A Study Of Dacomitinib (PF-00299804) In Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase 2 study of oral dacomitinib given every 12 hours over days 1-4 of each two-week cycle to patients with Non-small cell lung cancer. The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. All patients will receive repeated cycles of dacomitinib until disease progression, occurrence of unacceptable toxicity, or other withdrawal criteria are met.

Official Title
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Phase 2 Open Label Trial Of Oral Intermittent Dacomitinib In Patients With Advanced Nsclc

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Dacomitinib
* Drug: Dacomitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of histologically confirmed, advanced NSCLC (stage IIIB/IV). Evidence of T790M mutation to enroll in Cohort A. Evidence of measurable disease by radiographic technique. Adequate organ function. Exclusion Criteria: Patients with T790M mutation who stopped any prior EGFR-directed therapy without evidence of disease progression. Symptomatic brain metastases. Uncontrolled or significant cardiovascular disease. Pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Patients with NSCLC whose tumor has a documented T790M mutation in exon 20 of the Epidermal Growth Factor Receptor. | Drug: Dacomitinib<br>* Dacomitinib 45 mg every 12 hours Days 1-4 of the first week, and then 60 mg every 12 hours Days 1-4 of each 2-week cycle thereafter. The dose of dacomitinib for patients in Cohort A may be further escalated in increments of 15 mg.<br>|
| Experimental: Cohort B<br>Patients with NSCLC. No requirement of a specific molecular signature, but excluding known T790M mutations. | Drug: Dacomitinib<br>* Dacomitinib 45 mg every 12 hours Days 1-4 of the first week, and then 60 mg every 12 hours Days 1-4 of each 2-week cycle thereafter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) in Participants With T790M Mutation | BOR was best response from start of treatment until disease progression, according to the RECIST,v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. Progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. Stable disease=not qualify for CR, PR or progression. BOR was analyzed only for participants with T790M mutation according to the primary study objective. | From baseline until disease progression, up to 61 weeks. | 
| Objective Response Rate (ORR) in Participants With T790M Mutation | ORR was calculated as the percentage of participants with a confirmed CR or PR relative to the total number of participants enrolled. Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1 were used to define CR and PR. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. ORR was analyzed only for participants with T790M mutation according to the primary study objective. | From baseline to disease progression, up to 61 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) for Participants With T790M Mutation | DCR was 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. If baseline tumor assessment was inadequate for a participant, and the participant could not be assessed for RECIST responses and had no objective status of stable disease documented at least 6 weeks after the start date and before the progression, the participant was only counted in the denominator. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. DCR was analyzed only for participants with T790M mutation according to the study objective. | From baseline to baseline to disease progression, up to 61 weeks. | 
| Duration of Response in Participants With T790M Mutation | Duration of response was defined as the time from first documentation of response (CR or PR, whichever occurred first) to the date of disease progression or to death due to any cause, whichever occurred first. CR and PR were defined using RECIST, v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation. | From baseline to date of disease progression or death, up to 61 weeks. | 
| Progression-free Survival | Progression-free survival was defined as the time from the date of first dosing of dacomitinib to the date of disease progression by RECIST v1.1, per the investigators' assessment, or death due to any cause, whichever occurred first. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. | From baseline to disease progression or death, up to 61 weeks. | 
| Progression-free Survival at 4 Months | Progression-free survival at 4 months was defined as the percentage of participants who were alive without disease progression at 4 months relative to all participants enrolled. Disease progression was defined by RECIST v1.1. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. | Month 4 | 
| Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265 | Cmax was observed directly from data. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate. | Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0. | 
| Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265 | Tmax was observed directly from data as time of first occurrence. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate. | Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0. | 
| Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG) | ECGs recorded on Day 1 of Cycle 0 were used as baseline. For the ECGs assessments, the following directions were followed by the ECG central laboratory: Blinding of ECG readers to treatment, time, and day identifiers. Review of ECGs from a particular participant was performed by a single reader. Prespecification of the lead for internal measurements. Baseline and on-treatment ECG assessments were based on the same lead. | From Baseline to Cycle 0, Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small cell lung cancer, T790M mutation. dacomitinib