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

• ClinicalTrials.gov Identifier: NCT02367456
• Recruitment Status: Active, not recruiting
• First Posted: February 20, 2015
• Last Update Posted: December 17, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 13, 2015
• First Posted Date: February 20, 2015
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: April 28, 2015
• Actual Primary Completion Date: January 29, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2019)

• 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)
• 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)
• 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)

Original Primary Outcome Measures (submitted: February 13, 2015)

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)

Current Secondary Outcome Measures (submitted: June 9, 2019)

• 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)
• 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)
• 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)
• 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)
• 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)
• AUC for Azacitidine [ Time Frame: First 2 weeks of treatment ]
  Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)
• Cmax for Azacitidine [ Time Frame: First 2 weeks of treatment ]
  Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)
• Tmax for Azacitidine [ Time Frame: First 2 weeks of treatment ]
  Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)
• AUC for PF-04449913 [ Time Frame: First 5 months of treatment ]
  Area under the Concentration-Time Curve (ng*h/mL) (Safety lead-in phase)
• Cmax for PF-04449913 [ Time Frame: First 5 months of treatment ]
  Maximum Observed Plasma Concentration (ng/mL) (Safety lead-in phase)
• Tmax for PF-04449913 [ Time Frame: First 5 months of treatment ]
  Time to Reach Maximum Observed Plasma Concentration (hrs) (Safety lead-in phase)
• Ctrough for PF-04449913 [ Time Frame: First 1 month of treatment ]
  Minimum plasma concentration following daily dosing to steady state (ng/mL) (Expansion cohorts)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)

Original Secondary Outcome Measures (submitted: February 13, 2015)

• 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 unitl 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).
• Overal 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)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Combination Study of PF-04449913 (Glasdegib) and Azacitidine In Untreated MDS, AML and CMML Patients
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia
• Chronic Myelomonocytic Leukemia

Intervention

• 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

Study Arms

• Experimental: Arm A
  MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
  Interventions:

  • Drug: PF-04449913 (Glasdegib)
  • Drug: Azacitidine
• Experimental: Arm B
  AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
  Interventions:

  • Drug: PF-04449913 (Glasdegib)
  • Drug: Azacitidine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 9, 2019): 73
• Original Estimated Enrollment (submitted: February 13, 2015): 170
• Estimated Study Completion Date: January 31, 2021
• Actual Primary Completion Date: January 29, 2020 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, United Kingdom, United States
• Removed Location Countries: Taiwan

Administrative Information

• NCT Number: NCT02367456
• Other Study ID Numbers: B1371012; 2014-001345-24 ( EudraCT Number ); BRIGHT MDS&AML1012 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: December 2020