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

Phase 1RecruitingNCT07705334

SHY Therapeutics30 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced or Metastatic Solid Tumors Triple Negative Breast Cancer (TNBC)HR+ Breast Cancer

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Incidence of Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs)

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).

Time frame: 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.

Maximum Tolerated Dose (MTD)

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.

Time frame: Determined at the end of the Cycle 1 dose-limiting toxicity evaluation period (Cycle 1 is 21 days).

Recommended Phase 2 Dose (RP2D)

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.

Time frame: 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.

Secondary Outcomes

Maximum Plasma Concentration (Cmax)

Maximum observed plasma concentration of study drug.

Time frame: 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-Time Curve (AUC)

Area under the plasma concentration-versus-time curve for study drug.

Time frame: 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 to Maximum Plasma Concentration (Tmax)

Time from dosing to observed maximum plasma concentration of study drug.

Time frame: 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 (t1/2)

Terminal elimination half-life of study drug.

Time frame: 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).

Trough Plasma Concentration (Ctrough)

Plasma concentration of study drug immediately prior to the next dose.

Time frame: Pre-dose on Day 15 of Cycle 1 and pre-dose on Day 1 of subsequent cycles (each cycle is 21 days).

Overall Survival (OS)

Time from first dose until death from any cause.

Time frame: 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.

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) (Phase 1b)

Adverse events and serious adverse events graded per NCI CTCAE v6.0, collected during Phase 1b.

Time frame: From first dose through end of treatment plus a 30-day safety follow-up period.

Anti-Tumor Activity - Objective Response Rate

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).

Time frame: Baseline through study completion, an average of 18 months.

Anti-Tumor Activity - Best Overall Response (BOR)

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).

Time frame: Baseline through study completion, an average of 18 months.

Anti-Tumor Activity - Time to Response (TTR)

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).

Time frame: From baseline until first documented response, assessed up to an estimated 18 months.

Anti-Tumor Activity - Duration of Response (DOR)

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).

Time frame: Baseline through study completion, an average of 18 months.

Anti-Tumor Activity - Progression-Free Survival

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.

Time frame: Baseline through study completion, an average of 18 months.

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

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts