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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

NCT03416179

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia
  • 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

Clinical Trial IDs

  • ORG STUDY ID: B1371019
  • SECONDARY ID: 2017-002822-19
  • SECONDARY ID: BRIGHT
  • SECONDARY ID: BRIGHT AML1019
  • NCT ID: NCT03416179

Conditions

  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
glasdegibPF-04449913Arm A (Intensive Study)
daunorubicin + cytarabineArm A (Intensive Study)
azacitidineArm A (Non-intensive study)
PlaceboArm B (Intensive Study)
PlaceboArm B (Non-intensive study)
glasdegibArm A (Non-intensive study)
cytarabineArm A (Intensive Study)

Purpose

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).

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).
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (Intensive Study)ExperimentalGlasdegib + '7+3' Induction(s)
  • glasdegib
  • daunorubicin + cytarabine
  • cytarabine
Arm B (Intensive Study)Placebo ComparatorPlacebo + '7+3' Induction(s)
  • daunorubicin + cytarabine
  • Placebo
  • cytarabine
Arm A (Non-intensive study)ExperimentalGlasdegib + azacitidine
  • azacitidine
  • glasdegib
Arm B (Non-intensive study)Placebo ComparatorPlacebo + azacitidine
  • azacitidine
  • Placebo

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:5 years after last subject randomized
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Fatigue score measured by the MD Anderson Symptom Inventory (MDASI)-AML/MDS questionnaire
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Scale is from 0-10 where 0 is not present and 10 is as bad as you can image.
Measure:Rate of Complete Remission (CR) (including CR with minimal residual disease (MRD)-negative as assessed by multiparametric flow cytometry)
Time Frame:2 years after last dose of study therapy
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Duration of response (defined as CR [includes CR-MRD negative]/CRi or CR/CRh as appropriate)
Time Frame:2 years after last dose of study therapy
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Time to response (CR[includes CR-MRD negative)]/CR with partial hematologic rcovery (CRh) as appropriate)
Time Frame:2 years after last dose of study therapy
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Event-free Survival
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:
Measure:Patient Reported Outcomes (PROs) as measured by the M.D. Anderson Symptom Inventory AML/MDS Module (MDASI-AML/MDS)
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Measurement Scale from 0-10.
Measure:Adverse events as graded by NCI CTCAE v4.03
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:
Measure:Laboratory abnormalities as graded by NCI CTCAE v4.03
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:
Measure:For the intensive study, the plasma trough concentration (Ctrough) will be analyzed
Time Frame:PK samples taken on Induction(s) Day 1 (1 and 4 hours post induction); Induction(s) Day 10 (pre-dose, 1 and 4 hours post dose); Day 1 of each Consolidation cycle (pre-dose, 1 and 4 hours post dose)
Safety Issue:
Description:
Measure:QTc interval
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:
Measure:PROs as measured by Patient Global Impression of Change (PGIC)
Time Frame:5 years after last patient randomized, withdrawal, or death
Safety Issue:
Description:One question asking for description of leukemia symptoms.
Measure:Patient Reported Outcomes (PROs) as measured by EuroQoL 5 Dimension questionnaire 5-Level version (EQ-5D-5L)
Time Frame:5 years after last subject randomized, withdrawal, or death
Safety Issue:
Description:Series of questions that ask for information that best describes health.
Measure:Patient Reported Outcomes (PROs) as measured by Patient Global Impression of Symptoms (PGIS)
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:One question asking for information regarding leukemia symptoms.
Measure:Complete Remission with incomplete hematologic recovery (CRi)
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Rate of morphological leukemia-free state (MLFS)
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Rate of Partial Remission (PR)
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Rate of Complete Remission with partial hematological recovery (CRh) for the Non-intensive study only only
Time Frame:5 years after last subject randomized, consent withdrawal, or death
Safety Issue:
Description:Response as defined by the 2017 European LeukemiaNet (ELN) recommendations.
Measure:Minimum Observed Plasma Trough Concentratrion of glasdegib in the Intensive Study
Time Frame:Day 10 of Induction Cycle and Day 1 of each Consolidation Cycle
Safety Issue:
Description:Its the minimum trough concentration in plasma of glasdegib following multiple daily dosing to steady state.
Measure:Minimum Observed Plasma Trough Concentration of glasdegib in the Non-intensive study
Time Frame:Cycle 1 Day 15 and Cycles 2 and 3 on Day 1
Safety Issue:
Description:It is the minimum trough concentration in plasma of glasdegib following multiple daily dosing to steady state.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • glasdegib;
  • untreated;
  • Hedgehog Inhibitor

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