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

NCT02038777 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: B1371005NCT02038777
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 9

Brief Summary

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

Conditions

Acute Myeloid Leukemia

Keywords

Hematologic Malignancies

Outcome Measures

Primary Outcomes (17)

• 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.

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

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

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

  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)

• 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.

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

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

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

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

• Number of Participants With DLTs: Combination Cohort 1

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

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

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

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

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

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

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

  Baseline up to maximum 486 days

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

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

  Baseline up to maximum 514 days

• Number of Participants With DLTs: Combination Cohort 2

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

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

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

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

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

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

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

  Baseline up to maximum 343 days

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

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

  Baseline up to maximum 371 days

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

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

  Baseline up to maximum 736 days

• Number of Participants With DLTs: Combination Cohort 3

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

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

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

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

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

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

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

  Baseline up to maximum 841 days

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

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

  Baseline up to maximum 869 days

Secondary Outcomes (68)

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

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

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

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

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

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

• Single Dose- Area Under the Plasma Concentration Curve: From Time Zero to End of Dosing Interval (AUCtau), From Time Zero to Last Quantifiable Concentration (AUClast) and From Time Zero to Infinity (AUCinf) of PF-04449913 for Monotherapy Cohort

  AUCtau: 0 to 24, 24 to 48, 48 to 72 hours post PF-04449913 dosing on Day -5 of Cycle 1; AUClast and AUCinf: Pre-dose and 0.5, 1, 2, 4, 8, 24, 48, 72 hours post PF-04449913 dosing on Day -5 of Cycle 1

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

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

Study Arms (6)

Monotherapy Cohort

EXPERIMENTAL

PF-04449913 Monotherapy

Drug: PF-04449913

Combination Cohort 1

EXPERIMENTAL

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

Drug: PF-04449913; Drug: Low dose ARA-C (LDAC)

Combination Cohort 2

EXPERIMENTAL

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.

Drug: PF-04449913; Drug: Daunorubicin; Drug: Cytarabine

Azacitidine Combination Cohort

EXPERIMENTAL

PF-04449913 in combination with azacitidine

Drug: PF-04449913; Drug: Azacitidine

Continuation Cohort

EXPERIMENTAL

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

Drug: PF-04449913

Expansion Cohort of LDAC Combination for Efficacy

EXPERIMENTAL

PF-04449913 in combination with LDAC to evaluate efficacy

Drug: PF-04449913; Drug: LDAC

Interventions

PF-04449913 DRUG

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

Continuation Cohort; Monotherapy Cohort

Low dose ARA-C (LDAC) DRUG

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

Combination Cohort 1

Daunorubicin DRUG

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

Combination Cohort 2

Cytarabine DRUG

Cytarabine 100 mg/m2 on days 1 through 7.

Combination Cohort 2

Azacitidine DRUG

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

Azacitidine Combination Cohort

LDAC DRUG

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

Expansion Cohort of LDAC Combination for Efficacy

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead

Study Sites (9)

Japanese Red Cross Nagoya First Hospital

Nagoya, Aichi-ken, 453-8511, Japan

Location

Kobe University Hospital

Kobe, Hyōgo, 650-0017, Japan

Location

Tohoku University Hospital

Sendai, Miyagi, 980-8574, Japan

Location

Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital

Bunkyo-ku, Tokyo, 113-8677, Japan

Location

National Cancer Center Hospital

Chuo-ku, Tokyo, 104-0045, Japan

Location

Yamagata University Hospital

Yamagata, Yamagata, 990-9585, Japan

Location

Akita University Hospital

Akita, 010-8543, Japan

Location

Kyushu University Hospital

Fukuoka, 812-8582, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Hematologic Neoplasms

Interventions

glasdegib; Cytarabine; Daunorubicin; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Aza Compounds; Ribonucleosides

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 14, 2014
• First Posted: January 17, 2014
• Study Start: March 25, 2014
• Primary Completion: February 12, 2021
• Study Completion: December 28, 2023
• Last Updated: February 26, 2025
• Results First Posted: March 18, 2022

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

JP (9)