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 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GO408002018-002964-25
• Study Type: interventional
• Target: 24
• Locations: 5 countries
• Sites: 26

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).

Conditions

Acute Myeloid Leukemia

Keywords

AML

Outcome Measures

Primary Outcomes (19)

• Dose Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First Cycle of Induction Treatment

  Sponsor's decision to prematurely terminate the study was made at the end of the Phase 1. The planned Phase 2 was not initiated. This decision was not based on safety concerns, but rather due to the overall company strategy about the adult AML

  Cycle 1 of induction treatment (1 cycle is 28 days)

• Number of Participants With at Least One Adverse Event

  Sponsor's decision to prematurely terminate the study was made at the end of the Phase 1. The planned Phase 2 was not initiated. This decision was not based on safety concerns, but rather due to the overall company strategy about the adult AML.

  From Baseline until 28 days after the final dose of study drug (up to 2 years)

• 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)

  Sponsor's decision to prematurely terminate the study was made at the end of the Phase 1. The planned Phase 2 was not initiated. This decision was not based on safety concerns, but rather due to the overall company strategy about the adult AML

  From Baseline until 28 days after the final dose of study drug (up to 2 years)

• 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)

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Reported Frequency of Nausea, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Reported Severity of Nausea, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• 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

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Overall Score for Nausea, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Number of Participants Reporting Presence or Absence of Vomiting Over Time, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Reported Frequency of Vomiting, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Reported Severity of Vomiting, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• 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

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline Over Time in Overall Score for Vomiting, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Number of Participants Reporting Presence or Absence of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE Over Time

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Day 1 of each treatment cycle (1 cycle is 28 days) and at study drug discontinuation (up to 2 years)

• Change From Baseline in Reported Frequency of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline in Reported Severity of Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• 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

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Change From Baseline in Overall Score for Diarrhea Over Time, as Assessed Through Use of the NCI PRO-CTCAE

  The sponsor decided not to continue the study based on the overall Company strategy in AML. Although data were collected, the small sample size and insufficient follow up rendered any analysis scientifically meaningless. As a consequence, no data were analyzed and this outcome measure was not conducted

  Baseline, Day 1 of each treatment cycle (1 cycle is 28 days), and at study drug discontinuation (up to 2 years)

• Number of Participants, Per ELN Categories, With a Complete Remission (CR) at the End of Induction Treatment, Among Those Treated at the Recommended Phase 2 Dose

  Sponsor's decision to prematurely terminate the study was made at the end of the Phase 1. This decision was not based on safety concerns, but rather due to the overall company strategy about the adult AML. Therefore this outcome measure was not conducted and no data available to report.

  At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)

Secondary Outcomes (31)

• 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

  At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)

• 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

  At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)

• Dose-Escalation and Expansion Phases: Percentage of Participants With a Negative Minimal Residual Disease (MRD) Status at the End of Induction Treatment

  At the end of induction treatment (up to 2 cycles; 1 cycle is 28 days)

• Post-Consolidation Phase: Percentage of Participants Converting From MRD-Positive to MRD-Negative Status at Any Time During Treatment

  At the end of maintenance treatment (12 cycles, 1 cycle is 28 days)

• Kaplan-Meier Estimate of the Percentage of Participants in Event-Free Survival

  Up to 5 years

Study Arms (4)

Dose-Escalation Phase

EXPERIMENTAL

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; Drug: Cytarabine; Drug: Daunorubicin; Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)

Post-Consolidation Phase

EXPERIMENTAL

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

Expansion Phase: Favorable/Intermediate-Risk AML

EXPERIMENTAL

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; Drug: Cytarabine; Drug: Daunorubicin; Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)

Expansion Phase: High-Risk AML

EXPERIMENTAL

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; Drug: Cytarabine; Drug: Daunorubicin; Procedure: Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT)

Interventions

Idasanutlin DRUG

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.

Also known as: RO5503781, RG7388

Dose-Escalation Phase; Expansion Phase: Favorable/Intermediate-Risk AML; Expansion Phase: High-Risk AML; Post-Consolidation Phase

Cytarabine DRUG

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.

Dose-Escalation Phase; Expansion Phase: Favorable/Intermediate-Risk AML; Expansion Phase: High-Risk AML

Daunorubicin DRUG

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.

Dose-Escalation Phase; Expansion Phase: Favorable/Intermediate-Risk AML; Expansion Phase: High-Risk AML

Allogeneic Hematopoietic Stem Cell Transplant (Allo-HSCT) PROCEDURE

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.

Dose-Escalation Phase; Expansion Phase: Favorable/Intermediate-Risk AML; Expansion Phase: High-Risk AML

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (26)

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Sarah Cannon Research Institute at HealthONE

Denver, Colorado, 80218, United States

Location

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, 60637-1447, United States

Location

University of Iowa Hospitals and Clinics; Investigational Drug Services

Iowa City, Iowa, 52242, United States

Location

University of Kansas Clinical Research Center; Clinical Trials Office

Fairway, Kansas, 66205, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

State University of NY

Brooklyn, New York, 11203, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

The Alfred Hospital

Prahan, Victoria, 3181, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Centre Léon Bérard

Lyon, 69008, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

CHU de Nantes - Hotel Dieu

Nantes, 44093, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Institut Universitaire du Cancer de Toulouse-Oncopole

Toulouse, 31059, France

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia

Meldola, Emilia-Romagna, 47014, Italy

Location

ASST Papa Giovanni XXIII; Dipartimento Interaziendale di Farmacia Clinica

Bergamo, Lombardy, 24127, Italy

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz.

Madrid, 28040, Spain

Location

Hospital Universitario Virgen del Rocío; Servicio de Neuropediatra

Seville, 41013, Spain

Location

Hospital Universitari i Politècnic La Fe

Valencia, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

RG7388; Cytarabine; Daunorubicin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2019
• First Posted: February 21, 2019
• Study Start: March 25, 2019
• Primary Completion: September 10, 2020
• Study Completion: September 10, 2020
• Last Updated: June 21, 2022
• Results First Posted: June 21, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (12); FR (5); IT (2); AU (2); ES (5)