Phase Ib Study of TAS-102 Plus Radiation Therapy for the Treatment of the Liver in Patients With Hepatic Metastases From Colorectal Cancer

Abstract

SBRT for liver metastases has emerged as a viable option for treatment of unresectable liver metastases. Among patients with colorectal cancer, however, recent phase II data demonstrated a 1-year local control of 60%, suggesting room for improvement and need for novel strategies to enhance radiosensitivity. TAS 102, an orally administered combination of trifluridine and tipiracil hydrochloride, is an FDA approved regimen for refractor metastatic colorectal cancer. In this study, we evaluated TAS-102 as a radiosensitizer with the goal of improving the efficacy of radiation therapy. In this current abstract, we report the results of the Phase IB study.Patients were enrolled on an investigator-initiated, industry sponsored, prospective, single arm study (NCT03223779). Key eligibility included: histologically confirmed diagnosis of colorectal cancer with 1-4 liver metastases which are deemed unresectable, at least 1 lesion measuring ≥ 1 cm, ECOG PS 0-1, age 18+, and life expectancy > 3 months. Prior treatment including TACE, RFA, and chemotherapy or targeted agents was allowed after a 3-week washout. Prior liver directed RT, including SIRT, was not permitted. Pts were treated with liver RT in 5-6 fractions, delivered 2-4 fractions per week, with RT dose determined by Veff (30-50 Gy in 5 fractions, or 31.8-54 Gy in 6 fractions). TAS 102 dosing occurs on days 1-5 and 8-12. Patients were treated on a 3+3 dose escalation study design, with a starting dose of 20 mg/m2. Dose Limiting Toxicity (DLT) was defined as therapy-related diarrhea, neutropenia, nausea/vomiting, elevation of LFT's, skin toxicity, pain or thrombocytopenia deemed grade ≥ 3. The primary endpoint of the phase Ib component is to determine the maximum tolerated dose (MTD) of TAS-102 when given with SBRT to patients with hepatic metastases from colorectal cancer.From October 2017 to December 2020, 12 patients were enrolled. Median age was 63.5 (range: 32-88), and 7 pts were male (58%). Median RT dose was 50 Gy. On dose level 1 (20 mg/m2 BID), 3 patients were enrolled, none of whom experienced a dose limiting toxicity (DLT). Three patients were enrolled on dose level 2 (25 mg/m2 BID). Two patients completed treatment per protocol, however, the third patient was treated at a reduced dose, on dose level 1, due to elevated bilirubin on C1D1 prior to treatment start and safety concerns. Per protocol design, a fourth patient was enrolled on dose level 2 without toxicity. The third cohort (30 mg/m2 BID) has enrolled 5 patients; 3 have completed treatment as planned, and 2 stopped drug early due to diarrhea (n = 1) and thrombocytopenia (n = 1), both unrelated to study treatment. Of 12 patients, 2 have completed active follow-up, 3 are active in follow-up, and 7 have died. Per protocol design, one more patient is to be enrolled in dose level 3 prior to opening the Phase II portion.In our phase IB study, the MTD dose of TAS-102 with concurrent liver RT is expected to be 30 mg/m2. A phase II study is subsequently planned.