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

Primary Purpose

Acute Myeloid Leukemia

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Entospletinib
Daunorubicin
Cytarabine
Decitabine
Azacitidine
Sponsored by
Gilead Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UCLA
  • University of Chicago
  • Loyola University Medical Center
  • Indiana University
  • University of Kansas Medical Center Research Institute, Inc
  • Dana Farber Cancer Institute
  • Henry Ford Health System
  • Karmanos Cancer Institute
  • Weill Cornell Medical College - New York - Presbyterian Hospital
  • Duke Cancer Center
  • University Hospitals Case Medical Center
  • Ohio State University
  • Oregon Health & Science University
  • Saint Francis Cancer Center
  • Princess Margaret
  • Jewish General Hospital
  • Universitätsklinikum Frankfurt Medizinische Klinik II

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Entospletinib + daunorubicin + cytarabine (Group A)

Entospletinib + decitabine (Group B)

Entospletinib (Group C)

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
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
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
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
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

Duration of Exposure of Entospletinib
Event Free Survival (EFS)
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)
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
Percentage of Participants Who Experienced Laboratory Abnormalities
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.

Full Information

First Posted
January 16, 2015
Last Updated
November 13, 2019
Sponsor
Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT02343939
Brief Title
Entospletinib Monotherapy and in Combination With Chemotherapy in Adults With Acute Myeloid Leukemia (AML)
Acronym
ENTO in AML
Official Title
A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination With Chemotherapy in Patients With Acute Myeloid Leukemia (AML)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Terminated
Study Start Date
July 1, 2015 (Actual)
Primary Completion Date
September 4, 2018 (Actual)
Study Completion Date
February 21, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
148 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Entospletinib + daunorubicin + cytarabine (Group A)
Arm Type
Experimental
Arm Description
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.
Arm Title
Entospletinib + decitabine (Group B)
Arm Type
Experimental
Arm Description
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.
Arm Title
Entospletinib (Group C)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Entospletinib
Other Intervention Name(s)
GS-9973, ENTO
Intervention Description
Tablet(s) administered orally every 12 hours
Intervention Type
Drug
Intervention Name(s)
Daunorubicin
Intervention Description
60 mg/m^2 administered intravenously daily on Days 1 to 3 for up to two 14-day induction cycles
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
100 mg/m^2 administered intravenously daily on Days 1 to 7 for up to two 14-day cycles
Intervention Type
Drug
Intervention Name(s)
Decitabine
Intervention Description
20 mg/m^2 administered intravenously
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
75 mg/m^2 administered intravenously or subcutaneously
Primary Outcome Measure Information:
Title
Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
Description
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.
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)
Title
Percentage of Participants With Morphologic Complete Remission (CR) at the End of Induction
Description
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.
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)
Title
Percentage of Participants With Composite Complete Remission at the End of Induction
Description
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.
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)
Title
Percentage of Participants With Overall Response at the End of Induction
Description
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.
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)
Secondary Outcome Measure Information:
Title
Duration of Exposure of Entospletinib
Time Frame
First dose date up to approximately 3 years
Title
Event Free Survival (EFS)
Description
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.
Time Frame
First dose date up to approximately 38 months
Title
Overall Survival (OS)
Description
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.
Time Frame
First dose date up to approximately 38 months
Title
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)
Title
Percentage of Participants Who Experienced Laboratory Abnormalities
Description
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.
Time Frame
First dose date up to the last dose date plus 30 days (maximum: 18 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
UCLA
City
Los Angeles
State/Province
California
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
Country
United States
Facility Name
University of Kansas Medical Center Research Institute, Inc
City
Fairway
State/Province
Kansas
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
Country
United States
Facility Name
Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
Country
United States
Facility Name
Weill Cornell Medical College - New York - Presbyterian Hospital
City
New York
State/Province
New York
Country
United States
Facility Name
Duke Cancer Center
City
Durham
State/Province
North Carolina
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Saint Francis Cancer Center
City
Greenville
State/Province
South Carolina
Country
United States
Facility Name
Princess Margaret
City
Toronto
State/Province
Ontario
Country
Canada
Facility Name
Jewish General Hospital
City
Montreal
State/Province
Quebec
Country
Canada
Facility Name
Universitätsklinikum Frankfurt Medizinische Klinik II
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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