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AzTrials

Acute Myeloid LeukemiaPhase 1NCT02038777

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

A Phase 1 study testing PF-04449913, Low dose ARA-C (LDAC) and Daunorubicin in people with Acute Myeloid Leukemia, run by Pfizer at 9 sites in Japan.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 20 years and older
Conditions the study is for
Acute Myeloid Leukemia
What is being tested?
PF-04449913, Low dose ARA-C (LDAC) and Daunorubicin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
48 participants
Where
9 sitesJapan
Study dates
25 Mar 2014to 28 Dec 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

Japan9 sites

  • Akita University Hospital

    Akita, 010-8543

  • Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital

    Bunkyo-ku, Tokyo, 113-8677

  • National Cancer Center Hospital

    Chuo-ku, Tokyo, 104-0045

  • Kyushu University Hospital

    Fukuoka, 812-8582

  • Kobe University Hospital

    Kobe, Hyōgo, 650-0017

  • Japanese Red Cross Nagoya First Hospital

    Nagoya, Aichi-ken, 453-8511

  • Tohoku University Hospital

    Sendai, Miyagi, 980-8574

  • Tokyo Medical University Hospital

    Tokyo, 160-0023

  • Yamagata University Hospital

    Yamagata, Yamagata, 990-9585

Other trials in Japan

About this study

Official title: 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

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.

Being tested
PF-04449913, Low dose ARA-C (LDAC), Daunorubicin, Cytarabine, Azacitidine
Keywords
Hematologic Malignancies
Medical subject headings
Leukemia, Myeloid, Acute, Hematologic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PF-04449913Drug

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

  • PF-04449913Drug

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

  • Low dose ARA-C (LDAC)Drug

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

  • PF-04449913Drug

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

  • DaunorubicinDrug

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

  • CytarabineDrug

    Cytarabine 100 mg/m2 on days 1 through 7.

  • PF-04449913Drug

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

  • AzacitidineDrug

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

  • PF-04449913Drug

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

  • LDACDrug

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

Study groups in NCT02038777
Study groupRoleWhat they receive
Monotherapy CohortExperimentalPF-04449913 Monotherapy
Receives: Drug: PF-04449913
Combination Cohort 1ExperimentalPF-04449913 in combination with low dose ARA-C (LDAC)
Receives: Drug: PF-04449913; Drug: Low dose ARA-C (LDAC)
Combination Cohort 2ExperimentalPF-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.
Receives: Drug: PF-04449913; Drug: Daunorubicin; Drug: Cytarabine
Azacitidine Combination CohortExperimentalPF-04449913 in combination with azacitidine
Receives: Drug: PF-04449913; Drug: Azacitidine
Continuation CohortExperimentalPF-04449913 Monotherapy for one patient rolled-over from another trial in the same project.
Receives: Drug: PF-04449913
Expansion Cohort of LDAC Combination for EfficacyExperimentalPF-04449913 in combination with LDAC to evaluate efficacy
Receives: Drug: PF-04449913; Drug: LDAC

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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.

    Measured: 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)

  3. 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.

    Measured: 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

  4. 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'.

    Measured: 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

  5. 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.

    Measured: Day 1 up to Day 28 of Cycle 1 (28 days)

  6. 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.

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

  7. 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.

    Measured: Baseline up to maximum 486 days

  8. 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'.

    Measured: Baseline up to maximum 514 days

  9. 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.

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

  10. 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.

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

  11. 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.

    Measured: Baseline up to maximum 343 days

  12. 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'.

    Measured: Baseline up to maximum 371 days

  13. 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.

    Measured: Baseline up to maximum 736 days

  14. 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.

    Measured: Day 1 up to Day 28 of Cycle 1 (28 days)

  15. 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.

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

  16. 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.

    Measured: Baseline up to maximum 841 days

  17. 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'.

    Measured: Baseline up to maximum 869 days

Secondary outcomes (68)

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

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

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

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

  3. 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.

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

  4. 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.

    Measured: 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

  5. 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.

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

  6. 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.

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

  7. 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.

    Measured: 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

  8. Multiple Dose- Tmax of PF-04449913: Monotherapy Cohort

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing on Day 21 of Cycle 1

  9. 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.

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1

  10. 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.

    Measured: Pre-dose and 0.5, 1, 2, 4, 8, and 24 hours post PF-04449913 dosing Day 21 of Cycle 1

  11. 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.

    Measured: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day -5 and Day 21 of Cycle 1

  12. 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.

    Measured: 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

  13. 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.

    Measured: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

  14. 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.

    Measured: 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)

  15. 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.

    Measured: 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

  16. Multiple Dose- Tmax of PF-04449913: Combination Cohort 1

    Measured: 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

  17. 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.

    Measured: 0 to 24 hours post PF-04449913 dose on Day 10 and Day 21 of Cycle 1

  18. 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.

    Measured: 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

  19. 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.

    Measured: 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

  20. Multiple Dose- Tmax of Cytarabine: Combination Cohort 1

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

    Measured: 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

  21. 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.

    Measured: 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

  22. 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.

    Measured: 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

  23. 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.

    Measured: 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

  24. Multiple Dose- Tmax of Ara-uridine: Combination Cohort 1

    Ara-uridine was a metabolite of cytarabine.

    Measured: 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

  25. 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.

    Measured: 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)

  26. Multiple Dose- Tmax of PF-04449913: Combination Cohort 2

    Measured: 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

  27. 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.

    Measured: 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

  28. 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.

    Measured: 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

  29. 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.

    Measured: 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

  30. Multiple Dose- Tmax of Daunorubicin: Combination Cohort 2

    Measured: 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

  31. 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

    Measured: 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

  32. 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.

    Measured: 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

  33. 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.

    Measured: 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

  34. Multiple Dose- Tmax of Daunorubicinol: Combination Cohort 2

    Daunorubicinol was a metabolite of daunorubicin.

    Measured: 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

  35. 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.

    Measured: 0 to 24 hours post daunorubicin dosing on Day 3 of induction Cycle 1

  36. 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.

    Measured: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

  37. 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.

    Measured: Baseline, Day 21 of Cycle 1 (Unspecified- at any time on Day 21)

  38. 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.

    Measured: Day 1 up to end of treatment (maximum up to 486 days)

  39. 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.

    Measured: Day 1 up to end of treatment (maximum up to 343 days)

  40. 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.

    Measured: Day 1 up to end of treatment (maximum up to 486 days)

  41. 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.

    Measured: Day 1 up to end of treatment (maximum up to 486 days)

  42. 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.

    Measured: Day 1 up to end of treatment (maximum up to 486 days)

  43. 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.

    Measured: First dose of study drug up to death or date of last contact (maximum up to 514 days)

  44. 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.

    Measured: First dose of study drug up to death or date of last contact (maximum up to 1408 days)

  45. 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.

    Measured: From first dose of study drug up to disease progression (maximum duration of 1408 days)

  46. 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.

    Measured: Day 1 up to end of treatment (maximum up to 1408 days)

  47. 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.

    Measured: Day 1 up to end of treatment (maximum up to 1408 days)

  48. 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.

    Measured: Day 1 up to end of treatment (maximum up to 1408 days)

  49. 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.

    Measured: Baseline, Day 21 of Cycle 1(Predose)

  50. 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.

    Measured: 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

  51. Multiple Dose- Tmax of PF-04449913: Combination Cohort 3

    Measured: Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

  52. 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.

    Measured: 0 to 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

  53. 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.

    Measured: Pre-dose, 0.25, 1, 4, 6, 24 hours post PF-04449913 dosing on Day 7 and Day 21 of Cycle 1

  54. 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.

    Measured: 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

  55. Multiple Dose- Tmax of Azacitidine: Combination Cohort 3

    Measured: 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

  56. 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.

    Measured: 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

  57. 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.

    Measured: First dose of study drug up to death or date of last contact (maximum up to 841 days)

  58. 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.

    Measured: Baseline, at the end of treatment (hours unspecified, any day maximum up to 841 days)

  59. 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.

    Measured: Day 1 up to end of treatment (maximum up to 841 days)

  60. 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.

    Measured: Day 1 up to end of treatment (maximum up to 841 days)

  61. 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.

    Measured: Day 1 up to end of treatment (maximum up to 841 days)

  62. 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.

    Measured: Day 1 up to end of treatment (maximum up to 841 days)

  63. 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'.

    Measured: Baseline up to maximum 1146 days

  64. 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.

    Measured: Day 1 up to 28 days after last dose of study drug (Maximum up to 1436 days)

  65. 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.

    Measured: Baseline up to maximum 1436 days

  66. 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.

    Measured: Baseline up to maximum 1146 days

  67. 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.

    Measured: Day 1 up to 28 days after last dose of study drug (Maximum up to 1146 days)

  68. 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'.

    Measured: Baseline up to maximum 1436 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Jan 2014 (estimated)
  2. Study start25 Mar 2014
  3. Primary completion12 Feb 2021
  4. Study completion28 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
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.
Masking
None (open label)
Enrolment
48 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02038777
Sponsor's protocol ID
B1371005
Other IDs
NCT02038777
Status last verified
Feb 2025
First submitted
14 Jan 2014
Last updated
26 Feb 2025
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: 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.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing PF-04449913, Low dose ARA-C (LDAC) and Daunorubicin in people with Acute Myeloid Leukemia, run by Pfizer at 9 sites in Japan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Dose-limiting Toxicities (DLTs): Monotherapy Cohort (time frame: Day -5 up to Day 28 of Cycle 1 (33 days)). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02038777.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2025.

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