First-line Treatment With Dacomitinib Plus Anlotinib for Patients With Advanced NSCLC With EGFR 21L858R Mutations

Study Overview
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Brief Summary
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This is a multicenter, open label, Phase I/IIB study investigating the efficacy and safety of treatment with dacomitinib plus anlotinib as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) 21-L858R mutations. This study comprises two parts: 1. A dose escalation Phase I study to determine the recommended phase II dose. 2. a multi-center, open label, randomized controlled, Phase IIB study.

Official Title
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An Open Label, Multicenter, Phase I/IIB Study of Dacomitinib Plus Anlotinib for Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring Epidermal Growth Factor Receptor (EGFR) 21-L858R Mutations.

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Dacomitinib+Anlotinib
* Drug: Dacomitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age and ≤75 years; Provision of a voluntarily given, personally signed and dated, written informed consent document; Histologically documented, unresectable, inoperable, locally advanced, recurrent or metastatic stage IIIB or IV non-small cell lung cancer (NSCLC); It is acceptable for subjects with the presence of EGFR activating mutation (exon 19 deletion and the L858R mutation in exon 21) to be included in this Phase I study; Only subjects with the L858R mutation in exon 21 to be included in this Phase IIb; At least one measurable disease by RECIST criteria version 1.1; Patients with controlled or stable brain metastases; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, and life expectancy of at least 3 months; No prior treatment with systemic therapy for advanced NSCLC, including TCM treatments; Able to comply with required protocol procedures and able to receive oral medications; Adequate organ function, including: (1) Adequate bone marrow function Hemoglobin≥90g/L, absolute neutrophil count (ANC) should be ≥ 1.5x109/L, platelets should be ≥ 80x109/L; (2) Adequate liver function Total bilirubin ≤ 1.5 x upper normal limit (ULN), Aspartate Aminotransferase (AST) (SGOT) ≤ 2.5 x ULN (≤ 5.0 x ULN if hepatic metastases), Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x ULN (≤ 5.0 x ULN if hepatic metastases), Creatinine≤ 1.5 x upper normal limit (ULN), or ≥ 60 mL/min; (3) Cardiac function: LVEF≥50% assessed by Doppler ultrasound； Exclusion Criteria: Small cell lung cancer (including mixed small cell and non-small cell lung cancer) and squamous cell carcinoma with cavitation; Patients with concurrent EGFR T790M mutation or unknown mutation status or other mutation types; Diagnosis of any other malignancy during the last 5 years, or with other malignancies at present; Patients with pre-existing meningeal metastases; Patients who have concurrent other malignant tumors; Any history of hemoptysis, hematochezia, bloody sputum; Tumor invasion or adjacent major vessels; Patients with uncontrolled or significant systematic disease, including: active infection, thyroid dysfunction, uncontrolled hypertension, unstable angina pectoris, congestive heart failure, or myocardial infarction within 6 months, or severe arrhythmia requiring medication; A history of other diseases, or metabolic dysfunction, or physical examination or laboratory results suggestive of a disease or condition that precludes the use of an investigational drug, or may affect the interpretation of the study results, or expose the patient to a high risk of treatment complications; Any astrointestinal disorders resulting in inability to take medications orally, or requiring intravenous (IV) nutrition, or previous surgery impair drug absorption; Pregnant or lactating females; Patients allergic to any pharmaceutical ingredient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a multi-center, open-label, Phase I/IIB clinical study of Dacomitinib+Anlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) patients with EGFR 21L858R mutation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined treatment group<br>Dacomitinib+Anlotinib: Patients will be treated with combined Dacomitinib and Anlotinib. | Drug: Dacomitinib+Anlotinib<br>* The dose of each drug in the combination Decomitinib and Anlotinib will be escalated or de-escalated until the recommended phase II dose (RP2D) is reached. Patients will then be treated with RP2D orally once a day.<br>|
| Active Comparator: Dacomitinib monotherapy group<br>Dacomitinib: Patients will be treated with Dacomitinib. | Drug: Dacomitinib<br>* Dacomitinib orally on a continuous daily basis at a starting dose of 45 mg once a day until progressive disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall safety profile | Overall safety profile of combined Dacomitinib plus Anlotinib in Escalation Phase, including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE 4.03], and first cycle Dose Limiting Toxicities (DLTs). | Day 21 of Cycle 1, every 6 weeks until disease progression or death due to any cause, whichever occurred first (up to 22 months) | 
| Progression Free Survival (PFS) | Progression Free Survival (PFS) is defined as the time from start of treatment to the date of disease progression as defined by RECIST v1.1 per investigator review or death due to any cause, whichever occurred first. | Day 21 of Cycle 1, every 6 weeks until disease progression or death due to any cause, whichever occurred first (up to 22 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival is defined as the time from start of treatment to the date of death for any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive. | 48 months | 
| Best Overall Response (BOR) | Best overall response is best response from start of treatment until disease progression, and will calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST v1.1, relative to the total number of participants enrolled in the cohort. | From baseline until disease progression, up to 48 months |