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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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03850535
Recruitment Status : Recruiting
First Posted : February 21, 2019
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Idasanutlin Drug: Cytarabine Drug: Daunorubicin Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT) Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 25, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2024


Arm Intervention/treatment
Experimental: Dose-Escalation Phase
Participants 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.
Drug: Idasanutlin
Participants will self-administer idasanutlin tablets by mouth (PO) once daily (QD) for 5 days of each 28-day treatment cycle for up to 2 cycles of induction, up to 4 cycles of consolidation, and 12 cycles of maintenance, according to the study's protocol.
Other Names:
  • RO5503781
  • RG7388

Drug: Cytarabine
Cytarabine will be administered for 7 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 200 milligrams per meter squared (mg/m^2) of body surface area, once daily (QD) by intravenous (IV) infusion. At the investigator's discretion, cytarabine will also be administered as part of chemotherapy consolidation at a dose of 1.5 g/m^2 QD as IV infusion for 5 days of each 28-day cycle and for up to 4 cycles of treatment.

Drug: Daunorubicin
Daunorubicin will be administered for 3 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 60 mg/m^2 QD as IV infusion.

Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)
After induction treatment, participants who achieve remission will either receive chemotherapy consolidation treatment or undergo Allo-HSCT (as per local guidelines) at the investigator's discretion.

Experimental: Post-Consolidation Phase
Participants 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.
Drug: Idasanutlin
Participants will self-administer idasanutlin tablets by mouth (PO) once daily (QD) for 5 days of each 28-day treatment cycle for up to 2 cycles of induction, up to 4 cycles of consolidation, and 12 cycles of maintenance, according to the study's protocol.
Other Names:
  • RO5503781
  • RG7388

Experimental: Expansion Phase: Favorable/Intermediate-Risk AML
Participants 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.
Drug: Idasanutlin
Participants will self-administer idasanutlin tablets by mouth (PO) once daily (QD) for 5 days of each 28-day treatment cycle for up to 2 cycles of induction, up to 4 cycles of consolidation, and 12 cycles of maintenance, according to the study's protocol.
Other Names:
  • RO5503781
  • RG7388

Drug: Cytarabine
Cytarabine will be administered for 7 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 200 milligrams per meter squared (mg/m^2) of body surface area, once daily (QD) by intravenous (IV) infusion. At the investigator's discretion, cytarabine will also be administered as part of chemotherapy consolidation at a dose of 1.5 g/m^2 QD as IV infusion for 5 days of each 28-day cycle and for up to 4 cycles of treatment.

Drug: Daunorubicin
Daunorubicin will be administered for 3 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 60 mg/m^2 QD as IV infusion.

Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)
After induction treatment, participants who achieve remission will either receive chemotherapy consolidation treatment or undergo Allo-HSCT (as per local guidelines) at the investigator's discretion.

Experimental: Expansion Phase: High-Risk AML
Participants 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.
Drug: Idasanutlin
Participants will self-administer idasanutlin tablets by mouth (PO) once daily (QD) for 5 days of each 28-day treatment cycle for up to 2 cycles of induction, up to 4 cycles of consolidation, and 12 cycles of maintenance, according to the study's protocol.
Other Names:
  • RO5503781
  • RG7388

Drug: Cytarabine
Cytarabine will be administered for 7 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 200 milligrams per meter squared (mg/m^2) of body surface area, once daily (QD) by intravenous (IV) infusion. At the investigator's discretion, cytarabine will also be administered as part of chemotherapy consolidation at a dose of 1.5 g/m^2 QD as IV infusion for 5 days of each 28-day cycle and for up to 4 cycles of treatment.

Drug: Daunorubicin
Daunorubicin will be administered for 3 days of each 28-day cycle for up to 2 cycles of induction treatment at a dose of 60 mg/m^2 QD as IV infusion.

Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)
After induction treatment, participants who achieve remission will either receive chemotherapy consolidation treatment or undergo Allo-HSCT (as per local guidelines) at the investigator's discretion.




Primary Outcome Measures :
  1. 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) ]
  2. Number of Participants with at Least One Adverse Event [ Time Frame: From Baseline until 28 days after the final dose of study drug (up to 2 years) ]
  3. Number of Participants with Grade ≥3 Adverse Events, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) [ Time Frame: From Baseline until 28 days after the final dose of study drug (up to 2 years) ]
  4. Number of Participants Reporting Presence or Absence of Nausea Over Time, as Assessed Through Use of the National Cancer Institute (NCI) Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years) ]
    The recall period is over the past 7 days.

  5. Change from Baseline Over Time in Reported Frequency of Nausea, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Frequency of nausea is reported by participants on a 5-point Likert-type scale (Never, Rarely, Occasionally, Frequently, or Almost Constantly). The recall period is over the past 7 days.

  6. Change from Baseline Over Time in Reported Severity of Nausea, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Severity of nausea is reported by participants on a 5-point Likert-type scale (None, Mild, Moderate, Severe, or Very Severe). The recall period is over the past 7 days.

  7. Change from Baseline Over Time in Reported Degree of Interference with Daily Function Caused by Nausea, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Degree of interference with daily function caused by nausea is reported by participants on a 5-point Likert-type scale (Not At All, A Little Bit, Somewhat, Quite A Bit, or Very Much). The recall period is over the past 7 days.

  8. Change from Baseline Over Time in Overall Score for Nausea, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
  9. Number of Participants Reporting Presence or Absence of Vomiting Over Time, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years) ]
    The recall period is over the past 7 days.

  10. Change from Baseline Over Time in Reported Frequency of Vomiting, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Frequency of vomiting is reported by participants on a 5-point Likert-type scale (Never, Rarely, Occasionally, Frequently, or Almost Constantly). The recall period is over the past 7 days.

  11. Change from Baseline Over Time in Reported Severity of Vomiting, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Severity of vomiting is reported by participants on a 5-point Likert-type scale (None, Mild, Moderate, Severe, or Very Severe). The recall period is over the past 7 days.

  12. Change from Baseline Over Time in Reported Degree of Interference with Daily Function Caused by Vomiting, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Degree of interference with daily function caused by vomiting is reported by participants on a 5-point Likert-type scale (Not At All, A Little Bit, Somewhat, Quite A Bit, or Very Much). The recall period is over the past 7 days.

  13. Change from Baseline Over Time in Overall Score for Vomiting, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
  14. Number of Participants Reporting Presence or Absence of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE Over Time [ Time Frame: Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years) ]
    The recall period is over the past 7 days.

  15. Change from Baseline in Reported Frequency of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Frequency of diarrhea is reported by participants on a 5-point Likert-type scale (Never, Rarely, Occasionally, Frequently, or Almost Constantly). The recall period is over the past 7 days.

  16. Change from Baseline in Reported Severity of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Severity of diarrhea is reported by participants on a 5-point Likert-type scale (None, Mild, Moderate, Severe, or Very Severe). The recall period is over the past 7 days.

  17. Change from Baseline in Reported Degree of Interference with Daily Function Caused by Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
    Degree of interference with daily function caused by diarrhea is reported by participants on a 5-point Likert-type scale (Not At All, A Little Bit, Somewhat, Quite A Bit, or Very Much). The recall period is over the past 7 days.

  18. Change from Baseline in Overall Score for Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE [ Time Frame: Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years) ]
  19. Percentage of Participants with a Complete Remission (CR) at the End of Induction Treatment, Among Those Treated at the Recommended Phase 2 Dose [ Time Frame: At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. Kaplan-Meier Estimate of the Percentage of Participants in Event-Free Survival [ Time Frame: Up to 5 years ]
  6. Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival [ Time Frame: Up to 5 years ]
  7. 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 ]
  8. 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) ]
    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).

  9. 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) ]
    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.

  10. 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) ]
    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.

  11. 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) ]
    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.

  12. 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) ]
    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.

  13. 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) ]
    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.

  14. 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) ]
    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.

  15. 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) ]
    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.

  16. 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) ]
    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.

  17. 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) ]
  18. 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) ]
  19. 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) ]
  20. 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) ]
  21. 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) ]
  22. 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) ]
  23. 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) ]
  24. 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) ]
  25. 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) ]
  26. 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) ]
  27. 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) ]
  28. 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) ]
  29. 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) ]
  30. 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) ]
  31. 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) ]


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.


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


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): NCT03850535


Contacts
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Contact: Reference Study ID Number: GO40800 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. Only) global-roche-genentech-trials@gene.com

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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03850535     History of Changes
Other Study ID Numbers: GO40800
2018-002964-25 ( EudraCT Number )
First Posted: February 21, 2019    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description:

Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx).

For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).


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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 Hoffmann-La Roche:
AML
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors