A Phase Ib/II Clinical Trial to Evaluate the Safety and Efficacy of HLX208+HLX10 in NSCLC With BRAF V600E Mutation

Study Overview
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Brief Summary
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An open-label, multicenter phase Ib/II clinical study to evaluate safety, tolerability, pharmacokinetics, and efficacy of HLX208 (BRAF V600E Inhibitor) combined with HLX10 （anti-PD-1 monoclonal antibody）in advanced NSCLC patients with BRAF V600 mutation.

Detailed Description
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This is an open-label, multicenter phase Ib/II clinical study to evaluate safety, tolerability, pharmacokinetics, and efficacy of HLX208 (BRAF V600E Inhibitor) combined with HLX10 （anti-PD-1 monoclonal antibody）in advanced NSCLC patients with BRAF V600 mutation. For the phase Ib study, HLX208 is administered orally at two dose levels of 600mg BID or 900 mg BID. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks. For the phase II study, HLX208 is administered orally with the RP2D dose. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks.

Official Title
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A Phase Ib/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HLX208 （BRAF V600E Inhibitor） Combined With Serplulimab（HLX10, Anti-PD-1 Antibody） in Advanced NSCLC Patients With BRAF V600E Mutation.

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Combination Product: HLX208+HLX10


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 and ≤75 years old of age (in phase Ib study) or ≥18 and ≤80 years old of ag (in phase II study) at the time of informed consent. Signed written informed consent. BRAF V600E mutant advanced solid tumors (in phase Ib study) or advanced NSCLC (in phase II study) patients with positive PD-L1 expression (TPS or TC≥1%). Previous failure of standard therapy, intolerance to standard therapy, lack of standard therapy, or currently unsuitable for standard therapy. Prior systemic anti-neoplastic therapy (chemotherapy, radiotherapy, targeted therapy, or traditional Chinese medicine with anti-neoplastic indications) must have been ≥ 2 weeks from the first dose in this study with treatment-related AE resolved to NCI-CTCAE Grade ≤ 1 (except for alopecia) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Expected survival time ≥ 3 months. At least one measurable target lesion per RECIST v1.1 (brain metastasis could not be considered as the only measurable lesion). With normal major organ functions (no blood transfusions or treatment with colony-stimulating factor within 14 days prior to the first dose in this study). Be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bow Fertile subjects (male or female) must agree to take effective contraceptive measures from the time of signing the ICF until 90 days after the last dose of HLX208 or 6 months after the last dose of HLX10. Female subjects of childbearing potential must complete a pregnancy test with a negative result within 7 days prior to the first dose. Exclusion Criteria: For subjects in phase II study: previous treatment with BRAF inhibitors or MEK inhibitors or previous treatment with T cell co-stimulation or immune checkpoint therapy. Known EGFR mutations or ALK rearrangements (except in subjects with EGFR mutations whose disease has progressed after previous EGFR inhibitor treatment). Received strong CYP3A inhibitors or inducers treatment within 1 week prior to the first dose of investigational product. Received major surgery within 28 days prior to the first dose of investigational product. A major surgery is defined as a surgery that takes at least 3 weeks of postoperative recovery before receiving treatment in this study. With uncontrolled pleural effusion, pericardial effusion, or ascites. With symptomatic brain or meningeal metastases (unless the patient has been treated for >3 months, there is no evidence of progression on imaging within 4 weeks prior to the first dose, and the tumor-related clinical symptoms are stable). With active pulmonary tuberculosis. Patients with previous and current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe impaired pulmonary function that may interfere with the detection and management of suspected drug-related pulmonary toxicity. With any serious infection requiring systemic anti-infective therapy within 14 days prior to the first dose of the investigational product. History of other malignant tumors (except for cured carcinoma in situ of the cervical or basal cell carcinoma of the skin) within two years prior to the first dose of investigational product. Being positive (+) for hepatitis B surface antigen (HBsAg) or positive (+) for hepatitis B core antibody (HBcAb), and with hepatitis B virus deoxyribonucleic acid (HBV-DNA) ≥ 2500 copies/mL or 500 IU/mL. Being positive (+) for HCV RNA. Being positive (+) human immunodeficiency virus (HIV) antibody. History of serious cardiovascular and cerebrovascular diseases. Systemic treatment with corticosteroids (> 10 mg/day prednisone or equivalent) or other immunosuppressive agents within 14 days prior to the first dose of the investigational product or during the study. In the absence of active autoimmune disease, subjects are allowed to use inhaled or topical steroids, or adrenal hormone replacement therapy at an effective dose equivalent to ≤10 mg/day prednisone. Known active or suspected autoimmune diseases. Subjects with autoimmune related hypothyroidism receiving thyroid hormone replacement therapy are allowed to participate in the study. Subjects with stable type 1 diabetes receiving insulin therapy are allowed to participate in the study. Known alcohol of or drug abuse. Pregnant or lactating women. Received live vaccine within 28 days prior to the first dose of investigational product. Have other conditions not suitable for inclusion as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: HLX208 combined HLX10<br>For the phase Ib study, HLX208 is administered orally at two dose levels of 600mg BID or 900 mg BID. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks. For the phase II study, HLX208 is administered orally with the RP2D dose. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks. | Combination Product: HLX208+HLX10<br>* HLX208 is a BRAF V600E inhibitor ,and HLX10 is an anti-PD-1 monoclonal antibody.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD (for phase Ib study) | The maximum tolerated dose of HLX208 combined with HLX10. | From first dose to the end of Cycle 1 (each cycle is 3 weeks). | 
| DLT (for phase Ib study) | The proportion of patients experiencing dose limiting toxicity (DLT) events. | From first dose to the end of Cycle 1 (each cycle is 3 weeks). | 
| ORR (for phase II study) | Objective response rate assessed by the investigator per RECIST 1.1. | up to approximately up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-Free-Survival | approximately up to 36 months | 
| DCR | Disease-Control-Rate | approximately up to 24 months | 
| DOR | Duration of Overall Response | approximately up to 24 months | 
| TTR | Time to Tumor Response | approximately up to 24 months | 
| 12-month OS rate | 12-month OS rate | 12 months | 
| 6-month OS rate | 6-month OS rate | 6 months | 
| OS | Overall-Survival | approximately up to 48 months | 
| 12-month PFS rate | 12-month PFS rate | 12 months | 
| 6-month PFS rate | 6-month PFS rate | 6 months | 
| SAE | The proportion of patients experiencing SAE. | approximately up to 48 months | 
| AUC0-T | Area under the concentration-time curve from time 0 to the last concentration measurable time point. | From First administration of HLX 208 to 12 weeks. | 
| AUC0-∞ | Area under the concentration-time curve from time 0 to infinity. | From First administration of HLX 208 to 12 weeks. | 
| Cmax | Peak Plasma Concentration. | From First administration of HLX 208 to 12 weeks. | 
| Tmax | Time to first occurrence of Cmax | From First administration of HLX 208 to 12 weeks. | 
| t1/2 | Elimination half-life | From First administration of HLX 208 to 12 weeks. | 
| AUCss | Area under the steady-state concentration-time curve | From First administration of HLX 208 to 12 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HLX208, HLX10, BRAF V600E mutation