Study of TNG260 and an Anti-PD Antibody in STK11 Mutated Solid Tumors

Study Overview
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Brief Summary
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The goal of this interventional clinical trial is to learn about TNG260, a CoREST inhibitor, in combination with pembrolizumab in patients with advanced solid tumors with a known STK11 mutation. The main question[s] it aims to answer are: the recommended dose for Phase 2 to evaluate the safety and tolerability of the combination therapy to determine the pharmacokinetics of TNG260 to evaluate the initial antineoplastic activity Participants will receive study treatment until they experience an undesirable side effect, their disease progresses or until they withdraw consent.

Detailed Description
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This is a first-in-human Phase 1/2, open-label, multicenter, dose-escalation and expansion study designed to determine the maximum tolerated dose and recommended phase 2 dose(s) and evaluate the safety and tolerability, pharmacokinetics, and antineoplastic activity of escalating oral doses of TNG260 when administered with a standard dose of pembrolizumab in participants with locally advanced or metastatic STK11 mutated solid tumors.

Official Title
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A Phase 1/2, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of TNG260 as Single Agent and in Combination With an Anti-PD-1 Antibody In Patients With STK11 Mutated Advanced Solid Tumors

Conditions
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Non Small Cell Lung Cancer, Solid Tumors, Adult, Endometrial Cancer, Pancreatic Cancer, Cervical Cancer, Breast Cancer, Carcinoma of Unknown Primary

Intervention / Treatment
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* Drug: TNG260
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is ≥18 years of age at the time of signature of the main study ICF. Has ECOG performance status of 0 or 1. Has measurable disease based on RECIST v1.1. All participants must have documented STK11 mutation in a solid tumor, which is identified through a validated analytical method Has confirmed histologic or cytologic diagnosis of a locally advanced or metastatic solid tumor. Adequate organ function/reserve per local labs Adequate liver function per local labs Adequate renal function per local labs Negative serum pregnancy test result at screening Written informed consent must be obtained according to local guidelines Exclusion Criteria: Known allergies, hypersensitivity, or intolerance to TNG260, PD-1 antibody or its excipients Uncontrolled intercurrent illness that will limit compliance with the study requirements Active infection requiring systemic therapy Currently participating in or has planned participation in a study of another investigational agent or device Impairment of GI function or disease that may significantly alter the absorption of oral TNG260 Active prior or concurrent malignancy. Central nervous system metastases associated with progressive neurological symptoms Current active liver disease from any cause Clinically relevant cardiovascular disease A female patient who is pregnant or lactating

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 (Dose Escalation) and Phase 2 (Dose Expansion)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants with STK11-mutant solid tumors will receive escalating doses of TNG260 in combination with pembrolizumab to estimate the MTD | Drug: TNG260<br>* CoREST inhibitor, administered orally<br>Drug: Pembrolizumab<br>* Pembrolizumab, an anti-PD-1 antibody, administered intravenously<br>* Other names: Keytruda;|
| Experimental: Dose Expansion in NSCLC with KRAS Mutation<br>Participants with STK11-mutant and KRAS-mutant NSCLC (squamous and non squamous) will receive TNG260 at the identified RP2D in combination with pembrolizumab | Drug: TNG260<br>* CoREST inhibitor, administered orally<br>Drug: Pembrolizumab<br>* Pembrolizumab, an anti-PD-1 antibody, administered intravenously<br>* Other names: Keytruda;|
| Experimental: Dose Expansion in NSCLC with KRAS Wild type<br>Participants with STK11-mutant and KRAS-wild type NSCLC (squamous and non-squamous) will receive TNG260 at the identified RP2D in combination with pembrolizumab | Drug: TNG260<br>* CoREST inhibitor, administered orally<br>Drug: Pembrolizumab<br>* Pembrolizumab, an anti-PD-1 antibody, administered intravenously<br>* Other names: Keytruda;|
| Experimental: Dose Expansion in Advanced or Metastatic Solid Tumors<br>Participants with STK11-mutant solid tumors (including but not limited to pancreatic, endometrial, cervical, breast, and carcinoma of unknown primary) will receive TNG260 at the identified RP2D in combination with pembrolizumab | Drug: TNG260<br>* CoREST inhibitor, administered orally<br>Drug: Pembrolizumab<br>* Pembrolizumab, an anti-PD-1 antibody, administered intravenously<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the MTD and RP2D(s) (Phase 1 only) | To determine the MTD and RP2D(s) of TNG260 when administered in combination with pembrolizumab | 42 days | 
| Measure antitumor activity using RECIST 1.1 (Phase 2 only) | To assess antineoplastic activity of TNG260 when administered in combination with pembrolizumab in participants with locally advanced unresectable or metastatic STK11-mutated solid tumors by measuring ORR, DOR, and PFS by RECIST 1.1 | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure antitumor evidence of TNG260 + pembrolizumab antineoplastic activity by RECIST 1.1 (Phase 1 only) | To assess antineoplastic activity of TNG260 when administered in combination with pembrolizumab in participants with locally advanced unresectable or metastatic STK11-mutated solid tumors by measuring ORR, DOR, and PFS by RECIST 1.1 | 12 weeks | 
| Characterize Area Under the Curve (AUC) of TNG260 | Measure the plasma concentration versus time curve (AUC) of TNG260 alone and when administered in combination with pembrolizumab | 37 days | 
| Characterize the time to achieve Time to Maximal Concentration (Tmax) of TNG260 | To characterize the Tmax by measuring the plasma concentrations versus time of TNG260 alone and when administered in combination with pembrolizumab | 37 days | 
| Characterize Maximum Observed Plasma Concentration (Cmax) of TNG260 | To characterize the Cmax by measuring the plasma concentrations versus time of TNG260 alone and when administered in combination with pembrolizumab | 37 days | 
| Characterize Terminal Half-life (T1/2) of TNG260 | To characterize the T1/2 by measuring the plasma concentrations versus time of TNG260 alone and when administered in combination with pembrolizumab | 37 days | 
| Characterize pembrolizumab concentrations when administered with TNG260 | To characterize the pre treatment and trough concentration levels of pembrolizumab when administered in combination with TNG260 | 43 days | 
| Safety and tolerability of TNG260 by CTCAE 5.0 | To evaluate the safety and tolerability of TNG260 when administered as single agent and in combination with pembrolizumab by measuring the incidence, nature, and severity of AE and SAE graded according to CTCAE v5.0 | 42 days | 
| To measure changes in histone acetylation when administered with TNG260 | Measure changes in levels of histone acetylation in blood and/or tumor tissue, on study treatment relative to pre-treatment | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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STK11, KRAS, LKB1