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PF-04449913 in combination with low dose ARA-C (LDAC)

PF-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.

PF-04449913 in combination with azacitidine

PF-04449913 Monotherapy for one patient rolled-over from another trial in the same project.

PF-04449913 in combination with LDAC to evaluate efficacy

PF-04449913 administered orally and continuously in 28 day cycles.

PF-04449913

Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.

Low dose ARA-C (LDAC)

Daunorubicin given using 60 mg/m2 for 3-days.

Cytarabine 100 mg/m2 on days 1 through 7.

Azacitidine Combination Cohort; Azacitidine 75 mg/m2 for 7 days.

LDAC

Pfizer CT.gov Call Center

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.

MTD was determined in monotherapy cohort. Then two combination cohorts (Combination Cohorts 1 and 2) were added to evaluate the safety of glasdegib administered with chemotherapies. Another combination cohort (Combination Cohort 3) was added to evaluate the safety of glasdegib administered with Azacitidine. Then, Continuation Cohort which allows one Japanese patient enrolled from another trial in the same project was added. Afther that, Expansion Cohort of LDAC Combination for efficacy was added.

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

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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.

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.

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

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'.

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.

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'.

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'.

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.

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'.

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

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.

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.

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.

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.

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.

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.

Analysis is not final for this outcome measure at primary completion date (PCD), complete data will be posted at study completion date (SCD).

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.

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

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.

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

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.

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.

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.

Ara-uridine was a metabolite of cytarabine.

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

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

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.

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.

Daunorubicinol was a metabolite of daunorubicin.

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

Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD.

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.

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.

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 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 patients 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.

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 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.

Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. Safety assessments included number of participants with TEAEs, serious TEAEs, treatment Related TEAEs, Grade 3 or 4 TEAEs Based on NCI CTCAE v4.0, and with vital signs and laboratory test abnormalities.

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.

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.

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.

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.

Pfizer

Same event may appear as both an adverse event (AE) and serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

Participants with advanced hematologic malignancies received PF-04449913 25 mg tablets orally, a single dose on Day -5 of Cycle 1 and then continuously QD from Cycle 1/Day 1 in 28-day cycles, maximum up to 12 cycles or until disease progression or relapse, or participant withdrawal, or unacceptable toxicity (whichever occurred first).

Monotherapy Cohort: PF-04449913 25 mg

Participants with advanced hematologic malignancies received PF-04449913 50 mg tablets orally, a single dose on Day -5 of Cycle 1 and then continuously QD from Cycle 1/Day 1 in 28-day cycles, maximum up to 12 cycles or until disease progression or relapse, or participant withdrawal, or unacceptable toxicity (whichever occurred first).

Monotherapy Cohort: PF-04449913 50 mg

Participants with advanced hematologic malignancies received PF-04449913 100 mg tablets orally, a single dose on Day -5 of Cycle 1 and then continuously QD from Cycle 1/Day 1 in 28-day cycles, maximum up to 12 cycles or until disease progression or relapse, or participant withdrawal, or unacceptable toxicity (whichever occurred first).

Monotherapy Cohort: PF-04449913 100 mg

Participants with previously untreated AML/high-risk MDS and unfit for intensive chemotherapy, received PF-04449913 100 mg tablets continuously QD from Cycle 1/Day 3 in 28 day cycles and LDAC 20 mg was administered SC twice daily for first 10 days of the 28-day cycles, maximum up to up to 12 cycles or until disease progression or relapse, or participant refusal, or unacceptable toxicity occurs (whichever occurred first).

Combination Cohort 1 (Unfit Participants): PF-04449913 100 mg + LDAC 20 mg

Participants with previously untreated AML/high-risk MDS and fit for intensive chemotherapy, participants started receiving PF-04449913 100 mg tablets QD from Day -3 up to Day 28 for first induction cycle and then continuously QD from Cycle 1/Day 1 in 28 day cycles for rest of treatment duration along with Cytarabine 100 mg/m\^2 was administered daily by continuous IV infusion for first 7 days of Cycle and Daunorubicin 60 mg/m\^2 daily IV for first 3 days of Cycle. Participants with \<= 5% bone marrow blasts had second cycle of induction. Participants achieving a complete response after the completion of induction therapy were eligible to begin consolidation cycles. During consolidation, participants received PF-04449913 100 mg tablets orally QD in 28 day cycle along with Cytarabine 1g/m\^2 QD on Day 1, 3 and 5 of 28 day cycle. Consolidation was of 2 to 4 cycles. Post-consolidation participants received PF-04449913 100 mg tablets orally QD in 28 day cycle for maintenance up to maximum of 6 cycles.

Combination Cohort 2 (Fit Participants): PF-04449913 100 mg + Cytarabine + Daunorubicin

Participants with untreated AML and eligible for non-intensive chemotherapy received PF-04449913 100 mg tablets orally, continuously QD from Cycle 1/Day 2 in 28 day cycles along with azacitidine 75 mg/m\^2/day SC or IV daily on Days 1-7 of each 28-day cycle. Treatment continued for at least 6 cycles, or until disease progression or relapse, or participant withdrawal, or unacceptable toxicity, or death (whichever occurred first).

Combination Cohort 3: PF-04449913 100 mg + Azacitidine

Participants with myelofibrosis treated with PF-04449913 in B1371013 received the same dose (100 mg) of PF-04449913 as at the time of discontinuation from study B1371013 from Cycle 1/Day 1 until disease progression or relapse, or participant withdrawal, or unacceptable toxicity, or death (whichever occurred first).

Continuation Cohort (Monotherapy Cohort): PF-04449913 100 mg

Participants with previously untreated AML or high-risk MDS and unfit for intensive chemotherapy received PF-04449913 100 mg tablets continuously QD from Cycle 1/Day 1 in 28 day cycles and LDAC 20 mg SC twice daily for first 10 days of the 28 day cycles, until disease progression or relapse, or participant withdrawal, or unacceptable toxicity, or death (whichever occurred first).

Expansion Cohort (Unfit Participants): PF-04449913 100 mg+ LDAC 20 mg

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

Pfizer ClinicalTrials.gov Call Center

DLT evaluable analysis set included all enrolled participants who received at least 1 dose of study medication and who did not have major treatment deviations during first cycle (DLT observation period).

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

TEAEs

Serious TEAEs

Treatment related TEAEs

Grade 3 or 4 TEAEs

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

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

Lymphocytes/Leukocytes

Neutrophils/Leukocytes

Basophils/Leukocytes

Eosinophils/Leukocytes

Monocytes/Leukocytes

Prothrombin time

Blasts/Leukocytes

Lactate dehydrogenase

Protein

Urate

Chloride

Calcium

Urine specific gravity

Urine pH

Urine glucose

Urine ketones

Urine nitrite

Urine leukocyte esterase

Urine erythrocytes

Urine leukocytes

Safety analysis set included all enrolled participants who received at least 1 dose of study medication. Here, "number analyzed" signifies participants evaluable for the specific parameter.

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

Number of Participants With DLTs: Combination Cohort 1

Treatment Related TEAEs

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

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

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

Number of Participants With DLTs: Combination Cohort 2

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

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

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

Full analysis set (FAS) included all enrolled participants who received at least 1 dose of study medication on or after Cycle 1/Day 1.

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

Number of Participants With DLTs: Combination Cohort 3

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

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

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

Pharmacokinetic (PK) parameter analysis set included all treated participants with at least 1 PK parameters of interest of any of the study drugs.

Single Dose- Maximum Observed Plasma Concentration (Cmax) of PF-04449913: Monotherapy Cohort

PK parameter analysis set included all treated participants with at least 1 PK parameters of interest of any of the study drugs.

Single Dose- Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04449913: Monotherapy Cohort

Single Dose- Terminal Plasma Half-life (T1/2) of PF-04449913: Monotherapy Cohort

AUCtau

AUClast

AUCinf

PK parameter analysis set included all treated participants with at least 1 PK parameter of interest of any of the study drugs.

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

Single Dose- Clearance (CL/F) of PF-04449913: Monotherapy Cohort

Single Dose- Volume of Distribution (Vz/F) of PF-04449913: Monotherapy Cohort

Cmax

Cmin

Cavg

Ctrough

PK parameter analysis set included all treated participants with at least 1 PK parameters of interest of any of the study drugs. Here, "number analyzed" signifies participants evaluable for the specific parameter.

Multiple Dose Cmax, Minimum Observed Plasma Concentration (Cmin), Average Observed Plasma Concentration (Cavg), Trough Plasma Concentration (Ctrough) of PF-04449913: Monotherapy Cohort

PK parameter analysis set included all treated participants with at least 1 PK parameters of interest of any of the study drugs. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

Multiple Dose- Tmax of PF-04449913: Monotherapy Cohort

Multiple Dose- AUCtau of PF-04449913: Monotherapy Cohort

Multiple Dose- Clearance (CL/F) of PF-04449913: Monotherapy Cohort

Multiple Dose- Accumulation Ratio (Rac) of PF-04449913: Monotherapy Cohort

Multiple Dose- Steady State Accumulation Ratio (Rss) of PF-04449913: Monotherapy Cohort

Potential Biomarkers Levels: Monotherapy Cohort

Morphologic CR: AML

Morphologic CRi: AML

MLFs: AML

Stable disease: AML

Treatment failure: AML

Marrow complete remission: MDS

Stable disease: MDS

Disease progression: MDS

Treatment failure: MDS

Stable disease: CML

Disease progression: CML

FAS included all enrolled participants who received at least 1 dose of study medication on or after Cycle 1/Day 1. Here, "number analyzed" signifies participants evaluable for the specified rows.

Spots Global Cancer Trial Database for A Study Of PF-04449913 In Japanese Patients With Select Hematologic Malignancies

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

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