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, multicenter, 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 multiple sites in the United States (Phase 1, Phase 2a), and China (Phase 2a, expansion phase).
The study will be conducted in 2 parts: Phase 1 (dose escalation) and Phase 2a (efficacy/dose expansion).
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 the recommended phase 2 dose (RP2D) is established, the study will be expanded into a dose expansion phase (Phase 2a) in a small cohort of patients with advanced CRC or PDAC to obtain early proof of concept by biomarker changes and/or other clinical outcome measures.
3. Overview of Study Schedule
Both Phase 1 and Phase 2a 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).
Phase 1 Treatment Period: On Day 1 of Cycle 0 (C0D1), after completing pre-dose 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) to evaluate CT3001 preliminary efficacy and tolerability. At the completion of the study, the PI will determine whether to prescribe more appropriate treatment, restore initial therapy, or to refer the participant to his/her General Practitioner.
Phase 2a (Dose Expansion and Efficacy Assessment): Once Phase 1 of the study determines the MTD and/or RP2D, Phase 2a of the study will be initiated. Phase 2a of the study is a dose expansion study to evaluate the preliminary efficacy of CT3001 in patients with advanced CRC or PDAC (ORR and/or CBR per RECIST Version 1.1; TTP, DoR, DoCB, and PFS). During Phase 2a, the safety and tolerability of CT3001, and PK parameters, biomarker changes (carcinoembryonic antigen for CRC, carbohydrate antigen 19-9 for PDAC) in patients with advanced CRC or PDAC will be also evaluated / determined.
Number of Participants: Approximately 18 to 36 participants with advanced solid tumors will be enrolled in Phase 1, and approximately 42 participants with advanced CRC or PDAC will be enrolled in Phase 2a.
