A clinical trial to determine the safety and tolerability of GRWD5769 in patients with solid malignancies.

Module 1 aims to identify the minimum biologically active dose (MBAD), maximum tolerated dose (MTD)/maximum feasible dose (MFD), and recommended Phase 2 dose (RP2D) of GRWD5769 when administered as a monotherapy in participants with advanced solid tumours. Module 1 will initially include 4 separate parts (Parts A, B, C and D) as described below: Part A: Part A is an open label, dose escalation part using a Bayesian Optimal Interval (BOIN) design to determine the MTD/MFD and MBAD and RP2D of GRWD5769 when administered as a monotherapy. Up to 6 dose levels are planned to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PDc) of GRWD5769 in Part A in Part A (further information is included below). Part B (optional): Dose level cohorts which are at or above the MBAD (and which are at or below the MTD/MFD) may be expanded to include up to an additional 12 participants for further evaluation of the safety, tolerability, PK and PDc of GRWD5769. Part C (optional): Part C may commence following the identification of at least 3 biologically active doses from Part A. In this study part, a single cohort of up to 12 evaluable participants will be enrolled to evaluate safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PDc) parameters following intra-patient dose escalation of up to 3 dose levels of GRWD5769. Part D (optional): The study may be expanded to evaluate GRWD5769 at the MTD/MFD /RP2D in up to 3 solid tumour indications (up to 30 participants per arm), with subsets to be defined based on emerging data from Module 1 Part A, and Part B. Module 1 Part D may commence following the identification of the GRWD5769 monotherapy MTD/MFD and/or RPD2. In Module 1A, a single dose of GRWD5769 will be administered on Day 1 of Cycle 0, followed by a minimum 24-hour treatment free period. Dosing on Day 1 of Cycle 0 will not occur for Modules 1B, 1C, 1D. For Modules 1A, 1B, 1C, 1D, GRWD5769 capsules will be administered orally, twice daily (BID) from Cycle 1 in a "3 weeks on, 3 weeks off" dosing regimen, where the study drug will be given in alternate 21 day cycles from Day 1 to Day 21 inclusive. As such, participants will take the study drug twice daily for 21 days during odd numbered cycles (1, 3, 5, 7, etc), and not dose at all for Day 1 to Day 21 during even numbered cycles (2, 4, 6, 8 etc). The dosing interval and dose level will be confirmed for each cohort by the Safety Review Committee, based upon emerging data from the preceding cohort(s). Additional dose levels may not exceed a doubling (total daily dose) of the highest previously evaluated dose level. The indicative GRWD5769 Monotherapy dose escalation scheme is as follows: - GRWD5769 dose level of 25 mg; dosing frequency BID; 3-6 participants - GRWD5769 dose level of 50 mg; dosing frequency to be determined; 3-6 participants - GRWD5769 dose level of 100 mg; dosing frequency to be determined; 3-6 participants - GRWD5769 dose level of 200 mg; dosing frequency to be determined; 3-6 participants - GRWD5769 dose level of 400 mg; dosing frequency to be determined; 3-6 participants - GRWD5769 dose level of 600 mg; dosing frequency to be determined; 3-6 participants Participants will continue to receive study medication until evidence of disease progression; unacceptable toxicities; intercurrent illness or interruption of therapy that requires a delay of therapy for more than 3 weeks (21 days), they withdraw their informed consent or are withdrawn from the study. As described above, any participant who has completed 12 months on study and is still receiving clinical benefit from treatment with GRWD5769 may continue to receive GRWD5769 in a safety extension phase. Compliance with IMP dosing will be monitored and recorded. Where dosing occurs in the clinic, the date and time of IMP dosing will be recorded by site staff. For any at-home dosing of GRWD5769, participants will record the date and time of each administration in a participant diary. Participants who have completed 12 months on study may enter a safety extension phase where they may continue to receive GRWD5769 until evidence of disease progression. Participants will have an end of treatment visit within 7 days of cessation of therapy. Reasons for withdrawal of study therapy regardless of length of time on study include: • Disease progression as defined by iRECIST or unequivocal clinical progression as determined by the investigator • Unacceptable toxicity, defined as: o Occurrence of a DLT within the first cycle of treatment; o Occurrence of an AE that is related to treatment with the study drug which compromises the participant’s ability to continue; or o Persistent AE requiring a delay of therapy for more than 3 weeks (21 days) • Intercurrent illness or interruption of therapy that requires a delay of therapy for more than 3 weeks (21 days) • Participant chooses to withdraw from the study • Any other reason, in the opinion of the PI, that renders the participant no longer appropriate for study continuation. A final follow-up visit approximately 21 days (+ 7 days) post-last dose of GRWD5769.