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A Study Evaluating the Safety and Efficacy of Idasanutlin in Combination With Cytarabine and Daunorubicin in Patients Newly Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission

NCT03850535

Description:

This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin when it is given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance for treating participants with acute myeloid leukemia (AML).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety and Efficacy of Idasanutlin in Combination With Cytarabine and Daunorubicin in Patients Newly Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission
  • Official Title: A Phase Ib/II Study Evaluating the Safety and Efficacy of Idasanutlin in Combination With Cytarabine and Daunorubicin in Patients Newly Diagnosed With Acute Myeloid Leukemia (AML) and the Safety and Efficacy of Idasanutlin in the Maintenance of First AML Complete Remission

Clinical Trial IDs

  • ORG STUDY ID: GO40800
  • SECONDARY ID: 2018-002964-25
  • NCT ID: NCT03850535

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
IdasanutlinRO5503781, RG7388Dose-Escalation Phase
CytarabineDose-Escalation Phase
DaunorubicinDose-Escalation Phase

Purpose

This Phase Ib/II, open-label, multicenter, non-randomized study will evaluate the safety, efficacy, and pharmacokinetics of idasanutlin when it is given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance for treating participants with acute myeloid leukemia (AML).

Trial Arms

NameTypeDescriptionInterventions
Dose-Escalation PhaseExperimentalParticipants with newly diagnosed, previously untreated, favorable or intermediate risk AML (according to European LeukemiaNet [ELN] 2017 criteria) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin.
  • Idasanutlin
  • Cytarabine
  • Daunorubicin
Post-Consolidation PhaseExperimentalParticipants who are idasanutlin treatment-naive, had received induction and chemotherapy consolidation for AML outside of the study, and were in minimal residual disease (MRD)-positive remission after induction will be enrolled in this cohort to receive maintenance treatment with single-agent idasanutlin.
  • Idasanutlin
Expansion Phase: Favorable/Intermediate-Risk AMLExperimentalParticipants with newly diagnosed, previously untreated, favorable or intermediate risk AML (according to ELN 2017 criteria) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin (at the recommended Phase 2 dose) plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin.
  • Idasanutlin
  • Cytarabine
  • Daunorubicin
Expansion Phase: High-Risk AMLExperimentalParticipants with newly diagnosed, previously untreated, high-risk AML (defined as adverse risk according to ELN 2017 criteria, and secondary AML) will undergo the treatment sequence of induction, consolidation, and maintenance. For induction, participants will be treated with idasanutlin (at the recommended Phase 2 dose) plus cytarabine and daunorubicin. At the investigator's discretion for consolidation, either participants will be treated with idasanutlin and cytarabine or they will undergo Allo-HSCT. For maintenance, participants will be treated with single-agent idasanutlin.
  • Idasanutlin
  • Cytarabine
  • Daunorubicin

Eligibility Criteria

        Inclusion Criteria:

        Inclusion Criteria for All Study Phases:

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2

          -  Adequate hepatic and renal function

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive measures, and agreement to refrain from
             donating eggs with a failure rate of <1% per year during the treatment period and for
             at least 6 months after the final dose of idasanutlin, cytarabine, or daunorubicin.
             Women must refrain from donating eggs during this same period.

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive, measures, and agreement to refrain from donating sperm that together
             result in a failure rate of <1% per year during the treatment period and for 6 months
             after the final dose of idasanutlin, cytarabine, or daunorubicin. Men must refrain
             from donating sperm during this same period.

        Inclusion Criteria for Patients in the Dose-Escalation and Expansion Phases:

        - Documented/confirmed newly diagnosed acute myeloid leukemia (AML) not previously treated
        according to World Health Organization (WHO)

        Inclusion Criteria for Patients in the Post-Consolidation Phase:

        - Documented/confirmed AML according to WHO in remission after induction, within 21 days of
        end of last chemotherapy consolidation cycle, and were minimum residual disease (MRD)
        positive at the end of induction as per local laboratory assessment

        Exclusion Criteria:

        Exclusion Criteria for All Study Phases:

          -  Clinical evidence of central nervous system (CNS) leukemia

          -  Any Grade ≥2 non-hematologic toxicities prior to starting therapy

          -  Current treatment with any other investigational or commercial agents or therapies
             administered with the intention to treat their malignancy with the exception of
             hydroxyurea (HU) or 6-mercaptopurine (6-MP)

          -  Treatment-related AML

          -  Acute promyelocytic leukemia

          -  History of other malignancy that could affect compliance with the protocol or
             interpretation of results

          -  Any severe and/or uncontrolled medical conditions or other conditions that could
             affect their participation in the study, impair the ability of the investigator to
             evaluate the patient, or impair the patient's ability to complete the study

          -  Echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan showing ejection
             fraction ≤40%

          -  Non-malignant medical illnesses that are uncontrolled or whose control may be
             jeopardized by this study treatment, such as hereditary coagulation disorders,
             insulin-dependent diabetes mellitus not optimally controlled with medical management
             (e.g., presence of ketoacidosis), or active GI conditions affecting absorption

          -  Infection considered by the investigator to be clinically uncontrolled or of
             unacceptable risk to the patient upon the induction of neutropenia, that is, patients
             who are or should be on antimicrobial agents for the treatment of active infection

          -  Febrile patients within 72 hours of study treatment initiation

          -  Patients with a history of active or chronic infectious hepatitis unless serology
             demonstrates clearance of infection

          -  Patients who are unable to interrupt treatment with moderate to strong CYP2C8 inducers
             and inhibitors

          -  Patients who are unable to temporarily interrupt treatment with oral or parenteral
             anticoagulants/anti-platelet agents during treatment phase

          -  Patients who have a history of clinically significant liver cirrhosis

          -  Patients with extramedullary AML with no evidence of systemic involvement

          -  Pregnant or breastfeeding patients

          -  Known history of HIV-positive status

          -  Patients who might refuse to receive blood products and/or have a hypersensitivity to
             blood products

          -  Prior treatment with an MDM2 antagonist

          -  Patients with clinically relevant QTc prolongation, a family history of long QT
             syndrome

        Exclusion Criteria for Patients in the Phase Ib Dose-Escalation Phase:

        - Adverse risk patients as per European LeukemiaNet (ELN) 2017 criteria

        Exclusion Criteria for Patients in Phase Ib Post-Consolidation Phase:

          -  Any ongoing Grade ≥2 hematologic adverse events prior to starting therapy

          -  Previous hematopoietic stem cell transplant (HSCT)

        Exclusion Criteria for Patients in the Dose-Escalation Phase and Patients in the
        Favorable/Intermediate-Risk Cohort of the Expansion Phase:

        - Secondary AML, defined as AML evolving from antecedent hematologic disorder (AHD)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation Phase: Number of Participants with Dose-Limiting Toxicities (DLTs) During the First Cycle of Induction Treatment
Time Frame:Cycle 1 of induction treatment (1 cycle is 28 days)
Safety Issue:
Description:The recall period is over the past 7 days.

Secondary Outcome Measures

Measure:Dose Escalation and Expansion Phases: Percentage of Participants with a CR, Complete Remission with Incomplete Blood Count Recovery (CRi), or Complete Remission with Incomplete Platelet Count Recovery (CRp) at the End of Induction Treatment
Time Frame:At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Phases: Percentage of Participants with a CR or Complete Remission with Partial Hematologic Recovery (CRh) at the End of Induction Treatment
Time Frame:At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)
Safety Issue:
Description:
Measure:Dose-Escalation and Expansion Phases: Percentage of Participants with a Negative Minimal Residual Disease (MRD) Status at the End of Induction Treatment
Time Frame:At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)
Safety Issue:
Description:
Measure:Post-Consolidation Phase: Percentage of Participants Converting from MRD-Positive to MRD-Negative Status at Any Time During Treatment
Time Frame:At the end of maintenance treatment (12 cycles, 1 cycle is 28 days)
Safety Issue:
Description:
Measure:Kaplan-Meier Estimate of the Percentage of Participants in Event-Free Survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Kaplan-Meier Estimate of the Percentage of Participants in Relapse-Free Survival in Those who Achieve Remission (CR, CRi, CRp, or CRh)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Change from Baseline Over Time in the Participant-Reported Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Questionnaire Total Score
Time Frame:Baseline, Day 1 of each cycle of induction and consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The FACIT-Fatigue (Version 4) consists of 13 items that assess fatigue using a 7-day recall period. Items are scored on a 0 ("not at all") to 4 ("very much so") response scale. Relevant items are reverse scored, and all items are summed to create total scores where higher scores are indicative of better functioning (i.e., less fatigue).
Measure:Change from Baseline Over Time in Physical Function Scale Score of the Participant-Reported European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (EORTC QLQ-C30)
Time Frame:Baseline, Day 1 of first induction cycle only, Day 1 of each subsequent treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC QLQ-C30 (Version 3) Physical Function Scale comprises 5 items each scored on a 4-point scale that ranges from "not at all" to "very much". Higher scores are indicative of better functioning.
Measure:Change from Baseline Over Time in Role Function Scale Score of the Participant-Reported EORTC QLQ-C30
Time Frame:Baseline, Day 1 of first induction cycle only, Day 1 of each subsequent treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC QLQ-C30 (Version 3) Role Function Scale comprises 2 items each scored on a 4-point scale that ranges from "not at all" to "very much". Higher scores are indicative of better functioning.
Measure:Change from Baseline Over Time in Global Health Status/Quality of Life Scale Score of the Participant-Reported EORTC QLQ-C30
Time Frame:Baseline, Day 1 of first induction cycle only, Day 1 of each subsequent treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC QLQ-C30 (Version 3) Global Health Status/Quality of Life Scale comprises 2 items each scored on a 7-point scale that ranges from "very poor" to "excellent". Higher scores are indicative of better health-related quality of life.
Measure:Change from Baseline Over Time in Headache Symptom Score of the Participant-Reported European Organisation for Research and Treatment of Cancer (EORTC) Item Library Questionnaire
Time Frame:Baseline, Day 1 of each cycle of induction and consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC Item Library Headache scale comprises 1 item scored on a 4-point scale that ranges from "not at all" to "very much". Higher scores are indicative of higher symptom severity.
Measure:Change from Baseline Over Time in Dizziness Symptom Score of the Participant-Reported EORTC Item Library Questionnaire
Time Frame:Baseline, Day 1 of each cycle of induction and consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC Item Library Dizziness scale comprises 1 item scored on a 4-point scale that ranges from "not at all" to "very much". Higher scores are indicative of higher symptom severity.
Measure:Change from Baseline Over Time in Bruising Symptom Score of the Participant-Reported EORTC Item Library Questionnaire
Time Frame:Baseline, Day 1 of each cycle of induction and consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EORTC Item Library Bruising scale comprises 1 item scored on a 4-point scale that ranges from "not at all" to "very much". Higher scores are indicative of higher symptom severity.
Measure:Change from Baseline Over Time in the European Quality of Life 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Utility Score
Time Frame:Baseline, Day 1 of first induction cycle only, Day 1 of all cycles of consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EQ-5D-5L Index Utility score is calculated based on a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Published weighting systems allow for creation of a single summary score for the Index Utility score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction.
Measure:Change from Baseline Over Time in the EQ-5D-5L Visual Analogue Scale (VAS) Score
Time Frame:Baseline, Day 1 of first induction cycle only, Day 1 of all cycles of consolidation (1 cycle is 28 days), every 3 months starting at Cycle 1 of maintenance, and at study drug discontinuation (up to 2 years)
Safety Issue:
Description:The EQ-5D-5L VAS is designed for the participant to rate their current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Measure:Area Under the Plasma Concentration-Time Curve (AUC) of Idasanutlin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; Days 1 and 5 of consolidation Cycle 1; and Days 1 and 5 of maintenance Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:AUC of Cytarabine
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; and Days 1 and 5 of consolidation Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:AUC of Daunorubicin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Maximum Observed Plasma Concentration (Cmax) of Idasanutlin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; Days 1 and 5 of consolidation Cycle 1; and Days 1 and 5 of maintenance Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Cmax of Cytarabine
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; and Days 1 and 5 of consolidation Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Cmax of Daunorubicin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Total Clearance (CL) of Idasanutlin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; Days 1 and 5 of consolidation Cycle 1; and Days 1 and 5 of maintenance Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:CL of Cytarabine
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; and Days 1 and 5 of consolidation Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:CL of Daunorubicin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Volume of Distribution at Steady State (Vss) of Idasanutlin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; Days 1 and 5 of consolidation Cycle 1; and Days 1 and 5 of maintenance Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Vss of Cytarabine
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; and Days 1 and 5 of consolidation Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Vss of Daunorubicin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:Terminal Half-Life (t1/2) of Idasanutlin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; Days 1 and 5 of consolidation Cycle 1; and Days 1 and 5 of maintenance Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:t1/2 of Cytarabine
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1; and Days 1 and 5 of consolidation Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:
Measure:t1/2 of Daunorubicin
Time Frame:Pre-dose and at predefined intervals post-dose on Days 1, 3, and 5 of induction Cycle 1 (1 cycle is 28 days)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

Trial Keywords

  • AML

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