A modular, open-label, phase I/IIa study to evaluate the safety, tolerability, pharmacokinetics (PKs) and anti-tumour activity of a first-in-class (FIC) specific dUTPase inhibitor CV6-168 combined with anti-cancer treatments in patients (pts) with ad

TPS3170

Background: CV6-168 is a FIC DNA uracilation agent targeting the enzyme dUTPase with high specificity. CV6-168 induces misincorporation of uracil into DNA when combined with thymidylate synthase (TS) inhibitors resulting in significantly increased DNA damage and lethality in cancer cells and activation of immune stimulatory mechanisms. CV6-168 does not inhibit dihydropyrimidine dehydrogenase, the rate-limiting enzyme responsible for 5-FU catabolism avoiding fluoropyrimidine drug-drug interactions and complex dose modifications. This is a first-in-human, modular study initially investigating PK and safety of CV6-168 with bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA). Methods: Primary objective: characterise safety and tolerability of CV6-168 with 5-FU and FA. Secondary objectives: establish PK profile of CV6-168 and 5-FU alone and in combination and evaluate anti-tumour activity of the combination. Exploratory objectives: investigate multiple surrogate, tumour and circulating pharmacodynamic assays related to mechanism of action and predictive biomarkers for CV6-168 and 5-FU. Each module of this study investigates a different hypothesis, driven by emerging data. Module 1, investigating CV6-168/5-FU/FA, consists of Part A (dose escalation in up to 51 pts) where the maximum tolerated/feasible dose will be identified to guide dose optimisation; Part B, proof of concept [PoC] expansions and identification of the recommended Phase 2 dose/schedule; and optional Parts C (dose optimisation cohorts) and D (basket cohort expansions). Part A is a “3 + 3” dose escalation design in pts with incurable advanced solid tumours and Part B expansions, powered to compare response rates to historical data, will include 3 cohorts of different tumour types. Part C is a randomised comparison of 2 doses/schedules to be selected based on Part A and B data, with pt populations selected based on emerging data. Further Modules may explore: Combination of CV6-168/5-FU/FA with a PD-(L)1 inhibitor; Combinations with other standard of care treatments; Food effects on CV6-168 bioavailability; and Different CV6-168 formulations. This trial design 1) Allows one protocol responsive to emerging data for a compound with multiple hypotheses, supporting studies in multiple combinations, reducing time from emerging data to ‘first subject in study" compared with multiple individual studies; 2) Has the potential to reduce the number of pts unnecessarily exposed to a novel agent; and 3) Allows investigators to pre-empt emerging data and changes to the treatment landscape. These challenges in oncology drug development emphasize the need for flexible designs as the landscape of drug development continually evolves. Clinical trial information: ISRCTN12434145.