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

NCT02343939 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GS-US-339-15592016-003353-16
• Study Type: interventional
• Target: 148
• Locations: 3 countries
• Sites: 17

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).

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (4)

• 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.

  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)

• 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.

  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)

• 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.

  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)

• 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.

  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 Outcomes (5)

• Duration of Exposure of Entospletinib

  First dose date up to approximately 3 years

• Event Free Survival (EFS)

  First dose date up to approximately 38 months

• Overall Survival (OS)

  First dose date up to approximately 38 months

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events

  First dose date up to the last dose date plus 30 days (maximum: 18 months)

• Percentage of Participants Who Experienced Laboratory Abnormalities

  First dose date up to the last dose date plus 30 days (maximum: 18 months)

Study Arms (3)

Entospletinib + daunorubicin + cytarabine (Group A)

EXPERIMENTAL

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; Drug: Daunorubicin; Drug: Cytarabine

Entospletinib + decitabine (Group B)

EXPERIMENTAL

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; Drug: Decitabine; Drug: Azacitidine

Entospletinib (Group C)

EXPERIMENTAL

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

Interventions

Entospletinib DRUG

Tablet(s) administered orally every 12 hours

Also known as: GS-9973, ENTO

Entospletinib (Group C); Entospletinib + daunorubicin + cytarabine (Group A); Entospletinib + decitabine (Group B)

Daunorubicin DRUG

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

Entospletinib + daunorubicin + cytarabine (Group A)

Cytarabine DRUG

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

Entospletinib + daunorubicin + cytarabine (Group A)

Decitabine DRUG

20 mg/m\^2 administered intravenously

Entospletinib + decitabine (Group B)

Azacitidine DRUG

75 mg/m\^2 administered intravenously or subcutaneously

Entospletinib + decitabine (Group B)

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (17)

UCLA

Los Angeles, California, United States

Location

University of Chicago

Chicago, Illinois, United States

Location

Loyola University Medical Center

Maywood, Illinois, United States

Location

Indiana University

Indianapolis, Indiana, United States

Location

University of Kansas Medical Center Research Institute, Inc

Fairway, Kansas, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Location

Henry Ford Health System

Detroit, Michigan, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, United States

Location

Weill Cornell Medical College - New York - Presbyterian Hospital

New York, New York, United States

Location

Duke Cancer Center

Durham, North Carolina, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, United States

Location

Ohio State University

Columbus, Ohio, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Saint Francis Cancer Center

Greenville, South Carolina, United States

Location

Princess Margaret

Toronto, Ontario, Canada

Location

Jewish General Hospital

Montreal, Quebec, Canada

Location

Universitätsklinikum Frankfurt Medizinische Klinik II

Frankfurt, 60590, Germany

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; Daunorubicin; Cytarabine; Decitabine; Azacitidine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: January 16, 2015
• First Posted: January 22, 2015
• Study Start: July 1, 2015
• Primary Completion: September 4, 2018
• Study Completion: February 21, 2019
• Last Updated: November 15, 2019
• Results First Posted: November 15, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); US (14); DE (1)