Safety and Efficacy of Entospletinib With Vincristine and Dexamethasone in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

December 23, 2019 updated by: Gilead Sciences

A Phase 1b/2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (GS-9973) With Vincristine and Dexamethasone in Adult Subjects With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

The primary objective of this study is to evaluate the safety of entospletinib in combination with vincristine (VCR), and dexamethasone (DEX) in adults with previously treated relapsed or refractory B-cell lineage acute lymphoblastic leukemia (ALL).

This is a dose escalation study in which after 2 induction cycles participants may be put on maintenance for up to 36 cycles if they have obtained clinical benefit from the treatment.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada
        • Princess Margaret
  • Germany
      • Berlin, Germany, 12200
        • Medizinische Klinik mit Schwerpunkt Hepatologie & Gastroenterology
      • Wurzburg, Germany
        • Medizinische Klinik und Poliklinik I
  • United States
    • California
      • Duarte, California, United States, 91010
        • City of Hope
      • Los Angeles, California, United States, 90095
        • UCLA
      • Orange, California, United States, 92608
        • UC Irvine Medical Center
      • San Diego, California, United States, 92093
        • University of California San Diego (UCSD)
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10021
        • Memorial Sloan-Kettering
    • Ohio
      • Columbus, Ohio, United States, 43210
        • The Ohio State University
    • South Carolina
      • Greenville, South Carolina, United States, 29601
        • Bon Secour St. Francis Hospital
    • Washington
      • Seattle, Washington, United States, 98109
        • University of WA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Key Inclusion Criteria:

  • Adults with ALL in need of treatment

Key Exclusion Criteria:

  • Diagnosis of Burkitt's Leukemia, or lymphoid blast crisis of chronic myelogenous leukemia (CML)
  • History of myelodysplastic syndrome or solid organ transplantation
  • Prior allogeneic bone marrow progenitor cell transplant within 100 days or on active immunosuppression for graft versus host disease (GVHD) treatment or prophylaxis within 28 days prior to enrollment

Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ENTO 200 mg + VCR 0.5 mg

Monotherapy Lead-In (Day -7 to Day -1): Entospletinib (ENTO) 200 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 200 mg twice daily continuously in combination with vincristine (VCR) 0.5 mg intravenously (IV) on Days 1, 8, 15, and 22 of each cycle; dexamethasone (DEX) 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and central nervous system (CNS) prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a complete remission (CR) received stem cell transplant (SCT) (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a partial response [PR]) after induction were offered maintenance therapy with ENTO 200 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.
Drug: Vincristine
Other Names:
  • VCR
Drug: Dexamethasone
Other Names:
  • DEX
Drug: Entospletinib
Other Names:
  • GS-9973
  • ENTO
Drug: CNS Prophylaxis
Experimental: ENTO 400 mg + VCR 0.5 mg

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 0.5 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.
Drug: Vincristine
Other Names:
  • VCR
Drug: Dexamethasone
Other Names:
  • DEX
Drug: Entospletinib
Other Names:
  • GS-9973
  • ENTO
Drug: CNS Prophylaxis
Experimental: ENTO 400 mg + VCR 1.0 mg

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 1.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.
Drug: Vincristine
Other Names:
  • VCR
Drug: Dexamethasone
Other Names:
  • DEX
Drug: Entospletinib
Other Names:
  • GS-9973
  • ENTO
Drug: CNS Prophylaxis
Experimental: ENTO 400 mg + VCR 2.0 mg

Monotherapy Lead-In (Day -7 to Day -1): ENTO 400 mg tablet orally twice daily as a single agent.

Induction (two 28-day cycles): ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg IV on Days 1, 8, 15, and 22 of each cycle; DEX 20 mg twice daily orally on Days 8-11 and Days 22-25 (Cycle 1) and on Days 1-4 and Days 15-18 (Cycle 2); and CNS prophylaxis per institutional standards on Day 28 of each cycle.

Maintenance (up to 36, 28-day cycles): Participants who achieved a CR received SCT (if eligible) per investigator's discretion; others who obtained clinical benefit (ie, at least a PR) after induction were offered maintenance therapy with ENTO 400 mg twice daily continuously in combination with VCR 2.0 mg on Day 1 of each cycle and DEX (20 mg daily or 10 mg twice daily) on Days 1-4 and Days 15-18 of each cycle.
Drug: Vincristine
Other Names:
  • VCR
Drug: Dexamethasone
Other Names:
  • DEX
Drug: Entospletinib
Other Names:
  • GS-9973
  • ENTO
Drug: CNS Prophylaxis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
Time Frame: ENTO Lead-in and Cycle 1 (Day -7 through Day 28)

The occurrence of any of the following toxicities during Lead-in/Cycle 1 (Day -7 through Day 28) was considered a DLT if judged by the investigator to be possibly, probably, or definitely related to the administration of any drug in the treatment regimen (ENTO, VCR, DEX, institutional standard CNS prophylaxis):

  • Grade 4 (or higher) non-hematologic toxicity
  • Grade 3 non-hematologic toxicity lasting ≥ 7 days despite optimal supportive care

  • Any Grade 3 non-hematologic laboratory value if:

    • Medical intervention was required to treat, or
    • The abnormality led to hospitalization, or
    • The abnormality persisted for > 1 week
  • Grade 4 Neutropenia (absolute neutrophil count [ANC] < 500 /μL) persistent for greater than 14 days or associated with febrile neutropenia
  • Grade 4 thrombocytopenia (platelets < 25,000/μL) persisting for greater than 14 days (or greater than 25,000 /μL, but requiring prophylactic platelet transfusion to maintain this level)
ENTO Lead-in and Cycle 1 (Day -7 through Day 28)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants With Complete Remission (CR) at the End of Induction
Time Frame: End of Induction (Cycle 2, Day 28)

Assessment of clinical response was made according to National Comprehensive Cancer Network (NCCN) guidelines on acute lymphoblastic leukemia (ALL) Version 2, 2016. CR required all of the following:

  • No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
  • Trilineage hematopoiesis (TLH) and < 5% blasts in bone marrow aspirate.
  • ANC > 1000/μL.
  • Platelets > 100,000/μL.
End of Induction (Cycle 2, Day 28)
Percentage of Participants With Overall Remission at the End of Induction
Time Frame: End of Induction (Cycle 2, Day 28)

Assessment of clinical response was made according to NCCN guidelines on ALL Version 2, 2016. Overall remission included CR and complete remission with incomplete hematologic recovery (CRi). CR required all of the following:

  • No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
  • TLH and < 5% blasts in bone marrow aspirate.
  • ANC > 1000/μL.
  • Platelets > 100,000/μL.

CRi required all criteria for CR except platelet count and/or ANC:

  • Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL
End of Induction (Cycle 2, Day 28)
Percentage of Participants With Partial Response (PR) at the End of Induction
Time Frame: End of Induction (Cycle 2, Day 28)

PR required all of the following:

  • No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
  • TLH and bone marrow may contain ≥ 5% but less than 25% blast morphology.
  • ANC > 1000/μL.
  • Platelets > 100,000/μL.
End of Induction (Cycle 2, Day 28)
Percentage of Participants With Overall Response at the End of Induction
Time Frame: End of Induction (Cycle 2, Day 28)

Overall response included CR, CRi, and PR. CR required all of the following:

  • No circulating blasts or extramedullary disease (no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS involvement).
  • TLH and < 5% blasts in bone marrow aspirate.
  • ANC > 1000/μL.
  • Platelets > 100,000/μL.

CRi required all criteria for CR except platelet count and/or ANC:

  • Platelets ≤ 100,000/μL and/or ANC is ≤ 1000/μL

PR required all criteria for CR except for bone marrow blasts:

  • bone marrow may contain ≥ 5% but less than 25% blast morphology
End of Induction (Cycle 2, Day 28)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gilead Sciences

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 6, 2015

Primary Completion (Actual)

November 16, 2018

Study Completion (Actual)

December 17, 2018

Study Registration Dates

First Submitted

March 2, 2015

First Submitted That Met QC Criteria

March 26, 2015

First Posted (Estimate)

March 31, 2015

Study Record Updates

Last Update Posted (Actual)

January 2, 2020

Last Update Submitted That Met QC Criteria

December 23, 2019

Last Verified

December 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GS-US-339-1560
  • 2015-002768-18 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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