Safety and Efficacy of Entospletinib (ENTO [GS-9973]) Combined With Vincristine (VCR) in Adult Participants With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (NHL)

A Phase 1b-2, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (ENTO [GS-9973]) Combined With Vincristine (VCR) in Adult Subjects With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (NHL)

The primary objective of this study is to evaluate the safety of ENTO with VCR in participants with relapsed or refractory B-cell NHL.

Study Overview

• Status: Terminated
• Conditions: Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: Entospletinib; Drug: Vincristine

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Dijon Cedex, France
    • Centre Hospitalier Universitaire de Dijon Hôpital du Bocage
  • Pierre Benite, France
    • Centre Hospital Lyon Sud
  • Aquitaine
    • Pessac, Aquitaine, France
      • Groupe Hospitalier du Haut Leveque
  • NORD Pas-de-calais
    • Lille cedex, NORD Pas-de-calais, France
      • Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille)
  • Provence Alpes COTE D'azur
    • Marseille, Provence Alpes COTE D'azur, France
      • Institut Paoli Calmettes
• United States
  • Mississippi
    • Hattiesburg, Mississippi, United States
      • Forrest General Hospital
  • South Carolina
    • Charleston, South Carolina, United States
      • Medical University of South Carolina

Participation Criteria

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:

• Measurable disease by computed tomograph (CT)/ and/or positron-emission tomography CT (PET-CT)
• A) Dose Escalation Stage: Confirmed diagnosis of relapsed or refractory B-Cell NHL treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens (or autologous stem cell transplant) , or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician

• B) Dose Expansion Cohorts:

  • Expansion Cohort A: Diagnosis of relapsed or refractory DLBCL treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
  • Expansion Cohort B: Diagnosis of relapsed or refractory B-cell NHL (other than DLBCL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status ≥ 70
• Required screening laboratory data (within 2 weeks prior to administration of study drug) as defined in study protocol.
• Adequate organ function defined by the screening laboratory inclusion and Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram (ECHO) or multigated acquisition (MUGA)
• Discontinuation of all therapy (including radiotherapy, chemotherapy, tyrosine kinase inhibitors (TKIs), immunotherapy, or investigational therapy for the treatment of cancer at least 2 weeks prior to the initiation of study therapy
• All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before enrollment, with the exception of alopecia (any grade permitted)
• For female individuals of childbearing potential, willingness to use a protocol-recommended method of contraception from the Screening visit throughout the study and 30 days from the last dose of ENTO or VCR, whichever is later.
• For male individuals having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the start of study drug throughout the study treatment period and for 90 days following the last dose of ENTO or VCR, whichever is later and to refrain from sperm donation from the start of the study drug throughout the study treatment period and for 90 days following the last dose of ENTO or VCR, whichever is later.
• In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the individual's NHL
• Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions
• Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures

Key Exclusion Criteria:

• Diagnosis of Primary Mediastinal Large B-cell Lymphoma
• A life threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the individual's safety or interfere with the absorption or metabolism of ENTO
• Active or symptomatic central nervous system (CNS) disease or epidural involvement
• Uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements
• Current/ongoing Neuropathy (sensory or motor) Grade > 1 or any history of Grade ≥ 3 neuropathy with prior VCR or chemotherapy exposure (documentation by history is adequate to exclude)
• Contraindication to receive VCR or any planned protocol-specified chemotherapy
• Eligible for autologous stem cell transplant
• History of myelodysplastic syndrome, allogeneic stem cell or solid organ transplantation
• History of any other prior lymphoid malignancy other than the registrational histology or any other non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to the start of study drug, or any other cancer that has been in complete remission without treatment for ≥ 5 years prior to enrollment
• Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for ENTO
• Evidence of uncontrolled systemic bacterial, fungal, or viral infection at the start of study drug
• Ongoing drug-induced liver injury, chronic active Hepatitis C Virus (HCV), chronic active Hepatitis B Virus (HBV), human immunodeficiency virus (HIV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
• Current therapy with proton pump inhibitors
• Pregnancy or breastfeeding
• Ongoing active pneumonitis
• Prior treatment with a spleen tyrosine kinase (SYK) inhibitor

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation: ENTO; Participants will be enrolled sequentially in a 3 + 3 dose escalation design to receive escalating dose of ENTO+VCR at dose levels 1 to 4 with the objective of defining the maximum tolerated dose (MTD) or recommended dose for the dose expansion stage. Following the determination of the MTD of the dose levels 1 to 4 (or concurrently with the opening of dose level 4), the safety of administering ENTO with VCR when administered as a 4-day prolonged continuous infusion may be evaluated in the continuous infusion dose escalation level (dose level C1) with the objective of investigating the schedule of dosing ENTO when administered with VCR as a continuous infusion.	Drug: Entospletinib; ENTO spray dried dispersion tablets administered orally twice daily while in a fasted state; Other Names: GS-9973; ENTO; Drug: Vincristine; VCR administered intravenously; Other Names: VCR
Experimental: Dose Expansion: VCR+ENTO (Cohort A); Based on the tolerability, safety, and efficacy data from the dose escalation phase, participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) may receive VCR+ENTO.	Drug: Entospletinib; ENTO spray dried dispersion tablets administered orally twice daily while in a fasted state; Other Names: GS-9973; ENTO; Drug: Vincristine; VCR administered intravenously; Other Names: VCR
Experimental: Dose Expansion: VCR+ENTO (Cohort B); Based on the tolerability, safety, and efficacy data from the dose escalation phase, participants with relapsed or refractory B-cell NHL (non-DLBCL) may receive VCR+ENTO.	Drug: Entospletinib; ENTO spray dried dispersion tablets administered orally twice daily while in a fasted state; Other Names: GS-9973; ENTO; Drug: Vincristine; VCR administered intravenously; Other Names: VCR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Laboratory (Lab) Abnormalities Defined as Dose Limiting Toxicities (DLTs) in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage	Occurrence of any of the following toxicities during Cycle 1 was considered DLT if judged by the Investigator to be possibly, probably, or definitely related to the administration of any drug in the treatment regimen: Grade 4 (or higher) non-hematologic toxicity; Grade 3 non-hematologic toxicity lasting ≥ 7 days despite optimal supportive careNote: Grade 3 or higher neuropathy was considered DLT if occurring during Cycle 1 regardless of duration.; Any Grade 3 non-hematologic laboratory value if:Medical intervention was required to treat the patient, orAbnormality led to hospitalization, orAbnormality persisted for > 1 week; Grade 4 Neutropenia (absolute neutrophil count [ANC] < 500 /μL) persisting for > 14 days or associated with febrile neutropenia; Grade 4 thrombocytopenia (platelets < 25,000 cells/μL) persisting for > 14 days (or > 25,000 cells/μL, but requiring prophylactic platelet transfusion to maintain this level)	Cycle 1 (28-day cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage	The number of participants with AEs and lab abnormalities not defined as DLTs in participants in the dose escalation stage with relapsed or refractory B-cell NHL are presented.	Cycle 1 (28-day cycle)
Duration of Exposure to ENTO		Baseline to end of study (maximum: 24 weeks)
Number of VCR Doses		Baseline to end of study (maximum: 24 weeks)

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2016
• Primary Completion (Actual): October 3, 2016
• Study Completion (Actual): June 22, 2017

Study Registration Dates

• First Submitted: September 30, 2015
• First Submitted That Met QC Criteria: October 2, 2015
• First Posted (Estimate): October 6, 2015

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: DLBCL; Relapsed; Refractory
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Vincristine
• Other Study ID Numbers: GS-US-339-1562; 2015-002731-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No