A Study of Repotrectinib in Combination With Other Anticancer Therapies for the Treatment of Subjects With KRAS-Mutant Solid Tumors

Study Overview
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Brief Summary
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A Phase 1b/2 Study of Repotrectinib in Combination with Other Anticancer Therapies for the Treatment of Subjects with KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

Detailed Description
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Phase 1 Dose Escalation: To evaluate tolerability of repotrectinib at increasing dose levels in combination with other anticancer therapies for the treatment of subjects with locally advanced or metastatic KRAS-mutant solid tumors Phase 2 Efficacy Evaluation: Investigate the anti-tumor efficacy and safety of repotrectinib in combination with other anticancer therapies for the treatment of patients with locally advanced or metastatic KRAS-mutant solid tumors.

Official Title
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A Phase 1b/2 Study of Repotrectinib in Combination With Other Anticancer Therapies for the Treatment of Subjects With KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

Conditions
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KRAS Mutation-Related Tumors, Metastatic Solid Tumor, Advanced Solid Tumor

Intervention / Treatment
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* Drug: TPX-0005
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 (or as required by local regulation). Histological or cytological confirmation of unresectable or metastatic solid tumor malignancy harboring a KRAS mutation. No more than 3 prior standard treatments appropriate for tumor type and stage of disease. ECOG performance status ≤ 1. Existence of measurable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria). Subjects with asymptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible. Adequate organ function. Exclusion Criteria: Major surgery within four weeks of the start of treatment. Previous other cancer requiring treatment within the previous two years. Clinically significant cardiovascular disease. Any of the following cardiac criteria: Mean resting corrected QT interval (QTc) > 470 msec obtained from three ECGs and any factors that increase the risk of QTc prolongation or arrhythmic events Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity). Gastrointestinal disease or other malabsorption syndromes that would impact drug absorption. Subjects being treated with or anticipating the need for treatment with strong CYP3A inhibitors or inducers.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPX-0005 + Trametinib<br>TPX-0005 + Trametinib Dose Escalation and Dose Expansion Dose escalation: KRAS G12D mutant advanced solid tumors. Dose expansion: KRAS G12D locally advanced or metastatic NSCLC | Drug: TPX-0005<br>* Oral TPX-0005 capsules<br>* Other names: repotrectinib;Drug: Trametinib<br>* Oral trametinib tablets<br>* Other names: Mekinist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Safety and Tolerability | Evaluate the safety and tolerability of repotrectinib in combination with trametinib with treatment-related adverse events as assessed by CTCAE v5.0 | Three years | 
| Define the Recommended Phase 2 Dose (RP2D) |  | Approximately 22 months | 
| Define the objective response rate (ORR) |  | Two to three years after first dose of Repotrectinib in combination with other anticancer therapies | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum plasma concentration) of repotrectinib in combination with trametinib | Evaluate the maximum plasma concentration of repotrectinib in combination with trametinib | Up to 24 hours post-dose | 
| AUC (area under plasma concentration time curve) of repotrectinib in combination with trametinib | Determine the AUC of repotrectinib in combination with trametinib | Up to 24 hours post-dose | 
| Determine the preliminary efficacy of repotrectinib in combination with trametinib measured by ORR as assessed per RECIST v1.1 |  | Approximately three years | 
| Clinical benefit rate (CBR) |  | Approximately three years | 
| Progression free survival (PFS) |  | Approximately three years | 
| Duration of response (DOR) |  | Approximately three years | 
| Time to response (TTR) |  | Approximately three years | 
| Overall survival (OS) |  | Approximately three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS, KRAS-mutant, Metastatic Solid Tumor, Advanced Solid Tumor, Advanced/metastatic disease