A Phase I Study of RGT-264 in Subjects With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1 dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of RGT-264 as monotherapy in subjects with advanced solid tumors.

Detailed Description
-----------------
This first-in-human (FIH) study of RGT-264 will evaluate safety, pharmacokinetics (PK) and efficacy of RGT-264 in subjects with advanced solid tumors. The primary objective is to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and the recommended phase II dose (RP2D) of RGT-264 as monotherapy, and to evaluate the safety and tolerability of RGT-264. The secondary objectives include the assessments of PK profile and preliminary efficacy of RGT-264.

Official Title
-----------------
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of RGT-264 Phosphate Tablets in Subjects With Advanced Solid Tumors

Conditions
-----------------
Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: RGT-264 phosphate tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to sign the ICF and agree to comply with the requirements of the study; Subjects with pathologically confirmed advanced solid tumors who have failed standard-of-care therapy, or have no standard-of-care therapy available, or are currently not eligible for standard-of-care therapy; ECOG performance status score of 0 to 1; Expected survival ≥ 3 months; With at least one measurable lesion per RECIST v1.1; Subjects should discontinue all anti-tumor therapies prior to receiving study treatment, and the toxicity caused by prior anti-tumor therapy has recovered to ≤ Grade 1 per CTCAE v5.0; The specific requirements of washout period should be met before first dose; Adequate organ function Female subjects of childbearing potential must have a negative pregnancy test prior to the first dose and are required to use effective contraception from signing the ICF until 6 months after the last dose of study treatment Exclusion Criteria: Presence of risks that may significantly affect the absorption of the investigational product (e.g. inability to swallow, intestinal obstruction, chronic diarrhea, etc.); Having received immunotherapy and experienced ≥ Grade 3 immune-related adverse events (irAEs) or ≥ Grade 2 immune-related myocarditis; Having received systemic glucocorticoids (> 10 mg/day of prednisone or equivalent) or other immunosuppressants within 14 days prior to the first dose of investigational product; Presence of symptomatic parenchymal brain metastasis or leptomeningeal metastasis; Active, or previous autoimmune disease with the potential for relapse (excluding well-controlled type 1 diabetes mellitus; manageable hypothyroidism with hormone replacement therapy only).; Any other malignancy (except cured basal cell carcinoma of skin and in-situ carcinoma of the cervix) within 3 years prior to the first dose; History of serious cardiovascular and cerebrovascular diseases; Presence of active interstitial lung disease or history of interstitial lung disease requiring glucocorticoid treatment; Presence of severe chronic or active infections (including tuberculosis infection, etc.) requiring intravenous antimicrobial, antifungal or antiviral therapy; Active HBV or HCV infection; History of immunodeficiency or organ transplantation; Presence of uncontrolled third spacing fluid; Concomitant diseases or any other conditions that may seriously jeopardize the subject's safety or affect the subject's completion of the study, at the discretion of the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: There will be one arm in the study. Enrolled subjects will be treated with RGT-264 phosphate tablets alone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RGT-264 monotherapy<br>The study is composed of dose escalation stage and dose expansion stage. RGT-264 will be administered orally daily alone as monotherapy in both stages. In the dose escalation stage, the subjects will receive once daily of RGT-264 monotherapy across approximately 6 ascending dose levels. The starting dose is 10 mg/day. In the dose expansion stage, the subjects will receive RGT-264 treatment at the recommended dose from dose escalation part. | Drug: RGT-264 phosphate tablets<br>* RGT-264 phosphate tablets will be administered orally once daily (QD).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Dose-Limiting Toxicities (DLTs) at each cohort dose level in dose escalation stage | DLTs will be evaluated from Day 1 (the day of the first dose) to Day 21 after first dose of study treatment in escalation stage. Number of DLTs will be used in dose ascending and descending decisions. | Day 1 to Day 21 after first dose (21 days) | 
| Number of subjects with adverse events (AEs) | AEs will be characterized by type, seriousness, relationship to study treatment, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5.0) and timing. | From screening (Day -28 to Day -1) through up to 12 months or until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Assessments: Time to maximum plasma concentration (Tmax) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Maximum concentration (Cmax) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Elimination half-life (t1/2) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Area under the concentration-time curve over time 0 to t (AUC0-t) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Area under the concentration-time curve over time 0 to infinite (AUC0-inf) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Accumulation ratio (Rac) | Blood and urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | PK Blood (Cycle 1 Day 1 and Cycle 1 Day 15; PK Urine (Cycle 1 Day 1) (each cycle is 21 days) | 
| Pharmacokinetic Assessments: Cumulative urinary excretion | Urine samples will be collected for PK analyses for subjects enrolled in dose escalation stage. | Cycle 1 Day 1 (each cycle is 21 days) | 
| Tumor Response | Tumor response measured by radiologic imaging techniques at baseline and throughout the study. The same radiologic imaging techniques for each respective patient will be used throughout. Tumor response will be assessed by investigator according to RECIST v1.1. | Screening until disease progression, initiation of a new anti-tumor therapy, death, loss to follow-up, withdrawal of consent, or meeting other end-of-study criteria (whichever occurs first) (Assessed up to 12 months). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hematopoietic progenitor kinase 1 (HPK1), Dose Escalation, Dose Expansion, RGT-264, First-in-Human