Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC)


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Mark Saunders1,Antoine Hollebecque2,Aitana Calvo3,Thierry André4,Guilem Argiles5,Andres Cervantes6,Catherine Leger7,Aude Valette7,Nadia Amellal7,Ronan Fougeray7,Josep Tabernero5
1The Christie NHS Foundation Trust, Manchester,2Drug Development Department (DITEP: Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy Cancer campus, Villejuif,3Gregorio Marañon University General Hospital, Madrid,4Hôpital Saint-Antoine, service d'oncologie, 184, rue du Faubourg-Saint-Antoine, Paris,5Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona,6Department of Medical Oncology, Biomedical Research Institute, Incliva, University of Valencia,7Institut de Recherches Internationales Servier, Suresnes

Abstract

Background

Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy. The primary objective was to determine the safety and MTD among mCRC pts who have progressed after at least one prior line of treatment.

Method

This is a two-part study, starting with a 3+3 design, where pts received escalating trifluridine/tipiracil doses together with a fixed dose of oxaliplatin 85mg/m² (day 1). The second part combines this doublet with either bevacizumab or nivolumab to assess safety, pharmacokinetics and efficacy of each triplet.

Results

Fifteen of 17pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10pts previous line with oxaliplatin. Pts received a median of four cycles (range:1–23). The MTD was defined at trifluridine/tipiracil 35mg/m² bid and oxaliplatin 85mg/m² days 1-5 q14. Combination was well tolerated and only one DLT was observed (G3 febrile neutropenia). The most common (>20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5pts and thrombocytopenia in 4pts (all G1); 1pt experienced a G4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity G≥2 was observed in 2pts. ADRs were manageable with basic supportive care, with treatment delays or interruptions. Best overall response includes partial response (n=1, unconfirmed), stable disease (n=7).

Conclusion

At the MTD, incidence and severity of bone marrow suppression and gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. The second part of this study is now underway and has recently opened in the UK. Clinical trial: NCT02848443.