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)

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02568683
• Collaborator: (none)
• Enrollment: 10
• Locations: 7
• Arms: 3
• Actual Duration (Months): 16.3
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin Lymphoma	Drug: Entospletinib; Drug: Vincristine	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Feb 11, 2016
• Actual Primary Completion Date: Oct 3, 2016
• Actual Study Completion Date: Jun 22, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 [Cycle 1 (28-day cycle)]

   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 care Note: 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, or Abnormality led to hospitalization, or Abnormality 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)

Secondary Outcome Measures

1. Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage [Cycle 1 (28-day cycle)]

   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.

2. Duration of Exposure to ENTO [Baseline to end of study (maximum: 24 weeks)]

3. Number of VCR Doses [Baseline to end of study (maximum: 24 weeks)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Measurable disease by computed tomograph (CT)/ and/or positron-emission tomography CT (PET-CT)

• 1. 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
• 1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forrest General Hospital	Hattiesburg	Mississippi	United States
2	Medical University of South Carolina	Charleston	South Carolina	United States
3	Groupe Hospitalier du Haut Leveque	Pessac	Aquitaine	France
4	Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille)	Lille cedex	NORD Pas-de-calais	France
5	Institut Paoli Calmettes	Marseille	Provence Alpes COTE D'azur	France
6	Centre Hospitalier Universitaire de Dijon Hôpital du Bocage	Dijon Cedex		France
7	Centre Hospital Lyon Sud	Pierre Benite		France

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02568683
• Other Study ID Numbers: GS-US-339-1562; 2015-002731-17
• First Posted: Oct 6, 2015
• Last Update Posted: Apr 17, 2019
• Last Verified: Mar 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gilead Sciences: DLBCL; Relapsed; Refractory
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Vincristine

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in the United States and France. The first participant was screened on 11 February 2016. The last study visit occurred on 22 June 2017.
Pre-assignment Detail	13 participants were screened.

Arm/Group Title	ENTO 200 mg	ENTO 400 mg
Arm/Group Description	Participants received entospletinib (ENTO) 200 mg tablet twice daily + vincristine (VCR) 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
Period Title: Overall Study
STARTED	6	4
COMPLETED	0	0
NOT COMPLETED	6	4

Baseline Characteristics

Arm/Group Title	ENTO 200 mg	ENTO 400 mg	Total
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.	Total of all reporting groups
Overall Participants	6	4	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (13.6)	69 (8.1)	65 (11.6)
Sex: Female, Male (Count of Participants)
Female	3 50%	1 25%	4 40%
Male	3 50%	3 75%	6 60%
Race/Ethnicity, Customized (Count of Participants)
White	4 66.7%	1 25%	5 50%
Not Permitted	2 33.3%	3 75%	5 50%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	4 66.7%	1 25%	5 50%
Not Permitted	2 33.3%	3 75%	5 50%

Outcome Measures

1. Primary Outcome

Title	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
Description	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 care Note: 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, or Abnormality led to hospitalization, or Abnormality 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)
Time Frame	Cycle 1 (28-day cycle)

Outcome Measure Data

Analysis Population Description

DLT Analysis Set included participants in the Full Analysis Set (included all participants who received at least 1 dose of ENTO) who received 37 of 56 Cycle 1 doses of ENTO and completed the full Cycle 1 dose of VCR or who experienced a DLT during the DLT assessment window.

Arm/Group Title	ENTO 200 mg	ENTO 400 mg
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
Measure Participants	6	3
Count of Participants [Participants]	0 0%	2 50%

2. Secondary Outcome

Title	Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage
Description	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.
Time Frame	Cycle 1 (28-day cycle)

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set were analyzed.

Arm/Group Title	ENTO 200 mg	ENTO 400 mg
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
Measure Participants	6	4
AEs not defined as DLTs	6 100%	4 100%
Lab abnormalities not defined as DLTs	5 83.3%	4 100%

3. Secondary Outcome

Title	Duration of Exposure to ENTO
Time Frame	Baseline to end of study (maximum: 24 weeks)

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set were analyzed.

Arm/Group Title	ENTO 200 mg	ENTO 400 mg
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
Measure Participants	6	4
Mean (Standard Deviation) [weeks]	17.7 (6.09)	4.3 (2.68)

4. Secondary Outcome

Title	Number of VCR Doses
Time Frame	Baseline to end of study (maximum: 24 weeks)

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set were analyzed.

Arm/Group Title	ENTO 200 mg	ENTO 400 mg
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.	Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
Measure Participants	6	4
Mean (Standard Deviation) [doses]	8.7 (3.27)	2.3 (1.50)

Adverse Events

Time Frame	Baseline up to the last dose date plus 30 days (maximum exposure: 200 mg ENTO = 24 weeks; 400 mg ENTO = 8 weeks)
Adverse Event Reporting Description	Full Analysis Set included all participants who received at least 1 dose of ENTO.
Arm/Group Title	ENTO 200 mg		ENTO 400 mg
Arm/Group Description	Participants received ENTO 200 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 24 weeks.		Participants received ENTO 400 mg tablet twice daily + VCR 1.0 mg/m^2 administered via intravenous infusion every 14 days; up to 8 weeks.
All Cause Mortality
	ENTO 200 mg		ENTO 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ENTO 200 mg		ENTO 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/4 (25%)
General disorders
Pyrexia	1/6 (16.7%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Sinus pain	0/6 (0%)		1/4 (25%)
Other (Not Including Serious) Adverse Events
	ENTO 200 mg		ENTO 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anaemia	1/6 (16.7%)		0/4 (0%)
Neutropenia	0/6 (0%)		1/4 (25%)
Gastrointestinal disorders
Abdominal pain	1/6 (16.7%)		0/4 (0%)
Abdominal pain upper	2/6 (33.3%)		0/4 (0%)
Constipation	1/6 (16.7%)		1/4 (25%)
Diarrhoea	3/6 (50%)		1/4 (25%)
Dysphagia	1/6 (16.7%)		0/4 (0%)
Ileus	0/6 (0%)		1/4 (25%)
Nausea	2/6 (33.3%)		2/4 (50%)
Odynophagia	0/6 (0%)		1/4 (25%)
General disorders
Asthenia	1/6 (16.7%)		1/4 (25%)
Fatigue	2/6 (33.3%)		0/4 (0%)
Feeling drunk	0/6 (0%)		1/4 (25%)
Ill-defined disorder	1/6 (16.7%)		0/4 (0%)
Malaise	1/6 (16.7%)		0/4 (0%)
Oedema peripheral	1/6 (16.7%)		0/4 (0%)
Pyrexia	1/6 (16.7%)		0/4 (0%)
Immune system disorders
Seasonal allergy	2/6 (33.3%)		0/4 (0%)
Infections and infestations
Sepsis	0/6 (0%)		1/4 (25%)
Investigations
Alanine aminotransferase increased	1/6 (16.7%)		1/4 (25%)
Aspartate aminotransferase increased	1/6 (16.7%)		1/4 (25%)
Blood alkaline phosphatase increased	0/6 (0%)		1/4 (25%)
Blood creatinine increased	1/6 (16.7%)		0/4 (0%)
Gamma-glutamyltransferase increased	0/6 (0%)		1/4 (25%)
Weight decreased	1/6 (16.7%)		1/4 (25%)
Metabolism and nutrition disorders
Decreased appetite	0/6 (0%)		1/4 (25%)
Dehydration	1/6 (16.7%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		0/4 (0%)
Groin pain	1/6 (16.7%)		0/4 (0%)
Musculoskeletal pain	1/6 (16.7%)		0/4 (0%)
Pain in extremity	1/6 (16.7%)		0/4 (0%)
Nervous system disorders
Disturbance in attention	0/6 (0%)		1/4 (25%)
Headache	1/6 (16.7%)		0/4 (0%)
Hypoaesthesia	0/6 (0%)		1/4 (25%)
Neuropathy peripheral	0/6 (0%)		1/4 (25%)
Paraesthesia	1/6 (16.7%)		0/4 (0%)
Psychiatric disorders
Agitation	1/6 (16.7%)		0/4 (0%)
Confusional state	1/6 (16.7%)		0/4 (0%)
Mental status changes	1/6 (16.7%)		0/4 (0%)
Renal and urinary disorders
Dysuria	0/6 (0%)		1/4 (25%)
Pollakiuria	1/6 (16.7%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/6 (16.7%)		0/4 (0%)
Hiccups	1/6 (16.7%)		0/4 (0%)
Oropharyngeal pain	1/6 (16.7%)		0/4 (0%)
Rhinorrhoea	1/6 (16.7%)		0/4 (0%)
Skin and subcutaneous tissue disorders
Night sweats	1/6 (16.7%)		0/4 (0%)
Pruritus	1/6 (16.7%)		0/4 (0%)
Urticaria	0/6 (0%)		1/4 (25%)

Limitations/Caveats

Because the study was terminated after enrolling only 10 participants, the dose expansion stage and the planned efficacy analyses were not conducted.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years