LB-025 - PHARMACOKINETICALLY-GUIDED DOSING OF ORAL SORAFENIB IN PATIENTS WITH PEDIATRIC HEPATOCELLULAR CARCINOMA

C. Stewart¹, A. Christensen², M. Bourque², J. Sciasci³, J. Gartrell⁴, J. Panetta⁴; ¹St. Jude Children's Research Hospital, Memphis, USA, ²St. Jude Children's Research Hospital, Memphis, TN, United States, ³St. Jude Children's Research Hospital, Memphis, TN, USA, ⁴St. Jude Children's Research Hospital, Memphis, TN, .

Background: Sorafenib (SOR) has been approved for use in adults and has clinical activity in children with unresectable hepatocellular carcinoma (HCC). In a phase 1 trial (NCT00665990) in pediatric patients with recurrent and refractory solid tumors, the combination of fixed dose SOR, bevacizumab (BEV), and oral cyclophosphamide (CTX) was tolerable. In a prospective trial in pediatric patients with rare solid tumors, we are evaluating the addition of atezolizumab (ATZ). A primary objective of the trial is to determine if SOR systemic exposure can be targeted to an AUC by day 21 of course 1 in 60% of patients when given in combination with CTX, BEV, and ATZ.

Methods: This ongoing trial (NCT05468359) includes a safety and feasibility run-in phase in which 6 patients will be enrolled at the recommended phase 2 dosage of CTX, BEV, ATZ, with pharmacokinetically-guided dosing (PKGD) of SOR to an AUC0-12h between 20-55 µg*ml/hr. Serial plasma samples will be obtained after course 1/day 1 for SOR PKGD, and then subsequent plasma SOR PK studies will be performed on days 7, 14, and 21 during course 1 for PKGD. Plasma SOR concentrations will be measured using a CLIA certified LC MS/MS. A one-compartment PK model with zero-order absorption and first-order elimination will be fit to each patient’s SOR concentration-time data with ADAPT using Bayesian priors. The last patient studied was enrolled on the trial on November 2, 2023.

Results: SOR concentration-time data were used to perform PKGD for 6 pediatric patients including 4 males and 2 females median age (range) 13.4 (3.2, 22.2) years. All patients received SOR 90 mg/m2 as their initial dosage while their median (range) targeted dosage was 50 (25 to 145) mg/m2. The median (range) SOR CL/F during course 1 was 1.02 (0.43, 9.14) L/hr/m2. By course 1 day 14, 5 of 6 patients were successfully targeted. Of the 21 total PKGD studies, 13 were in target range (62% targeting success). Excluding the initial fixed dose study, 12 of 15 studies were in target range (80% targeting success).

Conclusion: Our safety run-in phase has met the objective of successfully targeting at least 60% of the patients. The median targeted SOR dose was 44% lower than the conventional dose of 90 mg/m2. No dose limiting toxicities (including SOR-related toxicities) have been observed in our patients.