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

NCT02404220 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GS-US-339-15602015-002768-18
• Study Type: interventional
• Target: 30
• Locations: 3 countries
• Sites: 13

Brief Summary

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.

Conditions

Acute Lymphoblastic Leukemia

Keywords

Syk inhibitor; Blood malignancy; Leukemia

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)

  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 Outcomes (4)

• Percentage of Participants With Complete Remission (CR) at the End of Induction

  End of Induction (Cycle 2, Day 28)

• Percentage of Participants With Overall Remission at the End of Induction

  End of Induction (Cycle 2, Day 28)

• Percentage of Participants With Partial Response (PR) at the End of Induction

  End of Induction (Cycle 2, Day 28)

• Percentage of Participants With Overall Response at the End of Induction

  End of Induction (Cycle 2, Day 28)

Study Arms (4)

ENTO 200 mg + VCR 0.5 mg

EXPERIMENTAL

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: Entospletinib; Drug: Vincristine; Drug: Dexamethasone; Drug: CNS Prophylaxis

ENTO 400 mg + VCR 0.5 mg

EXPERIMENTAL

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: Entospletinib; Drug: Vincristine; Drug: Dexamethasone; Drug: CNS Prophylaxis

ENTO 400 mg + VCR 1.0 mg

EXPERIMENTAL

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: Entospletinib; Drug: Vincristine; Drug: Dexamethasone; Drug: CNS Prophylaxis

ENTO 400 mg + VCR 2.0 mg

EXPERIMENTAL

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: Entospletinib; Drug: Vincristine; Drug: Dexamethasone; Drug: CNS Prophylaxis

Interventions

Entospletinib DRUG

Also known as: GS-9973, ENTO

ENTO 200 mg + VCR 0.5 mg; ENTO 400 mg + VCR 0.5 mg; ENTO 400 mg + VCR 1.0 mg; ENTO 400 mg + VCR 2.0 mg

Vincristine DRUG

Also known as: VCR

ENTO 200 mg + VCR 0.5 mg; ENTO 400 mg + VCR 0.5 mg; ENTO 400 mg + VCR 1.0 mg; ENTO 400 mg + VCR 2.0 mg

Dexamethasone DRUG

Also known as: DEX

ENTO 200 mg + VCR 0.5 mg; ENTO 400 mg + VCR 0.5 mg; ENTO 400 mg + VCR 1.0 mg; ENTO 400 mg + VCR 2.0 mg

CNS Prophylaxis DRUG

ENTO 200 mg + VCR 0.5 mg; ENTO 400 mg + VCR 0.5 mg; ENTO 400 mg + VCR 1.0 mg; ENTO 400 mg + VCR 2.0 mg

Eligibility Criteria

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

You may qualify if:

• Adults with ALL in need of treatment

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (13)

City of Hope

Duarte, California, 91010, United States

Location

UCLA

Los Angeles, California, 90095, United States

Location

UC Irvine Medical Center

Orange, California, 92608, United States

Location

University of California San Diego (UCSD)

San Diego, California, 92093, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan-Kettering

New York, New York, 10021, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

Bon Secour St. Francis Hospital

Greenville, South Carolina, 29601, United States

Location

University of WA

Seattle, Washington, 98109, United States

Location

Princess Margaret

Toronto, Ontario, Canada

Location

Medizinische Klinik mit Schwerpunkt Hepatologie & Gastroenterology

Berlin, 12200, Germany

Location

Medizinische Klinik und Poliklinik I

Würzburg, Germany

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia

Interventions

6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; Vincristine; Dexamethasone

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Limitations and Caveats

Due to the low response rate observed with ENTO + VCR + DEX in adults with relapsed or refractory B-ALL, the sponsor decided not to proceed with Phase 2 (dose-expansion) and the cohort was subsequently closed with no participant enrolled.

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: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2015
• First Posted: March 31, 2015
• Study Start: May 6, 2015
• Primary Completion: November 16, 2018
• Study Completion: December 17, 2018
• Last Updated: January 2, 2020
• Results First Posted: December 2, 2019

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); DE (2); US (10)