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

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.

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