Phase 1 dose escalation trial of TAS-102 (trifluridine/tipiracil) and temozolomide in the treatment of advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are understudied and have limited systemic treatment options. Prior studies for patients with advanced NETs have demonstrated promising results when antimetabolite agents, including fluoropyrimidines, were combined with temozolomide TMZ. TAS-102 (trifluridine/tipiracil) is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. This study evaluated the safety of TAS-102 in combination with TMZ in patients in neuroendocrine tumors. Escalating doses of TMZ (100, 150 and 200 mg/m2) on days 8-12 were given in combination with TAS-102 (35 mg/m2 twice a day) on days 1-5 and 8-12 of a 28 day cycle in subjects with advanced NETs. Primary endpoints were safety and determination of maximum tolerated dose (MTD). Growth factor support was mandated starting with level 2 to avoid treatment delays. Fifteen evaluable subjects were enrolled in the phase 1 study. No dose limiting toxicities (DLTs) were observed on level 1. One DLT was observed on level 2 (grade 3 fatigue and inability to resume treatment), and 1 on level 3 (grade 4 thrombocytopenia). The most common grade ≥ 3 adverse events included neutropenia (33%), lymphopenia (27%), and thrombocytopenia (27%). Disease control rate of 92% and partial response rate of 8% were observed in 13 evaluable subjects. This study established MTD of TAS-102 (35 mg/m2 twice daily) and TMZ (200 mg/m2 daily). This regimen was well tolerated. Early signs of clinically meaningful activity were observed. Further evaluation of the efficacy of this regimen is warranted.