XP-102 and XP-102 in Combination With Trametinib in Advanced Solid Tumor Patients With a BRAF V600 Mutation

Study Overview
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Brief Summary
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This is a first-in-human multi-center study which will be conducted in advanced malignant solid tumors patients. The solid tumor type is limited to melanoma, colorectal, non-small-cell lung, and thyroid cancer with positive BRAF V600 mutation. This study is divided into three stages: Phase Ia: a dose-escalation phase of XP-102; Phase Ib: a dose-escalation and sample size expansion phase of XP-102 plus trametinib; Phase IIa: an expansion phase of XP-102 plus trametinib.

Official Title
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A Dose-escalation and Expansion Phase I/IIa Study of XP-102 and XP-102 in Combination With Trametinib in Advanced Solid Tumor Patients With a BRAF V600 Mutation (ENHANCE)

Conditions
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Cancer, BRAF V600 Mutation, Melanoma, Colorectal Cancer, Thyroid Cancer, Nonsmall Cell Lung Cancer

Intervention / Treatment
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* Drug: XP-102
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Advanced malignant solid tumor patients with a BRAF V600 mutation (limited to melanoma, colorectal cancer, non-small cell lung cancer, or thyroid cancer). Must have failed conventional treatment or for whom no therapy of proven efficacy exists or who is not eligible for established treatment options. Prior treatment with BRAF inhibitors and/or MEK inhibitors is permitted； At least one measurable lesion (brain metastasis must not be the only measurable lesion) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1); ECOG performance status of 0 or 1; Expected survival ≥ 3 months; Adequate liver, renal, coagulation, cardiac, and hematologic function. A negative pregnancy test if female patient is of reproductive potential. For men and women of reproductive potential, agreement to use an effective contraceptive method from the time of screening and throughout their time on study. Patients must agree to, and be capable of, adhering to the study visit schedule and all other protocol requirements; Patients must understand and voluntarily sign the written informed consent form, before the initiation of any study-specific procedures in the trial. Exclusion Criteria: Active central nervous system (CNS) lesions. However, patients with asymptomatic and brain metastases who received treatment (including targeted brain radiotherapy, surgical treatment, glucocorticoid or other treatments) without disease progression for ≥ 3 months are eligible. Patients who received radiotherapy, immunotherapy, hormone therapy, targeted therapy, biotherapy, traditional Chinese medicine therapy, chemotherapy or any clinical trial treatment within 14 days before the first dose. Patients who have persistent toxicity caused by previous chemotherapeutic drugs or radiotherapy has not recovered to lower than grade 2 (except hair loss) according to CTCAE version 5.0; Patients who are allergic to active substances or excipients of XP-102 or trametinib. Significant traumatic injury within 28 days before the first dose of the investigational drug, or if major surgery is anticipated during the course of study treatment; According to the judgment of the investigator, patients with dysphagia, or any gastrointestinal diseases that may affect drug absorption or activity; Administration of strong inhibitors or inducers of CYP3A4 liver metabolic enzymes within 14 days before the first dose of the investigational drug; Patients who are receiving drugs that may prolong QT interval and unable or unwilling to stop treatment or switch to other alternative treatment before study enrollment; Symptomatic active fungal, bacterial and/or viral infections; including known HIV, active hepatitis B, active hepatitis C or active syphilis infection. Any poorly controlled disorders (such as serious mental, neurological, cardiovascular, respiratory, digestive, urinary, bleeding and coagulation, or other system diseases) that may significantly affect the clinical trial; Other situations not suitable for participation in the study as judged by the investigator.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - XP-102 Dose Escalation<br>XP-102 | Drug: XP-102<br>* XP-102 will be administered orally once or twice daily in a continuous regimen.<br>|
| Experimental: Part 2 - XP-102 + Trametinib Dose Escalation<br>XP-102 plus Trametinib | Drug: XP-102<br>* XP-102 will be administered orally once or twice daily in a continuous regimen.<br>Drug: Trametinib<br>* Trametinib will be administered 2mg orally once a day.<br>|
| Experimental: Part 3 - XP-102 + Trametinib Dose Expansion<br>XP-102 plus Trametinib | Drug: XP-102<br>* XP-102 will be administered orally once or twice daily in a continuous regimen.<br>Drug: Trametinib<br>* Trametinib will be administered 2mg orally once a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the safety of XP-102. | Number of participants with treatment related adverse events. | 28 days | 
| Evaluate the pharmacokinetics of XP-102. | Blood plasma concentration. | 28 days | 
| Establish maximum tolerated dose of XP-102. | Number of participants with dose limiting toxicity | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the pharmacokinetics of XP-102 + trametinib. | Blood plasma concentration. | 28 days | 
| Characterize tolerability of XP-102 in combination with trametinib. | Number of participants with dose limiting toxicity | 28 days | 
| Evaluate the pharmacokinetics of XP-102 administered with food | Blood plasma concentration. | 4 days | 
| Evaluate clinical activity/efficacy of XP-102. | Overall Response Rate with RECIST criteria v1.1. | Approximately every 8 weeks (up to 2 years) |