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A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients (BRIGHT 1012)

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ClinicalTrials.gov Identifier: NCT02367456
Recruitment Status : Active, not recruiting
First Posted : February 20, 2015
Last Update Posted : August 7, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
This multi center open label Phase 1b study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF-04449913) when combined with azacitidine in patients with previously untreated Higher Risk Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). This clinical study includes two components: (a) a safety lead in cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS cohort.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Drug: PF-04449913 (Glasdegib) Drug: Azacitidine Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 73 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: AN OPEN-LABEL PHASE 1B STUDY OF PF-04449913 (GLASDEGIB) IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH PREVIOUSLY UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROME, ACUTE MYELOID LEUKEMIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA
Actual Study Start Date : April 28, 2015
Estimated Primary Completion Date : January 29, 2020
Estimated Study Completion Date : January 28, 2021


Arm Intervention/treatment
Experimental: Arm A
MDS patients: 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 (+/- 3 days for each dose) of a 28 day cycle

Experimental: Arm B
AML patients: 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 (+/- 3 days for each dose) of a 28 day cycle




Primary Outcome Measures :
  1. Complete remission (CR) rate for MDS [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    CR rate - percentage of patients achieving CR as defined by modified IWG criteria (2006) for MDS (Expansion cohort)

  2. Complete remission (CR) rate for AML [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    CR rate - percentage of patients achieving CR as defined by ELN (2017) for AML (Expansion cohort)

  3. Adverse events (Safety lead-in phase) [ Time Frame: Screening through 28 days following last dose of study drug ]
    Adverse events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03), timing, seriousness and relationship to study therapy, and laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing (Safety lead-in phase)


Secondary Outcome Measures :
  1. Response Rate [ Time Frame: All cycles until progression, a median of 1 year ]
    Response rate - Percentage of participants achieving complete remission + partial remission as defined by modified IWG criteria (2006) (Safety lead-in phase)

  2. Hematologic Improvement [ Time Frame: All cycles until progression, a median of 1 year ]
    Hematologic Improvement, as defined by modified IWG criteria (2006) (Safety lead-in phase)

  3. Marrow Complete Response (mCR) [ Time Frame: All cycles until progression, a median of 1 year ]
    Marrow Complete Response, as defined by modified IWG criteria (2006) (Safety lead-in phase)

  4. Cytogenetic Response [ Time Frame: All cycles until progression, a median of 1 year ]
    Cytogenetic Response, as defined by modified IWG criteria (2006) (Safety lead-in phase)

  5. Stable Disease [ Time Frame: All cycles until progression, a median of 1 year ]
    Stable Disease, as defined by modified IWG criteria (2006) (Safety lead-in phase)

  6. AUC for Azacitidine [ Time Frame: First 2 weeks of treatment ]
    Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)

  7. Cmax for Azacitidine [ Time Frame: First 2 weeks of treatment ]
    Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)

  8. Tmax for Azacitidine [ Time Frame: First 2 weeks of treatment ]
    Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)

  9. AUC for PF-04449913 [ Time Frame: First 5 months of treatment ]
    Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)

  10. Cmax for PF-04449913 [ Time Frame: First 5 months of treatment ]
    Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)

  11. Tmax for PF-04449913 [ Time Frame: First 5 months of treatment ]
    Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)

  12. Ctrough for PF-04449913 [ Time Frame: First 1 month of treatment ]
    Minimum plasma concentration following daily dosing to steady state (ng/mL) (Expansion cohorts)

  13. QTc interval [ Time Frame: All cycles through end of treatment, a median of 1 year ]
    QTc interval corrected using Fridericia's Formula (msec) (Safety lead-in phase and Expansion cohorts)

  14. Overall Survival (OS) [ Time Frame: All cycles until death or 24 months from first visit of last patient ]
    Time from date of first study treatment to date of death due to any cause. Patients last known to be alive without date of death documented will be censored at the date of last contact. (Expansion cohorts)

  15. Marrow complete remission (MDS Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by modified IWG criteria (2006) (MDS expansion cohort)

  16. Partial remission (MDS Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by modified IWG criteria (2006) (MDS expansion cohort)

  17. Stable disease (MDS Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by modified IWG criteria (2006) (MDS expansion cohort)

  18. Partial or complete cytogenetic response (MDS Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by modified IWG criteria (2006) (MDS expansion cohort)

  19. Hematologic improvement (MDS Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by modified IWG criteria (2006) (MDS expansion cohort)

  20. Complete remission with incomplete hematologic recovery (AML Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by ELN criteria (2017) (AML expansion cohort)

  21. Complete remission with partial hematologic recovery (AML Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    CRh is defined as CR but with absolute neutrophil count >500/uL, platelets >50,000/uL, and not qualifying for CR (AML Expansion cohort)

  22. Morphologic leukemia free state (AML Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by ELN criteria (2017) (AML expansion cohort)

  23. Partial remission (AML Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by ELN criteria (2017) (AML expansion cohort)

  24. Stable disease (AML Expansion cohort) [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    As defined by ELN criteria (2017) (AML expansion cohort)

  25. Duration of CR [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    Duration of CR defined as duration from date of first achieving CR to date of disease progression after CR, or death due to any cause, whichever occurs first (Expansion cohorts)

  26. Time to CR [ Time Frame: All cycles until progression or 24 months from first visit of last patient ]
    Duration from date of first dose of study drug to date of CR (Expansion cohorts)

  27. Adverse events (Expansion cohorts) [ Time Frame: Date of informed consent through 28 days following last dose of study drug ]
    Type, frequency, severity, timing, and relationship to study therapy of adverse events and laboratory abnormalities (graded by NCI CTCAE v.4.03) (Expansion cohorts)



Information from the National Library of Medicine

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

Inclusion criteria:

  • Patients must have previously untreated MDS, AML, or CMML according to the WHO 2016 classification.
  • MDS patients must have Intermediate (>3 to 4.5 points), High Risk (>4.5 - 6) or Very High Risk (>6 points) disease according to the Revised International Prognostic Scoring System 2012 (IPSS-R).
  • Clinical indication for treatment with azacitidine for MDS or AML.

Exclusion criteria:

  • Patients with AML who are candidates for standard induction chemotherapy as first line treatment.
  • Patients with known active CNS leukemia.
  • Prior treatment with a smoothened inhibitor (SMOi) and/or hypomethylating agent.

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


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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02367456     History of Changes
Other Study ID Numbers: B1371012
2014-001345-24 ( EudraCT Number )
BRIGHT MDS&AML1012 ( Other Identifier: Alias Study Number )
First Posted: February 20, 2015    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Pfizer:
MDS
AML
CMML

Additional relevant MeSH terms:
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Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors