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Entospletinib Monotherapy and in Combination With Chemotherapy in Adults With Acute Myeloid Leukemia (AML) (ENTO in AML)

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ClinicalTrials.gov Identifier: NCT02343939
Recruitment Status : Terminated
First Posted : January 22, 2015
Results First Posted : November 15, 2019
Last Update Posted : November 15, 2019
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Entospletinib Drug: Daunorubicin Drug: Cytarabine Drug: Decitabine Drug: Azacitidine Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination With Chemotherapy in Patients With Acute Myeloid Leukemia (AML)
Actual Study Start Date : July 1, 2015
Actual Primary Completion Date : September 4, 2018
Actual Study Completion Date : February 21, 2019


Arm Intervention/treatment
Experimental: Entospletinib + daunorubicin + cytarabine (Group A)

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.

Drug: Entospletinib
Tablet(s) administered orally every 12 hours
Other Names:
  • GS-9973
  • ENTO

Drug: Daunorubicin
60 mg/m^2 administered intravenously daily on Days 1 to 3 for up to two 14-day induction cycles

Drug: Cytarabine
100 mg/m^2 administered intravenously daily on Days 1 to 7 for up to two 14-day cycles

Experimental: Entospletinib + decitabine (Group B)

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.

Drug: Entospletinib
Tablet(s) administered orally every 12 hours
Other Names:
  • GS-9973
  • ENTO

Drug: Decitabine
20 mg/m^2 administered intravenously

Drug: Azacitidine
75 mg/m^2 administered intravenously or subcutaneously

Experimental: Entospletinib (Group C)

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.

Drug: Entospletinib
Tablet(s) administered orally every 12 hours
Other Names:
  • GS-9973
  • ENTO




Primary Outcome Measures :
  1. Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) [ Time Frame: 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.

  2. Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction [ Time Frame: 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.

  3. Percentage of Participants With Composite Complete Remission at the End of Induction [ Time Frame: 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.

  4. Percentage of Participants With Overall Response at the End of Induction [ Time Frame: 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 :
  1. Duration of Exposure of Entospletinib [ Time Frame: First dose date up to approximately 3 years ]
  2. Event Free Survival (EFS) [ Time Frame: 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.

  3. Overall Survival (OS) [ Time Frame: 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.

  4. Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: First dose date up to the last dose date plus 30 days (maximum: 18 months) ]
  5. Percentage of Participants Who Experienced Laboratory Abnormalities [ Time Frame: 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.



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.


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

Key Inclusion Criteria:

  • 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 Exclusion Criteria:

  • 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.


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): NCT02343939


Locations
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United States, California
UCLA
Los Angeles, California, United States
United States, Illinois
University of Chicago
Chicago, Illinois, United States
Loyola University Medical Center
Maywood, Illinois, United States
United States, Indiana
Indiana University
Indianapolis, Indiana, United States
United States, Kansas
University of Kansas Medical Center Research Institute, Inc
Fairway, Kansas, United States
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
United States, New York
Weill Cornell Medical College - New York - Presbyterian Hospital
New York, New York, United States
United States, North Carolina
Duke Cancer Center
Durham, North Carolina, United States
United States, Ohio
University Hospitals Case Medical Center
Cleveland, Ohio, United States
Ohio State University
Columbus, Ohio, United States
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Saint Francis Cancer Center
Greenville, South Carolina, United States
Canada, Ontario
Princess Margaret
Toronto, Ontario, Canada
Canada, Quebec
Jewish General Hospital
Montreal, Quebec, Canada
Germany
Universitätsklinikum Frankfurt Medizinische Klinik II
Frankfurt, Germany, 60590
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol  [PDF] February 15, 2018
Statistical Analysis Plan  [PDF] June 19, 2019


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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02343939     History of Changes
Other Study ID Numbers: GS-US-339-1559
2016-003353-16 ( EudraCT Number )
First Posted: January 22, 2015    Key Record Dates
Results First Posted: November 15, 2019
Last Update Posted: November 15, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Azacitidine
Decitabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors