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A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia (BRIGHT AML1019)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03416179
Recruitment Status : Completed
First Posted : January 31, 2018
Results First Posted : June 25, 2021
Last Update Posted : February 1, 2022
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).


Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: glasdegib Drug: daunorubicin + cytarabine Drug: azacitidine Drug: Placebo Drug: cytarabine Procedure: HSCT Phase 3

Detailed Description:

Two separate registration trials conducted under one protocol number are proposed to adequately and independently evaluate the addition of glasdegib in intensive and non-intensive chemotherapy populations. Each study will have an experimental treatment arm and a placebo arm. Endpoints are the same for each study except where specifically indicated.

Assignment to the Intensive Study or the Non-Intensive Study will be made by the Investigator based on the 2017 European LeukemiaNet (ELN) recommendations.

Study B1371019 is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 730 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, multi-center, placebo controlled study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double blind study.
Primary Purpose: Treatment
Official Title: A RANDOMIZED (1:1), DOUBLE-BLIND, MULTI-CENTER, PLACEBO CONTROLLED STUDY EVALUATING INTENSIVE CHEMOTHERAPY WITH OR WITHOUT GLASDEGIB (PF-04449913) OR AZACITIDINE (AZA) WITH OR WITHOUT GLASDEGIB IN PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA
Actual Study Start Date : April 20, 2018
Actual Primary Completion Date : June 5, 2020
Actual Study Completion Date : January 17, 2022


Arm Intervention/treatment
Experimental: Arm A (Intensive Study)
Glasdegib + '7+3' Induction(s)
Drug: glasdegib

Daily Glasdegib (100 mg, PO), beginning on Day 1 and is to continue up to 2 years post randomization.

Following consolidation therapy, glasdegib or placebo will be administered daily for up to 2 years after randomization or until they have minimal residual disease (MRD) negative disease, whichever comes first.

Daily Glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.

Other Name: PF-04449913

Drug: daunorubicin + cytarabine

'7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days).

If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3');


Drug: cytarabine
Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information.

Procedure: HSCT
If required, and done per standard of care post Induction(s).

Placebo Comparator: Arm B (Intensive Study)
Placebo + '7+3' Induction(s)
Drug: daunorubicin + cytarabine

'7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days).

If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3');


Drug: Placebo

Matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization. Following consolidation therapy, placebo will be administered daily for up to 2 years after randomization or until they have MRD negative disease, whichever comes first.

Daily placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.


Drug: cytarabine
Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information.

Procedure: HSCT
If required, and done per standard of care post Induction(s).

Experimental: Arm A (Non-intensive study)
Glasdegib + azacitidine
Drug: azacitidine
Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death.

Drug: glasdegib

Glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment.

Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.


Placebo Comparator: Arm B (Non-intensive study)
Placebo + azacitidine
Drug: azacitidine
Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death.

Drug: Placebo
Matching placebo (PO) is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.




Primary Outcome Measures :
  1. Intensive Study: Overall Survival (OS) [ Time Frame: Baseline up to 25 months ]
    OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.

  2. Non-intensive Study: Overall Survival (OS) [ Time Frame: Baseline up to 25 months ]
    OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.


Secondary Outcome Measures :
  1. Intensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire [ Time Frame: Baseline up to 5 years ]
  2. Non-intensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire [ Time Frame: Baseline up to 5 years ]
  3. Intensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [ Time Frame: Baseline up to 5 years ]
  4. Non-intensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [ Time Frame: Baseline up to 5 years ]
  5. Intensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [ Time Frame: Baseline up to 5 years ]
  6. Non-intensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [ Time Frame: Baseline up to 5 years ]
  7. Intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi) [ Time Frame: Baseline up to 5 years ]
  8. Non-intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi) [ Time Frame: Baseline up to 5 years ]
  9. Intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS) [ Time Frame: Baseline up to 5 years ]
  10. Non-intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS) [ Time Frame: Baseline up to 5 years ]
  11. Intensive Study: Percentage of Participants With Partial Remission (PR) [ Time Frame: Baseline up to 5 years ]
  12. Non-intensive Study: Percentage of Participants With Partial Remission (PR) [ Time Frame: Baseline up to 5 years ]
  13. Non-intensive Study: Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) [ Time Frame: Baseline up to 5 years ]
  14. Intensive Study: Duration of Response [ Time Frame: Baseline up to 5 years ]
  15. Non-intensive Study: Duration of Response [ Time Frame: Baseline up to 5 years ]
  16. Non-intensive Study: Time to Response [ Time Frame: Baseline up to 5 years ]
  17. Intensive Study: Event-free Survival [ Time Frame: Baseline up to 5 years ]
  18. Non-intensive Study: Event-free Survival [ Time Frame: Baseline up to 5 years ]
  19. Intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score [ Time Frame: Baseline up to 5 years ]
  20. Non-intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score [ Time Frame: Baseline up to 5 years ]
  21. Intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score [ Time Frame: Baseline up to 5 years ]
  22. Non-intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score [ Time Frame: Baseline up to 5 years ]
  23. Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS) [ Time Frame: Baseline up to 5 years ]
  24. Non-intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS) [ Time Frame: Baseline up to 5 years ]
  25. Intensive Study: Participants Global Impression of Symptoms (PGIS) [ Time Frame: Baseline up to 5 years ]
  26. Non-intensive Study: Participants Global Impression of Symptoms (PGIS) [ Time Frame: Baseline up to 5 years ]
  27. Intensive Study: Participants Global Impression of Change (PGIC) [ Time Frame: Baseline up to 5 years ]
  28. Non-intensive Study: Participants Global Impression of Change (PGIC) [ Time Frame: Baseline up to 5 years ]
  29. Intensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  30. Non-intensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  31. Intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  32. Non-intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  33. Intensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  34. Non-intensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03 [ Time Frame: Baseline up to 5 years ]
  35. Intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib [ Time Frame: 1 and 4 hour post dose on Day 1 in first induction therapy; pre-dose, 1, and 4 hours post dose on day 1 in consolidation phase cycles 1 and 2 ]
  36. Non-intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib [ Time Frame: Pre-dose, 1 and 4 hour post dose on Day 1 and 15 of cycle 1; pre-dose, 1 and 4 hour post dose on day 1 of cycle 2 and 3 ]
  37. Intensive Study: QTc Interval [ Time Frame: Baseline up to 5 years ]
  38. Non-intensive Study: QTc Interval [ Time Frame: Baseline up to 5 years ]


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.


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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:

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):

  1. Subjects with untreated AML according to the World Health Organization (WHO) 2016 Classification2, including those with:

    • AML arising from MDS or another antecedent hematologic disease (AHD).
    • AML after previous cytotoxic therapy or radiation (secondary AML).
  2. 18 years of age (In Japan, 20 years of age).
  3. Adequate Organ Function as defined by the following:

    • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy.
    • Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome).
    • Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.
  4. QTc interval 470 msec using the Fridericia correction (QTcF).
  5. All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.

    • For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
  6. Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.
  7. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.
  8. Female subjects of non childbearing potential must meet at least 1 of the following criteria:

    1. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    2. Have medically confirmed ovarian failure; or
    3. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.

    All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.

  9. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.
  10. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
  11. Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments).

Exclusion Criteria:

Subjects with any of the following characteristics/conditions will not be included in the study:

  1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).
  2. AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.

    • Complex genetics may include t(9;22) cytogenetic translocation.
  3. Subjects with known active CNS leukemia.
  4. Participation in other clinical studies involving other investigational drug(s) (Phases 1 4) within 4 weeks prior study entry and/or during study participation.
  5. Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
  6. Subjects with another active malignancy on treatment with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case by case basis.
  7. Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms.
  8. Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.
  9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.
  10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only.
  11. Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator's judgment (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.
  12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.
  13. Concurrent administration of herbal preparations.
  14. Major surgery or radiation within 4 weeks of starting study treatment.
  15. Documented or suspected hypersensitivity to any one of the following:

    • For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side effects) or daunorubicin.
    • For subjects assigned to non intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.
  16. Known active drug or alcohol abuse.
  17. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  18. Pregnant females or breastfeeding female subjects.
  19. Known recent or active suicidal ideation or behavior.
  20. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.

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): NCT03416179


Locations
Show Show 149 study locations
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] April 12, 2019
Statistical Analysis Plan  [PDF] April 14, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03416179    
Other Study ID Numbers: B1371019
2017-002822-19 ( EudraCT Number )
BRIGHT ( Other Identifier: Alias Study Number )
BRIGHT AML1019 ( Other Identifier: Alias Study Number )
First Posted: January 31, 2018    Key Record Dates
Results First Posted: June 25, 2021
Last Update Posted: February 1, 2022
Last Verified: January 2022
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
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
glasdegib;
untreated;
Hedgehog Inhibitor
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Azacitidine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors