Abstract 464P
Background
5-FU is a key anti-cancer agent used across a broad range of tumours. The anti-cancer metabolite of 5-FU, fluorodeoxyuridine-monophosphate (FUDR-MP), binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. 5-FU is often dosed with leucovorin (LV) to enhance binding of FUDR-MP to TS. NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown. NuTide:302 is a three-part study in patients (pts) with advanced colorectal cancer (CRC) who have relapsed after ≥2 prior lines of 5-FU-containing regimens, investigating NUC-3373 in combination with agents commonly used to treat CRC.
Methods
Pts received 1500 mg/m2 NUC-3373 +/- 400 mg/m2 LV on Days 1 and 15 of a 28-day cycle. Plasma and PBMC samples were collected during first 2 cycles. Safety was assessed throughout.
Results
PK profiles from 17 matched pairs from Q2W dosed pts were available (n = 21 pts). PK parameters for NUC-3373 were similar +/- LV and interpatient variability was low. Increasing intracellular FUDR-MP concentrations were associated with an increase in intracellular dUMP concentrations. NUC-3373 was well tolerated +/- LV. Highest grade treatment-related adverse events (TRAEs) were grade 3 hyponatremia (1 pt) and grade 4 bilirubin increased (1 pt). No pts discontinued NUC-3373 due to TRAEs. Table: 464P
| NUC-3373 + LV Mean (%CV) | NUC-3373 Mean (%CV) | |
| Cmax(ug/ml) | 42.1 (32) | 39.6 (37) |
| AUC (0-t)(ug·h/ml) | 149.0 (68) | 135.0 (77) |
| Elimination half-life (hours) | 5.1 (25) | 5.0 (26) |
| Volume of distribution (L) | 174 (45) | 193 (41) |
| Clearance (L/hour) | 27.0 (49) | 30.9 (49) |
Conclusions
NUC-3373 demonstrated a favourable PK profile with a long plasma half-life and high volume of distribution. The association between increasing FUDR-MP with increasing dUMP concentrations indicates NUC-3373’s ability to inhibit TS, preventing conversion of dUMP to dTMP. PK parameters for NUC-3373 +/- LV were similar indicating LV has no PK interaction with NUC-3373. NUC-3373 was well tolerated +/- LV. These findings suggest that LV is an appropriate combination partner for NUC-3373.
Clinical trial identification
NCT03428958.
Editorial acknowledgement
Legal entity responsible for the study
NuCana plc.
Funding
NuCana plc.
Disclosure
J. Graham: Advisory/Consultancy: Pierre Fabre; Speaker Bureau/Expert testimony: Amgen; Travel/Accommodation/Expenses: Bayer; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: NuCana. K.K. Ciombor: Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Research to Practice; Advisory/Consultancy: Taiho Pharmaceutical; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Onyx; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Bristol-Myers Squibb ; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Array BioPharma; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): NuCana. F. Aroldi: Travel/Accommodation/Expenses: NuCana. A. Coveler: Advisory/Consultancy: Halozyme; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Merrimack; Advisory/Consultancy, Travel/Accommodation/Expenses: Abbvie; Research grant/Funding (institution): XBiotech; Research grant/Funding (institution): Newlink Genetics; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Onconova Therapeutics; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Gilead Sciences; Research grant/Funding (institution): Genentech ; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): AbGenomics International; Research grant/Funding (institution), Travel/Accommodation/Expenses: Halozyme; Research grant/Funding (institution): Novocure; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Amgen. J. Berlin: Advisory/Consultancy: Celgene; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: EMD Serono; Advisory/Consultancy: Cornerstone Pharmaceuticals; Advisory/Consultancy: Five Prime Therapeutics; Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy: Arno Therapeutics; Advisory/Consultancy, Travel/Accommodation/Expenses: Abbvie; Advisory/Consultancy: Eisai; Advisory/Consultancy: Bayer Health; Advisory/Consultancy: Isk biopharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Advisory/Consultancy: qed therapeutics; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Ipsen; Travel/Accommodation/Expenses: Bayer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Boston Biomedical; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Karyopharm Therapeutics; Research grant/Funding (institution): EMD Serono; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): PsiOxus Therapeutics. S. Blagden: Speaker Bureau/Expert testimony: Clovis Oncology; Speaker Bureau/Expert testimony: OCTIMET; Research grant/Funding (institution), Travel/Accommodation/Expenses: NuCana; Research grant/Funding (institution), Travel/Accommodation/Expenses: Tesaro; Licensing/Royalties: WO 2016075455 A1 circulating LARP1; Shareholder/Stockholder/Stock options, Spouse/Financial dependant: RNA Guardian; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Octimet; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Sierra Pharma; Research grant/Funding (institution): Redx Pharma. J. Evans: Advisory/Consultancy: Celgene; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: EMD Serono; Advisory/Consultancy: Cornerstone Pharmaceuticals; Advisory/Consultancy: Five Prime Therapeutics; Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy: Arno Therapeutics; Advisory/Consultancy, Travel/Accommodation/Expenses: Abbvie; Advisory/Consultancy: Eisai; Advisory/Consultancy: Bayer Health; Advisory/Consultancy: Isk biopharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Advisory/Consultancy: qed therapeutics; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Ipsen; Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Research grant/Funding (institution), Travel/Accommodation/Expenses: boston Biomedical; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Pharmacyclics; Research grant/Funding (institution): Karyopharm Therapeutics; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): PsiOxus Therapeutics; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Lilly. All other authors have declared no conflicts of interest.