Non-Hodgkin Lymphoma
Conditions
Keywords
DLBCL, Relapsed, Refractory
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.
Interventions
DRUGEntospletinib
ENTO spray dried dispersion tablets administered orally twice daily while in a fasted state
DRUGVincristine
VCR administered intravenously
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) | — |
Countries
France, United States
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 details
13 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| ENTO 200 mg 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. | 6 |
| ENTO 400 mg 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. | 4 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Study Terminated By Sponsor | 5 | 2 |
| Overall Study | Withdrew Consent | 1 | 0 |
Baseline characteristics
| Characteristic | ENTO 400 mg | Total | ENTO 200 mg |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 8.1 | 65 years STANDARD_DEVIATION 11.6 | 62 years STANDARD_DEVIATION 13.6 |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 1 / 6 | 1 / 4 |
Outcome results
Primary
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 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)
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ENTO 200 mg | 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 | 0 Participants |
| ENTO 400 mg | 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 | 2 Participants |
Secondary
Duration of Exposure to ENTO
Time frame: Baseline to end of study (maximum: 24 weeks)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ENTO 200 mg | Duration of Exposure to ENTO | 17.7 weeks | Standard Deviation 6.09 |
| ENTO 400 mg | Duration of Exposure to ENTO | 4.3 weeks | Standard Deviation 2.68 |
Secondary
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.
Time frame: Cycle 1 (28-day cycle)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ENTO 200 mg | Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage | AEs not defined as DLTs | 6 Participants |
| ENTO 200 mg | Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage | Lab abnormalities not defined as DLTs | 5 Participants |
| ENTO 400 mg | Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage | AEs not defined as DLTs | 4 Participants |
| ENTO 400 mg | Number of Participants With AEs and Lab Abnormalities Not Defined as DLTs in Participants With Relapsed or Refractory B-cell NHL: Dose Escalation Stage | Lab abnormalities not defined as DLTs | 4 Participants |
Secondary
Number of VCR Doses
Time frame: Baseline to end of study (maximum: 24 weeks)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ENTO 200 mg | Number of VCR Doses | 8.7 doses | Standard Deviation 3.27 |
| ENTO 400 mg | Number of VCR Doses | 2.3 doses | Standard Deviation 1.5 |