A Study of SHY-ONC6, a Novel Proteasome Inhibitor, in Adults With Advanced or Metastatic Solid Tumors

This is a Phase 1, first-in-human (FIH), open-label, multicenter study designed to evaluate the safety, tolerability, PK, and preliminary anti-tumor activity of SHY-ONC6 in participants with advanced or metastatic solid tumors who have progressed on or are intolerant to standard therapies. The study will consist of 2 parts: a dose escalation part (Phase 1a) and a dose expansion part (Phase 1b).

• SHY-ONC6 (Drug): Participants receive SHY-ONC6 administered orally once daily in 21-day cycles. SHY-ONC6 will be administered until the participant withdraws from study, experiences unacceptable toxicity or other safety event, or their disease progresses.

Primary outcomes

• Incidence of Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs) [Dose-limiting toxicities assessed from first dose through Day 21 of Cycle 1 (each cycle is 21 days). Adverse events and serious adverse events collected from first dose through 30 days after last dose.]: Adverse events and serious adverse events graded per NCI CTCAE v6.0; supported by laboratory tests, vital signs, physical examinations, and triplicate 12-lead ECG. Dose-limiting toxicities assessed during Cycle 1 (Days 1 through 21).
• Maximum Tolerated Dose (MTD) [Determined at the end of the Cycle 1 dose-limiting toxicity evaluation period (Cycle 1 is 21 days).]: MTD determined using the BOIN (Bayesian Optimal Interval) design, with a target dose-limiting toxicity rate of 0.30, based on dose-limiting toxicity incidence observed during Cycle 1.
• Recommended Phase 2 Dose (RP2D) [Phase 1a: at the end of Cycle 1 (each cycle is 21 days). Phase 1b: through end of treatment plus a 30-day safety follow-up period.]: Phase 1a: RP2D range determined from dose-limiting toxicity, adverse event, and serious adverse event incidence together with the MTD determination. Phase 1b: RP2D defined by integrated safety, efficacy, pharmacodynamic, and pharmacokinetic data.

Secondary outcomes

• Maximum Plasma Concentration (Cmax) [Cycle 1 Day 1; Day 2 (24 hours post-dose); Day 8; and pre-dose on Day 15. Pre-dose and post-dose on Day 1 of subsequent cycles (each cycle is 21 days).]: Maximum observed plasma concentration of study drug.
• Area Under the Plasma Concentration-Time Curve (AUC) [Cycle 1 Day 1; Day 2 (24 hours post-dose); Day 8; and pre-dose on Day 15. Pre-dose and post-dose on Day 1 of subsequent cycles (each cycle is 21 days).]: Area under the plasma concentration-versus-time curve for study drug.
• Time to Maximum Plasma Concentration (Tmax) [Cycle 1 Day 1; Day 2 (24 hours post-dose); Day 8; and pre-dose on Day 15. Pre-dose and post-dose on Day 1 of subsequent cycles (each cycle is 21 days).]: Time from dosing to observed maximum plasma concentration of study drug.
• Terminal Elimination Half-Life (t1/2) [Cycle 1 Day 1; Day 2 (24 hours post-dose); Day 8; and pre-dose on Day 15. Pre-dose and post-dose on Day 1 of subsequent cycles (each cycle is 21 days).]: Terminal elimination half-life of study drug.
• Trough Plasma Concentration (Ctrough) [Pre-dose on Day 15 of Cycle 1 and pre-dose on Day 1 of subsequent cycles (each cycle is 21 days).]: Plasma concentration of study drug immediately prior to the next dose.
• Overall Survival (OS) [From first dose until death, withdrawal, loss to follow-up, or study termination, assessed up to an estimated 12 months after last dose of study drug.]: Time from first dose until death from any cause.
• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1b) [From first dose through end of treatment plus a 30-day safety follow-up period.]: Adverse events and serious adverse events graded per NCI CTCAE v6.0, collected during Phase 1b.
• Anti-Tumor Activity - Objective Response Rate [Baseline through study completion, an average of 18 months.]: Objective response rate defined as the proportion of patients with a confirmed best overall response of either complete response or partial response, as determined per investigator assessment by RECIST v1.1 (PCWG3 for prostate cancer with bone disease).
• Anti-Tumor Activity - Best Overall Response (BOR) [Baseline through study completion, an average of 18 months.]: Best response recorded from first dose until disease progression (complete response, partial response, stable disease, or progressive disease), per RECIST v1.1 (PCWG3 for prostate cancer with bone disease).
• Anti-Tumor Activity - Time to Response (TTR) [From baseline until first documented response, assessed up to an estimated 18 months.]: Time from first dose to first documented complete response (CR) or partial response (PR) per RECIST v1.1 (PCWG3 for prostate cancer with bone disease).
• Anti-Tumor Activity - Duration of Response (DOR) [Baseline through study completion, an average of 18 months.]: Time from first documented complete response (CR) or partial response (PR) to disease progression or death from any cause, per RECIST v1.1 (PCWG3 for prostate cancer with bone disease).
• Anti-Tumor Activity - Progression-Free Survival [Baseline through study completion, an average of 18 months.]: Time from first dose to first documented disease progression per RECIST v1.1 (PCWG3 for prostate cancer with bone disease) or death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or female ≥18 years of age.
* Life expectancy >3 months.
* ECOG performance status 0-1.
* Histologically/cytologically confirmed advanced or metastatic solid tumors that have progressed on or are intolerant/unsuitable for standard therapies. Eligible tumor types: TNBC, HR+ breast cancer, colon cancer, gastric cancer, HCC, NSCLC (adeno and squamous), mesothelioma, pancreatic cancer, HRPC, soft tissue sarcoma; other tumor types after Medical Monitor discussion. Stable CNS metastases ≥4 weeks post-radiotherapy and off steroids ≥14 days are permitted.
* ≥1 measurable lesion per RECIST v1.1 (prostate cancer with bone-only disease and elevated PSA assessed by PCWG3).
* Accessible tumor for biopsy
* Adequate organ/bone marrow function.
* Willingness and ability to provide informed consent.
* Negative serum pregnancy test and use of effective contraception through 90 days after last dose for women of childbearing potential.
* Male participants must use barrier contraception or abstinence and not donate sperm through 90 days after last dose.

Exclusion Criteria:

* High-risk cardiovascular disease.
* Concurrent anti-cancer treatment.
* Active infection requiring systemic treatment within 2 weeks pre-dose.
* History of another malignancy (with standard exceptions for in situ disease, non-melanoma skin cancers, and remission ≥2 years).
* Active HBV (HBV-DNA >ULN), HCV (HCV-RNA >ULN), or HIV (well-controlled HIV with CD4 ≥350 cells/µL and undetectable viral load permitted); AIDS-defining opportunistic infection within 12 months.
* Compromised pulmonary function within 6 months pre-dose .
* Pregnancy or breastfeeding.
* Recent radiotherapy, systemic anti-tumor therapy, other investigational therapy without appropriate washout.
* Major surgery ≤4 weeks pre-dose.
* Unable to swallow tablets or conditions affecting GI absorption.
* Any medical or psychiatric disorders affecting compliance and/or interpretation of study results.
* Persistent toxicities from prior anti-cancer therapy (exceptions apply)
* Clinically significant corneal disease.
* Unable to comply with prohibited concomitant medication restrictions.