A phase 1b/2, open-label study of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (Deductive).

Abstract

TPS499 Background: Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The combination of atezolizumab and bevacizumab (which blocks VEGF-A ligand binding to VEGFR2) has improved the standard of care in advanced hepatocellular cancer with a median PFS of 6.8 months and 1-year overall survival of 67.2%. All the currently used agents in the second-line setting, have been evaluated in pts with HCC only after exposure to sorafenib. Treatment option for the patients with HCC that progress on atezolizumab and bevacizumab, are therefore limited. Methods: Deductive (NCT03970616) is a phase 2, multicenter, open-label study to assess the safety and efficacy of tivozanib in combination with durvalumab in patients with advanced HCC. Cohort A (n=20) includes patients with untreated advanced HCC. Cohort B (n=20) includes patients with advanced HCC who have progressed on/after treatment with prior bevacizumab and atezolizumab. Eligibility criteria include age >18 years, histologically or cytologically confirmed HCC, measurable or evaluable disease, Child-Pugh Class A, and ECOG PS of 0 or 1. Subjects will receive tivozanib 0.89 mg orally once daily for 21 consecutive days followed by 7 days off, and durvalumab 1500 mg intravenously every 4 weeks, and will be treated until progression or unacceptable toxicity. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 until the end of treatment, and every 12 weeks during the first year and every 6 months thereafter until disease progression or start of another anti-cancer therapy. The primary objective is to establish the safety and tolerability of tivozanib in combination with durvalumab in subjects who are untreated (cohort A) or have been pre-treated with both bevacizumab and atezolizumab (cohort B). Secondary endpoints include estimation of objective response rate (ORR), median PFS and OS. Exploratory endpoints are to assess the durvalumab pharmacokinetics in the presence of tivozanib. Deductive is currently enrolling at 12 sites in the United States. Clinical trial information: NCT03970616.