Study of Dacomitinib and Osimertinib for Patients With Advanced EGFR Mutant Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of dacomitinib and osimertinib, at increasing doses, to find out what effects, if any, this combination of drugs has on people with metastatic EGFR mutant lung cancer that has not been treated with an EGFR TKI.

Official Title
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Phase 1 Study of Combination Dacomitinib and Osimertinib for Patients With Metastatic EGFR Mutant Lung Cancers

Conditions
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Metastatic Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Dacomitinib
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Advanced biopsy-proven metastatic non-small cell lung cancer Somatic activating mutation in EGFR in a tumor biopsy No prior EGFR inhibitor treatment (gefitinib, afatinib, erlotinib, dacomitinib, osimertinib) however, prior treatment with other chemotherapies are allowed Archival tissue available from a pre-treatment tumor biopsy or willing to undergo a tumor biopsy prior to study initiation. Measurable (RECIST 1.1) indicator lesion not previously irradiated Karnofsky performance status (KPS) ≥ 70% Age >18 years old Ability to swallow oral medication Agree to use effective methods of contraception from the time of screening until 3 months after treatment discontinuation (for males and females of child-bearing potential) Adequate organ function AST, ALT ≤ 3 x ULN Total bilirubin ≤1.5x ULN Creatinine ≤ 1.5x ULN OR calculated creatinine clearance ≥ 60ml/min Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3 Hemoglobin≥9.0 g/dL Platelets ≥100,000/mm^3 Exclusion Criteria: Pregnant or lactating women Any radiotherapy within 1 week of starting treatment on protocol. Any major surgery within 1 weeks of starting treatment on protocol. Any evidence of active clinically significant interstitial lung disease A mean QTc >470ms (Fridericias correction), clinically important arrhythmia, conduction or morphology of resting ECG (eg complete LBBB, 1st -3rd degree heart block, any factors that increase the risk of QTc prolongation or risk of arrhythmia) Cardiovascular disease or cerebrovascular disease, CVA or MI < 6 months prior to study enrollment, unstable angina, NYHA >Grade II CHF, or serious cardiac arrhythmia uncontrolled by medication or with the potential to interfere with protocol treatment History of pneumonitis or interstitial lung disease (ILD), drug induced ILD, radiation pneumonitits that required steroid treatment, and any evidence of clinically active ILD Serious chronic GI conditions associated with diarrhea Symptomatic, unstable brain metastases requiring escalating doses of steroids Continue to have unresolved > CTCAE grade 1 toxicity from any previous treatment

Ages Eligible for Study
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Minimum Age: 19 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: Dacomitinib and Osimertinib<br>Patients will begin on combination dacomitinib and osimertinib at the prescribed doses. A cycle will be 28 days in duration. The study will use a standard 3+3 dose escalation design. Per MD discretion, telemedicine visits may be utilized for cycles where imaging is not collected, and physical exam, vital sign and labs collection will only be required concurrent with imaging visits. | Drug: Dacomitinib<br>* Dose level 1 Dacomitinib, Dose level 2 Dacomitinib, Dose level 3 Dacomitinib. Three patients will need to be enrolled at each dose level and assessed for DLT for 1 full cycle (28 days for cycle 1) before dose escalation decision is made.<br>Drug: Osimertinib<br>* Dose level 1, 2 and 3 Osimertinib 40mg daily. Three patients will need to be enrolled at each dose level and assessed for DLT for 1 full cycle (28 days for cycle 1) before dose escalation decision is made.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose | The MTD will be defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity (DLT). DLT is defined as any of the toxicity events described below that occurs within cycle 1 of treatment with the combination of dacomitinib and osimertinib. | 1 year | 
| Best overall response rate | Tumor response will be assessed using RECIST 1.1.The NCI Common Terminology Criteria for Adverse Events Version 5 (NCI-CTCAE) will be used to grade toxicities during the trial. Dose-limiting toxicities (DLTs) are defined as any of the following events occurring during the first cycle of treatment | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dacomitinib, Osimertinib, EGFR Mutant Lung Cancers, 18-411