.
PF-04449913 administered orally and continuously in 28 day cycles.
Azacitidine Combination Cohort; Azacitidine 75 mg/m2 for 7 days.
PF-04449913 administered orally and continuously in 28 day cycles.
Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.
Bunkyo-ku, Tokyo, Japan
National Cancer Center Hospital
Chuo-ku, Tokyo, Japan
Yamagata University Hospital
Yamagata, Yamagata, Japan
Akita University Hospital
Akita, Japan
Kyushu University Hospital
Fukuoka, Japan
Tokyo Medical University Hospital
Tokyo, Japan
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Monotherapy Cohort
Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.
Time frame: 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
Number of Participants With Worst On-study Laboratory Abnormalities: Monotherapy Cohort
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'.
Time frame: 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
Number of Participants With DLTs: Combination Cohort 1
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.
Time frame: Day 1 up to Day 28 of Cycle 1 (28 days)
Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 1
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.
Time frame: Day 1 up to 28 days after last dose of study drug (maximum up to 514 days)
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 1
Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.
Time frame: Baseline up to maximum 486 days
Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 1
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'.
Time frame: Baseline up to maximum 514 days
Number of Participants With DLTs: Combination Cohort 2
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.
Time frame: Day -3 up to anytime between Day 21 and Day 28 of first induction cycle (24 to 31 days)
Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 2
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.
Time frame: Day 1 up to 28 days after last dose of study drug (maximum up to 371 days)
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 2
Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.
Time frame: Baseline up to maximum 343 days
Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 2
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'.
Time frame: Baseline up to maximum 371 days
Percentage of Participants Achieving Disease Modifying Response (DMR): Expansion Cohort
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.
Time frame: Baseline up to maximum 736 days
Number of Participants With DLTs: Combination Cohort 3
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.
Time frame: Day 1 up to Day 28 of Cycle 1 (28 days)
Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Combination Cohort 3
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.
Time frame: Day 1 up to 28 days after last dose of study drug (maximum up to 869 days)
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Abnormalities: Combination Cohort 3
Vital signs included blood pressure (sitting or supine) and heart rate. Clinically significant changes in vital signs were determined by the investigator's discretion.
Time frame: Baseline up to maximum 841 days
Number of Participants With Worst On-study Laboratory Abnormalities: Combination Cohort 3
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'.
Time frame: Baseline up to maximum 869 days
Single Dose- Maximum Observed Plasma Concentration (Cmax) of PF-04449913: Monotherapy Cohort
Time frame: Pre-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 Cohort
Time frame: Pre-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 Cohort
Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1
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 Cohort
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.
Time frame: AUCtau: 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
Single Dose- Clearance (CL/F) of PF-04449913: Monotherapy Cohort
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.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1
Single Dose- Volume of Distribution (Vz/F) of PF-04449913: Monotherapy Cohort
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.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1
Multiple Dose Cmax, Minimum Observed Plasma Concentration (Cmin), Average Observed Plasma Concentration (Cavg), Trough Plasma Concentration (Ctrough) of PF-04449913: Monotherapy Cohort
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.
Time frame: Cmax, 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
Multiple Dose- Tmax of PF-04449913: Monotherapy Cohort
Time frame: Pre-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 Cohort
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.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1
Multiple Dose- Clearance (CL/F) of PF-04449913: Monotherapy Cohort
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.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1
Multiple Dose- Accumulation Ratio (Rac) of PF-04449913: Monotherapy Cohort
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.
Time frame: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day -5 and Day 21 of Cycle 1
Multiple Dose- Steady State Accumulation Ratio (Rss) of PF-04449913: Monotherapy Cohort
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.
Time frame: AUCtau: 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
Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Monotherapy Cohort
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.
Time frame: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)
Number of Participants With Best Response: Monotherapy Cohort
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.
Time frame: Day 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)
Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 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.
Time frame: Cmax, 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
Multiple Dose- Tmax of PF-04449913: Combination Cohort 1
Time frame: Pre-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 1
AUCtau was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.
Time frame: 0 to 24 hours post PF-04449913 dose on Day 10 and Day 21 of Cycle 1
Multiple Dose- CL/F of PF-04449913: Combination Cohort 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.
Time frame: Pre-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- Cmax, Cmin, Cavg, and Ctrough of Cytarabine: Combination Cohort 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.
Time frame: Cmax, 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
Multiple Dose- Tmax of Cytarabine: Combination Cohort 1
LDAC= low dose ara-cytarabine/low dose cytarabine.
Time frame: 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
Multiple Dose- T1/2 of Cytarabine: Combination Cohort 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.
Time frame: 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
Multiple Dose- AUCinf and AUCtau of Cytarabine: Combination Cohort 1
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.
Time frame: AUCinf: 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
Multiple Dose- Cmax, Cmin, and Ctrough of Ara-uridine: Combination Cohort 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.
Time frame: Cmax, 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
Multiple Dose- Tmax of Ara-uridine: Combination Cohort 1
Ara-uridine was a metabolite of cytarabine.
Time frame: 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
Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 2
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.
Time frame: Cmax, 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)
Multiple Dose- Tmax of PF-04449913: Combination Cohort 2
Time frame: Pre-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 2
AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.
Time frame: Pre-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- CL/F of PF-04449913: Combination Cohort 2
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.
Time frame: Pre-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- Cmax, Cmin, Cavg, and Ctrough of Daunorubicin: Combination Cohort 2
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.
Time frame: Cmax, 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
Multiple Dose- Tmax of Daunorubicin: Combination Cohort 2
Time frame: 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
Multiple Dose- T1/2 of Daunorubicin: Combination Cohort 2
Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium
Time frame: 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 at induction Cycle 1
Multiple Dose- AUCinf and AUCtau of Daunorubicin: Combination Cohort 2
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.
Time frame: AUCinf: 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
Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Daunorubicinol: Combination Cohort 2
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.
Time frame: Cmax, 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
Multiple Dose- Tmax of Daunorubicinol: Combination Cohort 2
Daunorubicinol was a metabolite of daunorubicin.
Time frame: 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
Multiple Dose- AUCtau of Daunorubicinol: Combination Cohort 2
Daunorubicinol was a metabolite of daunorubicin. AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.
Time frame: 0 to 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1
Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Combination Cohort 1
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.
Time frame: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)
Ratio of GLI1 Levels at Baseline to Day 21 Cycle1: Combination Cohort 2
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.
Time frame: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)
Number of Participants With Best Response: Combination Cohort 1
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.
Time frame: Day 1 up to end of treatment (maximum up to 486 days)
Number of Participants With Best Response: Combination Cohort 2
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.
Time frame: Day 1 up to end of treatment (maximum up to 343 days)
Percentage of Participants With Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR: Combination Cohort 1
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.
Time frame: Day 1 up to end of treatment (maximum up to 486 days)
Duration of Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 1
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 frame: Day 1 up to end of treatment (maximum up to 486 days)
Time to Response: Combination Cohort 1
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.
Time frame: Day 1 up to end of treatment (maximum up to 486 days)
Overall Survival: Combination Cohort 1
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.
Time frame: First dose of study drug up to death or date of last contact (maximum up to 514 days)
Overall Survival (OS): Expansion Cohort
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.
Time frame: First dose of study drug up to death or date of last contact (maximum up to 1408 days)
Number of Participants With Best Response: Expansion Cohort
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.
Time frame: From first dose of study drug up to disease progression (maximum duration of 1408 days)
Percentage of Participants With CR/CRi and DMR: Expansion Cohort
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.
Time frame: Day 1 up to end of treatment (maximum up to 1408 days)
Duration of Response: Expansion Cohort
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 frame: Day 1 up to end of treatment (maximum up to 1408 days)
Time to Response: Expansion Cohort
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.
Time frame: Day 1 up to end of treatment (maximum up to 1408 days)
Ratio of GLI1 Levels at Baseline to Day 21 Cycle 1: Expansion Cohort
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.
Time frame: Baseline, Day 21 of Cycle 1(Predose)
Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of PF-04449913: Combination Cohort 3
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.
Time frame: Cmax, 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
Multiple Dose- Tmax of PF-04449913: Combination Cohort 3
Time frame: Pre-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 3
AUCtau, was determined by linear/log trapezoidal method. For AUC, tau (dosing interval) was 24 hours.
Time frame: 0 to 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1
Multiple Dose- CL/F of PF-04449913: Combination Cohort 3
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.
Time frame: Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1
Multiple Dose- Cmax, Cmin, Cavg, and Ctrough of Azacitidine: Combination Cohort 3
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.
Time frame: Cmax: 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
Multiple Dose- Tmax of Azacitidine: Combination Cohort 3
Time frame: 0.25, 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 3
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.
Time frame: AUCinf: 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
Overall Survival: Combination Cohort 3
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.
Time frame: First dose of study drug up to death or date of last contact (maximum up to 841 days)
Ratio of GLI1 Levels at Baseline to End of Treatment: Combination Cohort 3
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.
Time frame: Baseline, at the end of treatment (hours unspecified, any day maximum up to 841 days)
Number of Participants With Best Response: Combination Cohort 3
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.
Time frame: Day 1 up to end of treatment (maximum up to 841 days)
Percentage of Participants With CR/CRi and DMR: Combination Cohort 3
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.
Time frame: Day 1 up to end of treatment (maximum up to 841 days)
Duration of Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 3
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 frame: Day 1 up to end of treatment (maximum up to 841 days)
Time to Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) and DMR Response: Combination Cohort 3
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.
Time frame: Day 1 up to end of treatment (maximum up to 841 days)
Number of Participants With Laboratory Test Abnormalities: Continuation Cohort
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'.
Time frame: Baseline up to maximum 1146 days
Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Expansion Cohort
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.
Time frame: Day 1 up to 28 days after last dose of study drug (Maximum up to 1436 days)
Number of Participants With Clinically Significant Vital Signs: Expansion Cohort
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.
Time frame: Baseline up to maximum 1436 days
Number of Participants With Clinically Significant Vital Signs: Continuation Cohort
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.
Time frame: Baseline up to maximum 1146 days
Number of Participants With TEAEs, Serious TEAEs, Treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0: Continuation Cohort
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.
Time frame: Day 1 up to 28 days after last dose of study drug (Maximum up to 1146 days)
Number of Participants With Laboratory Test Abnormalities: Expansion Cohort
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'.
Time frame: Baseline up to maximum 1436 months