Entospletinib Monotherapy and in Combination With Chemotherapy in Adults With Acute Myeloid Leukemia (AML)
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT02343939
- Lead Sponsor
- Gilead Sciences
- Brief Summary
This study will evaluate the efficacy, safety, and tolerability of entospletinib when administered as monotherapy or in combination with chemotherapy in adults with acute myeloid leukemia (AML).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 148
- Adults with AML in need of treatment
- Group A : Individuals ≥ 18 years of age with previously untreated AML by World Health Organization (WHO) criteria who are able and should receive up to 2 cycles of induction chemotherapy with 7+3 as determined by the treating physician
- Group B: Individuals > 70 years of age with previously untreated AML by WHO criteria; or individuals ≤ 70 years of age with previously untreated AML who refuse or are unable to receive chemotherapy with 7+3 as determined by the treating physician
- Group C: Individuals ≥ 18 years of age with relapsed/refractory AML by WHO criteria; or with relapsed/refractory AML with mixed-lineage leukemia (MLL); or with previously untreated AML by WHO criteria and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent as determined by the treating physician
Key
- Known active central nervous system or leptomeningeal lymphoma
- Subjects with acute promyelocytic leukemia (M3)
- Treatment with proton pump inhibitors (PPIs) within 7 days prior to enrollment.
NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Entospletinib + daunorubicin + cytarabine (Group A) Daunorubicin Dose Escalation: Entospletinib up to 400 mg for 14 days and then entospletinib up to 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Dose Expansion: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Some participants will have the option to receive post-induction therapy with entospletinib 400 mg in combination with cytarabine/cytosine arabinoside (ARA-C). Participants may receive maintenance therapy with 28-day cycles of entospletinib 400 mg for up to twelve 28-day cycles, if the participant is not eligible for stem cell transplant. Entospletinib + daunorubicin + cytarabine (Group A) Cytarabine Dose Escalation: Entospletinib up to 400 mg for 14 days and then entospletinib up to 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Dose Expansion: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Some participants will have the option to receive post-induction therapy with entospletinib 400 mg in combination with cytarabine/cytosine arabinoside (ARA-C). Participants may receive maintenance therapy with 28-day cycles of entospletinib 400 mg for up to twelve 28-day cycles, if the participant is not eligible for stem cell transplant. Entospletinib + decitabine (Group B) Decitabine Dose Escalation: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with decitabine for 10 days beginning on Day 1 of every 28-day cycle (at least 2 cycles of induction therapy but no more than 4 cycles). Participants who are intolerant of decitabine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Dose Expansion: Entospletinib 400 mg for 14 days for the safety run-in participants or Entospletinib 400 mg for 5 days for the randomization participants. Then entospletinib 400 mg in combination with decitabine or azacitidine (at least 2 cycles of induction therapy but no more than 4 cycles). Some participants will have the option to receive maintenance therapy with entospletinib in combination with decitabine or azacitidine. Participants who are intolerant of decitabine or azacitidine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Entospletinib + decitabine (Group B) Azacitidine Dose Escalation: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with decitabine for 10 days beginning on Day 1 of every 28-day cycle (at least 2 cycles of induction therapy but no more than 4 cycles). Participants who are intolerant of decitabine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Dose Expansion: Entospletinib 400 mg for 14 days for the safety run-in participants or Entospletinib 400 mg for 5 days for the randomization participants. Then entospletinib 400 mg in combination with decitabine or azacitidine (at least 2 cycles of induction therapy but no more than 4 cycles). Some participants will have the option to receive maintenance therapy with entospletinib in combination with decitabine or azacitidine. Participants who are intolerant of decitabine or azacitidine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Entospletinib + daunorubicin + cytarabine (Group A) Entospletinib Dose Escalation: Entospletinib up to 400 mg for 14 days and then entospletinib up to 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Dose Expansion: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with daunorubicin and cytarabine for up to two 14-day cycles. Some participants will have the option to receive post-induction therapy with entospletinib 400 mg in combination with cytarabine/cytosine arabinoside (ARA-C). Participants may receive maintenance therapy with 28-day cycles of entospletinib 400 mg for up to twelve 28-day cycles, if the participant is not eligible for stem cell transplant. Entospletinib + decitabine (Group B) Entospletinib Dose Escalation: Entospletinib 400 mg for 14 days and then entospletinib 400 mg in combination with decitabine for 10 days beginning on Day 1 of every 28-day cycle (at least 2 cycles of induction therapy but no more than 4 cycles). Participants who are intolerant of decitabine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Dose Expansion: Entospletinib 400 mg for 14 days for the safety run-in participants or Entospletinib 400 mg for 5 days for the randomization participants. Then entospletinib 400 mg in combination with decitabine or azacitidine (at least 2 cycles of induction therapy but no more than 4 cycles). Some participants will have the option to receive maintenance therapy with entospletinib in combination with decitabine or azacitidine. Participants who are intolerant of decitabine or azacitidine may switch to entospletinib monotherapy maintenance at any time after completing the first 2 cycles. Entospletinib (Group C) Entospletinib Dose Escalation: Entospletinib up to 800 mg for 28-day cycles until the participant meets criteria for study treatment discontinuation per the study protocol. Dose Expansion: Entospletinib 400 mg for 28-day cycles until the participant meets criteria for study treatment discontinuation per the protocol.
- Primary Outcome Measures
Name Time Method Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) Group A: Cycle 0 Day 1 to Cycle 2 Day 28; Group B: Cycle 0 Day 1 to Cycle 1 Day 28; Group C: Cycle 1 Day 1 to Cycle 1 Day 28 (Cycle length: for Cycle 0 = 14 days, for all other cycles = 28 days) DLTs refer to toxicities experienced during the first 28 days of study treatment that have been judged to be clinically significant and related to study treatment. DLT assessment was applicable only for Phase 1b and Phase 2 safety run-in participants.
Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Morphologic CR included CR and cytogenetic CR (CRc). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/microliter (mcL); Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis.
Percentage of Participants With Composite Complete Remission at the End of Induction At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Composite complete remission included CR, CRc, and morphologic complete remission with incomplete blood count recovery (CRi). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets.
Percentage of Participants With Overall Response at the End of Induction At the end of induction (Group A: up to end of Cycle 2; Group B: up to end of Cycle 4) (cycle length = up to 28 days); Group C: From Day 1 until meeting the criteria for study treatment discontinuation (up to approximately 3 years) Clinical response was assessed according to the International Working Group criteria (Cheson 2003). Overall response included CR, CRc, CRi, and partial remission (PR). CR required all of the following: \< 5% blasts in bone marrow aspirate; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; No extramedullary disease; No blasts with Auer rods detected; and Independent of transfusions. CRc, in addition to CR criteria, required reversion to a normal karyotype with an abnormal karyotype at the time of diagnosis. CRi required all of the CR criteria except the criterion of neutrophils and platelets. PR required all of the following: ≥ 50% decrease in blasts in bone marrow aspirate to a range of 5% to 25%; Neutrophils ≥ 1,000/mcL; Platelets ≥ 100,000/mcL; Independent of transfusions; and A value of ≤ 5% blasts was also considered a PR if Auer rods were detected.
- Secondary Outcome Measures
Name Time Method Duration of Exposure of Entospletinib First dose date up to approximately 3 years Percentage of Participants Who Experienced Laboratory Abnormalities First dose date up to the last dose date plus 30 days (maximum: 18 months) Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant.
Event Free Survival (EFS) First dose date up to approximately 38 months EFS was defined as the time interval from the start of the study therapy until the date of treatment failure, acute myeloid leukemia (AML) relapse, or death from any cause, whichever occurred first. Participants who received other anti-cancer therapy (prior to the event if any) were censored. Median EFS was analyzed using Kaplan-Meier (KM) method.
Overall Survival (OS) First dose date up to approximately 38 months OS was defined as the time interval from the start of the study therapy to death from any cause. Median OS was analyzed using KM method.
Percentage of Participants Experiencing Treatment-Emergent Adverse Events First dose date up to the last dose date plus 30 days (maximum: 18 months)
Trial Locations
- Locations (17)
University of Kansas Medical Center Research Institute, Inc
🇺🇸Fairway, Kansas, United States
Universitätsklinikum Frankfurt Medizinische Klinik II
🇩🇪Frankfurt, Germany
Weill Cornell Medical College - New York - Presbyterian Hospital
🇺🇸New York, New York, United States
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
UCLA
🇺🇸Los Angeles, California, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
Princess Margaret
🇨🇦Toronto, Ontario, Canada
Indiana University
🇺🇸Indianapolis, Indiana, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Duke Cancer Center
🇺🇸Durham, North Carolina, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Saint Francis Cancer Center
🇺🇸Greenville, South Carolina, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States