A Study to Determine the Effect of CT3001 in Patients With Advanced Solid Tumors

1. Study Rationale CT3001 is being developed by the Sponsor as a treatment for patients with solid tumors, including colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC), among others. Treatments of solid tumors typically include surgery, chemotherapy, radiation, or a combination approach. Although surgical resection is potentially curative in some cases, most advanced solid tumor patients are not candidates for this approach and require multidisciplinary care including chemotherapy or radiation. In addition, cytotoxic chemotherapy drugs generally lack specificity and can lead to severe side effects, and radiation alone cannot cure most forms of cancer (Najafi et al. 2021). Therefore, cancer immunotherapy is becoming increasingly utilized as part of multidisciplinary cancer care. The tumor microenvironment (TME) contributes to the development of solid tumors, and helps shape the body's antitumor immune response (Simsek and Klotzsch 2022, Wang et al. 2023). The presence and functionality of immune cells, particularly regulatory T cells (Treg) and cytotoxic T lymphocytes (CTLs), are regulated by cellular and soluble factors of the TME (Balta et al. 2021). Cancers can hijack the body's antitumor response by promoting an immunosuppressive TME. Therefore, novel therapies that restore the antitumor immune response in the TME are of increasing interest in the treatment of solid tumors (Balta et al. 2021). The investigational product (IP) in this study is CT3001, which is a first-in-class, small molecule inhibitor of G-protein coupled receptor 35 (GPR35). GPR35 is an oncogenic G-protein coupled receptor (GPCR) with abnormally high expression in solid tumors. GPR35 is tumorigenic and promotes tumor immune escape. CT3001 inhibits GPR35 driven Yes-associated Protein (YAP) oncogene activation. YAP activation can cause tissue overgrowth and tumorigenesis, whereas YAP inactivation impairs tissue development and regeneration (Moroishi et al. 2015). YAP is also essential for tumor immune escape involving Treg function and CTL activity (Lebid et al. 2020, Ni et al. 2018, Stampouloglou et al. 2020). In addition, CT3001 has been shown to suppress differentiation of Treg cells from naïve CD4+ T cells under indoleamine 2,3-dioxygenase 1 (IDO1)-positive/TME-like culture conditions in vitro and increase CD8+ T cell tumor infiltration in human peripheral blood mononuclear cell (PBMC)-reconstituted mice bearing a HT29 colon cancer xenograft.
2. Overall Study Design This is an FIH, open-label, dose escalation and dose expansion study of CT3001 to determine the safety, tolerability, PK, PD, and preliminary efficacy. The study will be conducted in 2 parts: Phase 1 (dose escalation) and Phase 2b (combination with SOC chemotherapy). The study will be conducted in 2 parts: Phase 1 (dose escalation) and Phase 2b (combination with SOC chemotherapy). Phase 1 aims to determine the safety, tolerability, and PK of CT3001 in patients with advanced solid tumors for whom there is no available therapy likely to confer clinical benefit, or patients who are not candidates for such therapy. Once the MTD and a preliminary RP2D is established, the study will proceed directly to a combination study with SOC chemotherapy (Phase 2b), without continuing originally planned Phase 2a monotherapy in a small cohort of patients with advanced CRC to determine CT3001 tolerability when combined with a SOC chemotherapy and to obtain preliminary efficacy assessment in this segment of patients as a dose optimization step for tolerability vs. efficacy of CT3001 in later clinical development. In the 2b study, a three-dose escalation dosing scheme of CT3001 (lower or higher than the preliminary RP2D determined in Phase 1) will be employed in combination with SOC chemotherapy to explore the safety, tolerability, pharmacokinetics, and preliminary efficacy of CT3001 in advanced CRC patients.
3. Overview of Study Schedule

Phase 1 will include a Screening Period, a Treatment Period, and a Follow-up Period, as follows:

• Screening Period (up to 28 days prior to the date of first dose of CT3001): All patients will be asked to provide informed consent before entering Screening. Following a review of the inclusion and exclusion criteria, eligible patients will be enrolled (thereby becoming study participants).
• Treatment Period:
• On Day 1 of Cycle 0 (C0D1), after completing predose assessments, participants will be administered a single dose of CT3001 and undergo intensive PK sampling for 48 hours (i.e., through to C0D3). Participants may be hospitalized from C0D1 through to C0D4, if required by the sites, to perform frequent blood draws for PK and safety assessments. Dosing with CT3001 will then be paused until the Safety Monitoring Committee (SMC) can review the safety data.
• Following SMC review and approval, participants will then be administered CT3001 orally (QD or BID) from C1D1 to C1D21, with PK sampling occurring on C1D1 to C1D8. Again, participants may be hospitalized from C1D1 through to C1D8, if required by the sites, to perform frequent blood draws for PK and safety assessments.
• From Cycle 2 onwards, participants will receive CT3001 (orally QD or BID) in repeated 21-day cycles (i.e., Cycle 2, Cycle 3, Cycle 4, Cycle 5, etc.). Administration of CT3001 will continue for at least 6 months (approximately 8 cycles), unless early termination (ET) occurs due to the start of a new anticancer treatment, disease progression, participant refusal, unacceptable toxicity, death, or lost to follow-up.
• Safety Follow-up Period: 28 days (± 5 days) after the last dose of CT3001.
• Survival Follow-up Period: approximately every 12 weeks after the last dose of CT3001 up until ET or 12 months from the last dose of CT3001.

Phase 2b combination study will include a Screening Period, a Treatment Period, and a Follow-up Period, as follows:

• Screening Period (Up to 28 days prior to the first administration of CT3001 in combination with SOC (FOLFOX) chemotherapy): All patients will be asked to provide informed consent before entering Screening. Following review of the inclusion and exclusion criteria, eligible patients will be enrolled, and baseline assessments will be performed.
• Treatment Period:
• Phase 2b will evaluate CT3001 in combination with SOC chemotherapy (FOLFOX) in repeated 14-day cycles, aligned with the routine Q2W FOLFOX schedule. On C1D1, after completion of predose assessments and the first FOLFOX administration, participants will receive a single oral dose of CT3001 and undergo intensive PK sampling through C1D3. Participants may be hospitalized from C1D1 through C1D3, or up to C1D8 if required by the site, to support intensive PK and safety assessments. Following SMC review on C1D3, and if safety findings are acceptable, CT3001 BID dosing will begin on C1D4 and continue through C1D14. Additional intensive PK sampling will be performed from C1D7 to C1D8. From Cycle 2 onward, participants will receive CT3001 orally BID on a continuous schedule in combination with FOLFOX on Day 1 of each 14-day cycle. For each dose level, the first 3 to 6 participants will serve as a sentinel group, and opening of the next cohort will occur only after completion of the prespecified initial safety observation period and SMC review of emerging safety and tolerability data.
• Safety Follow-up Period: 28 days (± 5 days) after the last dose of CT3001.
• Survival Follow-up Period: approximately every 12 weeks after the last dose of CT3001 until EOT or 12 months from the last dose of CT3001, whichever occurs first.

Number of Participants:

• Phase 1: Approximately 18 to 36 patients with advanced solid tumors (3 to 6 participants per dose escalation cohort, up to a maximum of 7 escalation doses).
• Phase 2b: Approximately 30-45 patients with advanced CRC.