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

Module 2 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 used in combination with cemiplimab-rwlc 350 mg in participants with advanced solid tumours. Module 2 may commence following identification of the GRWD5769 monotherapy MBAD in Module 1, Part A (ACTRN12623000108617; this will be the starting dose level for Module 2). Module 2 will initially include 3 separate parts (Parts A, B and C) as described below: Part A: Part A is an open label, dose escalation part using a Bayesian Optimal Interval design (BOIN) design to determine the MTD/MFD of GRWD5769 when administered in combination with cemiplimab-rwlc 350 mg. GRWD5769 starting dose will be the dose that meets the definition of MBAD and as approved by the Safety Review Committee (SRC). The approved GRWD5769 dose level 1 will be 100mg twice daily (BID) as approved by SRC. Part B (optional): Module 2 Part B may commence following the identification of the GRWD5769 combination therapy MBAD. Dose level cohorts which are at or above the MBAD (and which are at or below the combination therapy MTD/MFD) may be expanded to include up to an additional 24 participants for further evaluation of the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PDc) of GRWD5769 in combination with cemiplimab-rwlc 350 mg. Part C: Module 2 Part C may commence following the identification of the GRWD5769 combination therapy MTD and/or RPD2. The study may be expanded to evaluate GRWD5769 at the MTD/MFD/RP2D in combination with cemiplimab-rwlc 350 mg in up to 3 cohorts of solid tumour indications (up to 30 participants per arm), with subsets to be defined based on emerging data from Module 2 Part A. For Module 2 Part A, an initial single dose of GRWD5769 will be administered on Day 1, of Cycle 0, followed by a minimum 24-hour treatment free period, then twice daily dosing will commence. For each dose level cohort in Module 2 GRWD5769 capsules will be administered orally, twice daily (BID) on Days 1-21 for a 3 week treatment period, followed by a 3 week treatment break. GRWD5769 capsules will be taken BID at every odd numbered cycle. This odd-numbered treatment cycle will be followed by a 3 week break from treatment at every even-numbered cycle. This is a "3 weeks on, 3 weeks off" treatment for GRWD5769. In conjunction with GRWD5769, Cemiplimab-rwlc will be administered as an intravenous infusion of 350 mg over 30 minutes, every 3 weeks (Q3W) regardless of whether the cycle is even or odd numbered. Administration of cemiplimab-rwlc 350mg will commence at Cycle 1 for Module 2 Part A and Module 2 Part C. Administration of cemiplimab-rwlc 350mg for Module 2 Part B will commence at Cycle 2. Each dose of cemiplimab-rwlc 350mg will be administered in the clinic, under the supervision of site staff. In each study part, participants will continue to receive study medication until they withdraw their informed consent or are withdrawn from the study. 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 and cemiplimab-rwlc 350mg until evidence of disease progression. Participants will have an end of treatment visit within 7 days of cessation of therapy and again for a final follow up visit 30 days following cessation of therapy. Participants enrolled in Module 2 will have a telephone call at 90 days following last dose of cemplimab-rwlc 350mg. 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.