Study of HL-085 Plus Docetaxel in Patients With KRAS Mutant NSCLC

Study Overview
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Brief Summary
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This is a phase I, open label, dose escalation study to evaluate tolerability, safety , pharmacokinetics and efficacy in patients with KRAS mutant NSCLC by using HL-085 and Docetaxel.

Official Title
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A Phase I , Single Arm, Dose Escalation Study to Evaluate Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy of HL-085 Plus Docetaxel in Patients With KRAS Mutant NSCLC

Conditions
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Nsclc

Intervention / Treatment
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* Drug: HL-085
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: KRAS mutation NSCLC. One measurable lesion as defined by RECIST 1.1 criteria for solid tumors. Chemotherapy, immunotherapy or radiotherapy ≥ 4 weeks prior to starting the study treatment. Surgery (except for tumor biopsy) or severe trauma ≤ 14 days prior to starting the study treatment. ECOG performance status of 0-1. Life expectancy ≥ 3 months. Ability to take the medicine orally. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Hypersensitivity to study drug ingredients or their analogues. Prior therapy with MEK-inhibitor. Receiving any other anti-cancer therapy at the same time . Active central nervous system (CNS) lesion. Bleeding symptoms at Grade 3 within 4 weeks prior to starting study treatment. ECG QTcB≥480msec in screening, or history of congenital long QT syndrome； Uncontrolled concomitant diseases or infectious diseases. Retinal diseases (Retinal Vein Occlusion (RVO) or Retinal pigment epithelial detachment (RPED) , et al.). History of HIV,HCV,HBV infection. Interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis will be excluded. Serum HCG test is positive. Other conditions that increase the risk of study and influence the result.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Interventional Model Description: If no Dose-limiting toxicity (DLT) occurs in the first three subjects in Cycle 1, the dose will be escalated to the next dose level; If a DLT occurs in one of the first three subjects, three additional subjects will be enrolled for the same dose cohort, and undergo the same procedures. Dose -escalation is performed based on the scheduled dose groups until DLT occurs in two or more subjects in a dose group which consists of 3 or 6 subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dose escalation of HL-085 plus Docetaxel<br>HL-085 will be administered as BID with specified dose. And Docetaxel will be taken as the instruction in the label ( 75mg/m2，IV). f no Dose-limiting toxicity (DLT) occurs in the first three subjects in Cycle 1, the dose will be escalated to the next dose level; If a DLT occurs in one of the first three subjects, three additional subjects will be enrolled for the same dose cohort, and undergo the same procedures. Dose -escalation is performed based on the scheduled dose groups until DLT occurs in two or more subjects in a dose group which consists of 3 or 6 subjects. | Drug: HL-085<br>* HL-085 ( Capsule) is one MEK inhibitor.<br>Drug: Docetaxel<br>* Docetaxel is an antineoplastic drug by inhibiting microtubule depolymerization, and attenuating of the effects of bcl-2 and bcl-xL gene expression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) | Number of Treatment-Related Adverse Events as Assessed by CTCAE v4.03 will be counted. | Duration of the study, estimated to be approximately 24 months | 
| Maximum tolerated dose (MTD) | The dose level immediately below the dose level at which more than 2 patients from a cohort of 3 to 6 patients experience a dose-limiting toxicity (DLT) | DLTs within the first cycle of therapy (up to 35 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | ORR is the proportion of patients with a best overall response of complete response (CR) or partial response (PR), as assessed per response evaluation criteria in solid tumors (RECIST) v1.1. | Duration of the study, estimated to be approximately 24 months | 
| Peak Plasma Concentration (Cmax) | Cmax is the maximum plasma concentration of HL-085 or metabolite(s). | Duration of the study, estimated to be approximately 24 months | 
| Area under the plasma concentration verus time curve(AUC) | AUC of HL-085 or metabolites(s) after repeated dosing | Duration of the study, estimated to be approximately 24 months |