A phase I study of TAS-102 in combination with oxaliplatin (TAS-OX) for refractory metastatic colorectal cancer (mCRC).

Abstract

630 Background: TAS-102 is an oral combination of the anti-metabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI), preventing the degradation of FTD. It is approved as mCRC monotherapy with improved survival. Oxaliplatin is often reintroduced in mCRC after progressive disease (PD) on maintenance 5-FU although response is poor. The decreased efficacy may be related to acquired 5-FU resistance. We therefore explored the safety and efficacy of oxaliplatin in combination with an alternative and non cross-resistant anti-metabolite, TAS-102. Methods: Phase 1 of TAS-OX is a 3+3 dose-escalating study at a starting dose of TAS-102 25 mg/m2 and oxaliplatin 85 mg/m2 with three dose levels (table). TAS-102 is administered days 1-5 and oxaliplatin day 1, every 2 weeks. Eligible patients previously received 5FU, oxaliplatin, irinotecan, appropriate biologics, had measurable disease, usual laboratory parameters, and ECOG PS 0-1. The primary objective was to determine the recommended phase II dose (RP2D). Results: Twelve patients were evaluable for dose limiting toxicity (DLT). No DLTs were observed. Treatment related grade ≥ 3 AEs were neutropenia (n = 4) and thrombocytopenia (n = 1). No AEs resulted in treatment discontinuation. Two patients (dose levels 2 and 3) required dose reductions for prolonged neutropenia. Median number of cycles for all treated patients was 6 ± 4. The disease control rate (DCR) at 8 weeks was 67%. Best response in all evaluable patients was 1 PR (8%) 7 (59%) SD and 4 (33%) PD. Conclusions: The RP2D of TAS-102 is 35 mg/m2 in combination with oxaliplatin 85 mg/m2. No DLTs were observed and no unexpected AEs were seen. The DCR in this heavily pretreated patient population is encouraging. Phase II is now enrolling at this dose (NCT 02848079). Clinical trial information: NCT02848079. [Table: see text]

Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors

“…The results of this study were also consistent with recent phase I reports of other FTD/TPI combinations in mCRC, although FTD/ TPI was dosed at a lower level in the triplet combination than in the other combination regimens (22)(23)(24)(25). In a phase I/II study of FTD/TPI plus bevacizumab in refractory mCRC, the recommended phase II dose was FTD/TPI 35 mg/m 2 (twice daily on days 1-5 and 8-12 of a 28-day cycle) and bevacizumab 5 mg/kg every 2 weeks (24).…”

“…Three dose-escalation studies of FTD/TPI and oxaliplatin in patients with previously treated mCRC arrived at a MTD of FTD/TPI 35 mg/m 2 (twice daily on days 1-5 of a 14day cycle) plus oxaliplatin 85 mg/m 2 (on day 1 of a 14-day cycle; refs. 22,23,25). These studies showed manageable safety and preliminary antitumor activity of the FTD/TPI-containing regimens in patients with previously treated mCRC (22)(23)(24)(25).…”

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

“…Two other phase I, dose-escalation studies evaluated the re-introduction of oxaliplatin, given in combination with FTD/TPI, in patients with refractory mCRC. 13 , 14 In each study, 12 patients were administered FTD/TPI on the same schedule and at the same dose as in this study, and neutropenia was the most common grade ≥3 AE.…”

<p>Refractory Metastatic Colorectal Cancer: Current Challenges and Future Prospects</p>

“…16 Oxaliplatin plus TAS-102 is being investigated in a phase 2 trial, consequent to a phase 1 study demonstrating a DCR of 67% at 8 weeks and no dose-limiting toxicities. 17 Despite supportive preclinical data, a phase 1/2 trial of TAS-102 plus panitumumab in 56 patients with RAS WT mCRC (with no prior anti-EGFR or regorafenib) reported a 33.3% PFS rate at 6 m, below the prespecified threshold for activity. 18 With regard to immunotherapy, a phase 2 study of TAS-102 plus nivolumab in patients with proficient MMR (pMMR) refractory mCRC was disappointing, with no observed responses and median PFS of 2.8 m. 19…”

“…47 Trastuzumab plus the oral dual-target TKI, lapatinib, appears to be an efficacious combination in mCRC based on the phase 2 "HERACLES" trial. 48 In the heavily pretreated cohort, the median PFS was 21 weeks [95% CI [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] 50 The combination was chosen due to efficacy not seen with either single agent in preclinical models. Although this regimen is now standard for refractory disease, these drugs are not universally funded by health schemes, and the cost and efficiency of screening many patients must be considered.…”