This study will investigate if modulating the tumor microenvironment with biologic agents like XL-092 will have synergistic effect when combined with checkpoint based immunotherapeutic treatment of patients with hepatocellular carcinoma (HCC).
Patients must have unresectable hepatocellular carcinoma.
Patients must be treatment naïve for systemic therapy in the unresectable setting.
≥ 18 years and ECOG performance status 0-1
Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of mineralocorticosteroid).
Prior treatment with XL092, or PD-1/PD-L1 or CTLA-4 inhibitors.
Receipt of any type of small molecule kinase inhibitor such as cabozantinib or other MET or Dual MET/HGF monoclonal antibodies or MET/HGF tyrosine kinase inhibitors (TKIs), or any other VEGFR TKIs (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
Parallel
Zanzalintinib
DrugNext generation tyrosine kinase inhibitor (TKI) with the target inhibition profile identical to cabozantinib but with a superior pharmacokinetic profile.
Durvalumab
DrugDurvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279)
Tremelimumab
DrugTremelimumab is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma designed to attach to and block CTLA-4, a protein that controls the activity of T cells
Recommended phase 2 dose (RP2D) of XL-092 with Durvalumab plus Tremelimumab
Recommended phase 2 dose (RP2D) of XL-092 with Durvalumab plus Tremelimumab will be determined per a Dose Limiting Toxicity period of 28 days during the Safety Lead-in period using CTCAE v5.0 criteria.
Objective Response Rate (ORR) (im RECIST)
Proportion of patients with Complete Response (CR) or Partial Response (PR), per immune modified RECIST v1.1. Per imRECIST: CR: -100% Change in Sum of Diameters from Baseline (non-target lesion). PR: ≤ -30% change in sum of diameters from baseline.
Objective Response Rate (ORR)
Proportion of patients with Complete Response (CR) or Partial Response (PR), per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Rate of Disease Conversion
Proportion of patients able to undergo liver resection or transplantation after completion of treatment.
Disease Control Rate (DCR)
Proportion of patients with Complete Response (CR), Partial Response (PR) or Stable Disease (SD), per immune modified RECIST v1.1. Per imRECIST: CR: -100% Change in Sum of Diameters from Baseline (non-target lesion). PR: ≤ -30% change in sum of diameters from baseline. SD: \>-30% to \< +20% change in sum of diameters from baseline.
Progression-free Survival (PFS)
Time after start of treatment (months) when 50% of patients are free of disease progression (Median PFS). Per RECISIT v1.1, Progressive Disease: ≥20%increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Click on the lead sponsor to view all of their trials.
