Safety, Tolerability and Pharmacokinetics Study of QLH11906 in Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations.

Study Overview
=================
Brief Summary
-----------------
This is an open label, phase 1 clinical study to evaluate the safety and tolerability of different doses of QLH11906 monotherapy in patients with relapsed/refractory, unresectable locally advanced or metastatic advanced solid tumors with abnormal MAPK pathway, and determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD, if MTD cannot be determined) and Recommended Dose in Phase II Clinical Studies (Recommended Phase II Dose, RP2D).

Official Title
-----------------
A Phase I Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Oral Pan-RAF Inhibitor QLH11906 in Subjects With Advanced Solid Tumors Harboring MAPK Pathway Alterations.

Conditions
-----------------
Advanced Solid Tumors Harboring MAPK Pathway Alterations

Intervention / Treatment
-----------------
* Drug: QLH11906


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subjects participated voluntarily, signed the informed consent, and were able to abide by the research procedures. Subjects with advanced (metastatic or unresectable) solid tumors with histologically confirmed MAPK signaling pathway alteration. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Subjects are able to swallow and retain oral medication without any clinically significant gastrointestinal abnormalities that alter absorption. Subjects (including women and men) agree to use effective contraception for contraception from the time of signing the informed consent form to 180 days after the last use of the study drug. Female subjects of childbearing age cannot be pregnant or breastfeeding. Exclusion Criteria: Subjects received systemic anticancer therapy within 2 weeks prior to the first dose. Subjects received radical radiotherapy within 4 weeks before the first administration, or received local palliative radiotherapy for bone metastases within 1 week. Subjects who have received inhibitors or inducers of CYP3A4 within 1 week before the first dose; or within 5 half-lives of the drug; or subjects who need to continue to receive these drugs during the study period. Active bacterial, fungal, or viral infection requiring systemic therapy within 1 week prior to the first dose. Subjects with symptomatic central nervous system (CNS) metastases and/or cancerous meningitis. Cardiovascular and cerebrovascular diseases with clinical significance. Clinically uncontrollable serous effusion (eg, pleural effusion that cannot be controlled by drainage or other methods). Active gastrointestinal disease or other conditions that significantly interfere with drug absorption. Known immediate or delayed hypersensitivity reactions or idiosyncratic reactions to the investigational treatment-related chemotherapeutic drugs and their excipients. Human immunodeficiency virus (HIV) positive test result and Treponema pallidum antibody positive. Hepatitis B virus surface antigen (HBsAg) positive and viral deoxyribonucleic acid (HBV DNA) > 2000 IU/ml or 104 copies/ml (only the centers that can perform qualitative examination, the HBV DNA test result is positive or high detection limit); hepatitis C virus antibody positive and viral ribonucleic acid (HCV RNA) positive. Other malignant tumors occurred within 2 years before study enrollment. (Except: Bowen's disease; cured basal cell or squamous cell skin cancer; prostate cancer with a Gleason score of 6; treated cervical carcinoma in situ.) Pregnant or lactating women. Any pre-existing serious or unstable disease (except for the above-mentioned malignant tumors), mental disease or any disease or medical condition that the investigator considers may interfere with the subject's safety, obtaining informed consent, or complying with research procedures. Concurrent participation in other clinical trials using experimental therapies.

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QLH11906<br>QLH11906 Tablets | Drug: QLH11906<br>* QLH11906 only<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD/MAD | The Maximum Tolerated Dose (MTD) will be determined during dose escalation using a Bayesian Optimal Interval (BOIN) design.The maximum administrated dose (MAD) is defined as the highest dose of all groups if MTD can not be determined. | Up to 24 approximately months | 
| RP2D | Recommended dose for phase II trials | Up to 24 approximately months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) /Serious Adverse Events (SAEs) |  | Up to 24 approximately months | 
| Area under the concentration-time curve（AUC） | Pharmacokinetic (PK) parameters of QLH11906 monotherapy, including Area under the concentration-time curve（AUC） | Up to 24 approximately months | 
| Overall response rate (ORR) | The efficacy evaluated by the investigator in accordance with RECIST 1.1 criteria, including objective response rate(ORR). | Up to 24 approximately months | 
| Duration of response (DoR) | The efficacy evaluated by the investigator in accordance with RECIST 1.1 criteria, including duration of response(DOR). | Up to 24 approximately months | 
| Disease control rate (DCR) | The efficacy evaluated by the investigator in accordance with RECIST 1.1 criteria, including disease control rate(DCR). | Up to 24 approximately months | 
| Maximum concentration (Cmax) | Pharmacokinetic (PK) of QLH11906 monotherapy, including Maximum concentration (Cmax) | Up to 24 approximately months |