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A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In 1st Line MDS, AML and CMML Patients

This study is currently recruiting participants.
Verified November 2017 by Pfizer
Sponsor:
ClinicalTrials.gov Identifier:
NCT02367456
First Posted: February 20, 2015
Last Update Posted: November 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Pfizer
  Purpose
This multi center randomized (1:1), double blind, placebo controlled Phase 1b/2 study is designed to compare the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of PF 04449913 or placebo when combined with azacitidine in patients with previously untreated Intermediate 2 or High Risk Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML) with 20-30% blasts and multi lineage dysplasia, and Chronic Myelomonocytic Leukemia (CMML). This clinical study includes two components: (a) a Phase 1b safety lead in and (b) a randomized Phase 2.

Condition Intervention Phase
Myelodysplastic Syndrome Drug: PF-04449913 (Glasdegib) Drug: Azacitidine Drug: PF-04449913 (Glasdegib) Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind Phase 1b/2 Study Of Pf-04449913 (Glasdegib) In Combination With Azacitidine In Patients With Previously Untreated Intermediate-2 Or High-risk Myelodysplastic Syndrome, Acute Myeloid Leukemia With 20-30% Blasts And Multi-lineage Dysplasia, Or Chronic Myelomonocytic Leukemia

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • RR (hematology) [ Time Frame: All cycles up until 30 months from randomization ]
    Response rate (percentage of patients achieving CR + PR) as defined by modified IWG criteria (2006) (Phase 2)


Secondary Outcome Measures:
  • RR(Hematology) [ Time Frame: All Cycles up until 30 months from randomization ]
    Response Rate - (Percentage of Participants achieving CR + PR) as defined by modified IWG criteria (2006)(Phase 1)

  • Hematologic Improvement [ Time Frame: All cycles up until 30 months from randomization ]
    Hematologic Improvement, as defined by modified IWG (2006) (Phase 1).

  • Marrow Complete Response (mCR) [ Time Frame: All cycles up until 30 months from randomization ]
    Marrow Complete Response, as defined by modified IWG (2006) (Phase 1).

  • Cytogenetic Response [ Time Frame: All cycles up until 30 months from randomization ]
    Cytogenic Response as defined by modified IWG (2006) (Phase 1).

  • Transfusion Independence [ Time Frame: All cycles up until 30 months from randomization ]
    Proportion of patients becoming transfusion independent on study in patients who were transfusion dependent at the time of study entry (Phase 1).

  • Stable Disease [ Time Frame: All cycles up until 30 months from randomization ]
    Stable Disease as defined by modified IWG (2006) (Phase 1).

  • QTc interval [ Time Frame: Cycle 1 through Cycle 6 and End of Treatment up until 30 months from randomization ]
    QTc interval corrected using Fridericia's Formula (msec) (Phase 1)

  • AUC for PF-04449913 [ Time Frame: 0. .25, .5, 1, 2, 4, 6, and 24 hours post-dose ]
    Area under the Concentration-Time Curve (ng*h/mL) (Phase 1).

  • Cmax for PF-04449913 [ Time Frame: 0, .25, .5, 1, 2, 4, 6, and 24 hours post-dose ]
    Maximum Observed Plasma Concentration (ng/mL) (Phase 1).

  • Tmax for PF-04449913 [ Time Frame: 0, .25, .5, 1, 2, 4, 6, and 24 hours post-dose ]
    Time to Reach Maximum Observed Plasma Concentration (hrs) (Phase 1).

  • AUC for Azacitidine [ Time Frame: 0, .25, .5, 1, 2, and 6 hours post-dose ]
    Area under the Concentration-Time Curve (ng*h/mL) (Phase 1).

  • Cmax for Azacitidine [ Time Frame: 0, .25, .5, 1, 2, and 6 hours post-dose ]
    Maximum Observed Plasma Concentration (ng/mL) (Phase 1).

  • Tmax for Azacitidine [ Time Frame: 0, .25, .5, 1, 2 and 6 hours post-dose ]
    Time to Reach Maximum Observed Plasma Concentration (hrs) (Phase 1).

  • Duration of Hematologic Improvement (HI) [ Time Frame: All cycles until disease progression or up until 30 months from randomization ]
    Duration of HI defined as time from start of first documented HI to first documented disease progression or relapse after HI or death due to any cause, whichever occurs first (Phase 2).

  • Time to Best Response or any hematologic improvement [ Time Frame: All cycles up until 30 months from randomization ]
    Time from randomization to achieving best response CR, PR or any HI. (Phase 2 only).

  • Survival: Probability of Participant Survival [ Time Frame: 12, 18 and 24 months ]
    Probability of survival at 12, 18 and 24 months after randomization (Phase 2).

  • Hematologic Improvement [ Time Frame: All cycles up until 30 months from randomization ]
    Hematologic Improvement, as defined by modified IWG (2006) (Phase 2).

  • Transfusion independence [ Time Frame: All cycles up until 30 months from randomization ]
    Proportion of patients becoming transfusion independent on study in patients who were transfusion dependent at the time of study entry (Phase 2).

  • QTc interval [ Time Frame: Cycle 1 through Cycle 6 and End of Treatment up until 30 months from randomization ]
    QTc interval corrected using Fridericia's Formula (msec) (Phase 2)

  • Marrow Complete Response (mCR) [ Time Frame: All cycles up until 30 months from randomization ]
    Marrow Complete Response, as defined by modified IWG (2006) (Phase 2).

  • Cytogenic Response [ Time Frame: All cycles up until 30 months from randomization ]
    Cytogenic Response as defined by modified IWG (2006) (Phase 2).

  • Stable Disease [ Time Frame: All cycles up until 30 months from randomization ]
    Stable Disease as defined by modified IWG (2006) (Phase 2).

  • Duration of Response [ Time Frame: All cycles until progression or up until 30 months from randomization ]
    Duration of response (DR) defined as time from start of first documented disease response [Complete Response (CR) or Partial Response (PR)] to first documented disease progression or death due to any cause, whichever occurs first (Phase 2).

  • Time to First Response or any hematologic improvement [ Time Frame: All cycles up until 30 months from randomization ]
    Time from randomization to first achieving CR, PR or HI (Phase 2).

  • Time to reaching >30% bone marrow blasts [ Time Frame: All cycles up until 30 months from randomization ]
    From Randomization to first reaching >30% bone marrow blasts (Phase 2).

  • Ctrough [ Time Frame: Cycle 1 Day 15 and Cycle 2 Day 1 ]
    Minimum Observed Plasma Trough Concentration (ng/mL)(Phase 2).

  • Overall Survival (OS) [ Time Frame: Randomization till death up until 30 months from randomization ]
    Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact (Phase 2).

  • Event Free Survival [ Time Frame: All Cycles up until 30 months from randomization ]
    Time from Randomization to first documentation of bone marrow blasts >30% or death for any reason whichever occurs first (Phase 2).

  • EQ-5D [ Time Frame: Baseline and Every Cycle up until 30 months from randomization ]
    Change From Baseline in Euro Quality of Life - Health State Profile Utility, Visual Analog Scale (VAS), and Dimension Health State EuroQol Score at Every Cycle (Phase 2).

  • EORTC-QLQ-C30 [ Time Frame: Baseline and Every Cycle up until 30 months from randomization ]
    European Organization of Research and the Treatment of Cancer- Quality of Life Core Questionnaire (Phase 2)


Estimated Enrollment: 170
Actual Study Start Date: April 28, 2015
Estimated Study Completion Date: November 6, 2021
Estimated Primary Completion Date: November 7, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
Drug: PF-04449913 (Glasdegib)
Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles
Drug: Azacitidine
75mg/m2 on Days 1-7 of a 28 day cycle or on Days 1-5, 8-9 of a 28 day cycle
Active Comparator: Arm B
PF-04449913 (Glasdegib) Placebo 100 mg + Azacitidine 75 mg/m2
Drug: Azacitidine
75mg/m2 on Days 1-7 of a 28 day cycle or on Days 1-5, 8-9 of a 28 day cycle
Drug: PF-04449913 (Glasdegib) Placebo
Daily dose of the Placebo for PF-04449913 100 mg tablet in a continuous regimen of 28 day cycles.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patient must meet all the following inclusion criteria to be eligible for enrollment into the study:

  1. Morphologically confirmed diagnosis of one of the following:

    1. MDS according to the WHO 2008 classification and bone marrow blasts > or = 5%
    2. AML with 20-30 % BM blasts and multi lineage dysplasia, according to WHO 2008 classification and WBC < 20x109/L
    3. CMML according to the WHO 2008 classification (Appendix 1) and BM blasts between 10% 19% and WBC < 13x109/L
  2. MDS patients must have Intermediate 2 (1.5 to 2.0 points) or High Risk (≥2.5 points) disease according to the International Prognostic Scoring System 1997 (IPSS).
  3. MDS patients must have normal levels of vitamin B12 within the institutional range of normal as determined within 28 days of study entry.
  4. AML patients with 20- 30% BM blasts and multi lineage dysplasia, must have stable blast counts per Investigator's judgment.
  5. Clinical indication for treatment with azacitidine for MDS, AML or CMML.

Exclusion Criteria:

Patients with any of the following may not be included in the study:

  1. Patients with AML who are candidates for standard induction chemotherapy as first line treatment.
  2. Therapy related (secondary to radiation or chemotherapy) MDS or AML.
  3. Prior hypomethylating agents or cytotoxic chemotherapy for MDS, AML or CMML (prior immunosuppressive therapy and hydroxyurea are permitted provided that treatment is stopped within 8 and 2 weeks from study entry, respectively).
  4. Previous hematopoietic stem cell transplant.
  5. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or hypomethylating agent (HMA).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02367456


Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

  Show 31 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02367456     History of Changes
Other Study ID Numbers: B1371012
2014-001345-24 ( EudraCT Number )
First Submitted: February 13, 2015
First Posted: February 20, 2015
Last Update Posted: November 22, 2017
Last Verified: November 2017

Keywords provided by Pfizer:
MDS
AML
CMML

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors