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
NCT ID: NCT03850535
Last Updated: 2022-06-21
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE1/PHASE2
24 participants
INTERVENTIONAL
2019-03-25
2020-09-10
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Interventions
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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.
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.
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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
\- Adverse risk patients as per European LeukemiaNet (ELN) 2017 criteria
* Any ongoing Grade ≥2 hematologic adverse events prior to starting therapy
* Previous hematopoietic stem cell transplant (HSCT)
\- Secondary AML, defined as AML evolving from antecedent hematologic disorder (AHD)
18 Years
ALL
No
Sponsors
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Hoffmann-La Roche
INDUSTRY
Responsible Party
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Principal Investigators
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Clinical Trials
Role: STUDY_DIRECTOR
Hoffmann-La Roche
Locations
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UCLA Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Sarah Cannon Research Institute at HealthONE
Denver, Colorado, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, Illinois, United States
University of Iowa Hospitals and Clinics; Investigational Drug Services
Iowa City, Iowa, United States
University of Kansas Clinical Research Center; Clinical Trials Office
Fairway, Kansas, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
State University of NY
Brooklyn, New York, United States
Icahn School of Medicine at Mount Sinai
New York, New York, United States
Wake Forest Baptist Medical Center
Winston-Salem, North Carolina, United States
The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
The Alfred Hospital
Prahan, Victoria, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Centre Léon Bérard
Lyon, , France
Institut Paoli Calmettes
Marseille, , France
CHU de Nantes - Hotel Dieu
Nantes, , France
Hôpital Saint-Louis
Paris, , France
Institut Universitaire du Cancer de Toulouse-Oncopole
Toulouse, , France
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia
Meldola, Emilia-Romagna, Italy
ASST Papa Giovanni XXIII; Dipartimento Interaziendale di Farmacia Clinica
Bergamo, Lombardy, Italy
Hospital de la Santa Creu i Sant Pau
Barcelona, , Spain
Hospital Universitario Vall d'Hebron
Barcelona, , Spain
Hospital Universitario Fundacion Jimenez Diaz.
Madrid, , Spain
Hospital Universitario Virgen del Rocío; Servicio de Neuropediatra
Seville, , Spain
Hospital Universitari i Politècnic La Fe
Valencia, , Spain
Countries
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Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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2018-002964-25
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
GO40800
Identifier Type: -
Identifier Source: org_study_id
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