Abstract B048: NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302)
Authors: Khan Khurum , Mukherjee Uma , Schlechter Benjamin L , Ciombor Kristen K , Skolariki Aglaia , Coveler Andrew L , Graham Janet S , Peters Mary Linton , Cohen Stacey A , Mettu Niharika , Marijon Hélène , Cosgrove David , McKissock Fiona G , Oelmann Elisabeth , Bloss Jeffrey D , Blagden Sarah P , de Gramont Aimery , Berlin Jordan , Evans T.R. Jeffry 
Published: December 2023

Background:  Fluoropyrimidines, such as 5-FU, exert anti-cancer activity via fluorodeoxyuridine-monophosphate (FUDR-MP). NUC-3373, a phosphoramidate transformation of FUDR-MP,  generates high intracellular levels of FUDR-MP; avoiding toxic metabolite generation; and improving pharmacokinetics to enable more convenient administration.  NuTide:302 is a three-part study investigating NUC-3373 in combination with chemotherapy agents used for the treatment of metatstaic CRC (mCRC). Part 1 established the safety of NUC-3373 in combination with  leucovorin (LV) . Part 2 investigated NUC-3373 + LV in dose-escalation cohorts with either irinotecan (NUFIRI) or oxaliplatin (NUFOX) and determined the MTDs. Parts 1 and 2 established that LV had no effect on the safety or PK profile of NUC-3373 and the addition of oxaliplatin and irinotecan was well-tolerated. Here we present data from Part 3 (ongoing) which investigates NUFIRI and NUFOX in combination with bevacizumab (NUFIRI-bev; NUFOX-bev).

Methods: Patients (pts) who had received 1 prior fluropyrimindine-containing therapy for mCRC were treated with either NUFIRI-bev (1,500 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 180 mg/m2 irinotecan (Q2W); 5 mg/kg  bevacizumab (Q2W)) or NUFOX-bev (1,875 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 85 mg/m2 oxaliplatin (Q2W); 5 mg/kg  bevacizumab (Q2W)). 

Results:   At the time of data cut-off, 14 pts had been treated (NUFIRI-bev n=8; NUFOX-bev n=6); median age 60 (range: 37-81), 36% female, 38% ECOG 0 and 36% with liver metastases. In the NUFIRI-bev arm, there were no Grade 3 TRAEs.  Seven pts (88%) achieved prolonged SD (median= 5.5 mo; range= 3.7-7.4) and 5 pts are ongoing. In the NUFOX-bev arm, Grade 3 TRAEs (occurring in 2 pts) were pancreatitis, ALT increased and hypokalaemia. Four pts (67%) achieved prolonged SD (median= 5 mo; range= 3-6.5) and 5 pts are ongoing. Updated safety and efficacy data will be presented.

Conclusions:This study demonstrated safety and anti-tumour activity of NUFIRI-bev and NUFOX-bev  in previously treated mCRC patients .  A randomised Phase 2 study is currently investigating the safety and efficacy of NUFIRI-bev vs FOLRIFI-bev in 171 second-line pts with CRC (NuTide:323).  Clinical trial information: NCT03428958

Citation Format: Khurum Khan, Uma Mukherjee, Benjamin L Schlechter, Kristen K Ciombor, Aglaia Skolariki, Andrew L Coveler, Janet S Graham, Mary Linton Peters, Stacey A Cohen, Niharika Mettu, Hélène Marijon, David Cosgrove, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Sarah P Blagden, Aimery de Gramont, Jordan Berlin, T.R. Jeffry Evans. NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B048.