Erlotinib Is Being Studied With Or Without An Investigational Drug, PF-02341066, In Patients With Lung Cancer

Study Overview
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Brief Summary
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This is a Phase 1/2 study comparing the safety and anti-tumor activity of erlotinib alone versus erlotinib in combination with PF-02341066 in patients with advanced non-small cell lung cancer.

Official Title
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Phase 1/2, Open Label, Randomized Study Of The Safety, Efficacy, And Pharmacokinetics Of Erlotinib With Or Without Pf 02341066 In Patients With Advanced Non Small Cell Adenocarcinoma Of The Lung.

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Erlotinib
* Drug: PF-02341066


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically proven diagnosis of Non-Small Cell Lung Cancer (NSCLC) that is locally advanced or metastatic and of the adenocarcinoma subtype (including mixed adenosquamous histology) evident disease progression by Response Evaluation Criterion in Solid Tumors (RECIST) after at least one but no more than 2 chemotherapy regimens for advanced disease tumors must have measurable disease as per RECIST Exclusion Criteria: known interstitial lung disease prior treatment with an agent that is known or proposed to be active by action on EGFR tyrosine kinase or c-Met/HGF (Phase 2 Portion)

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erlotinib<br> | Drug: Erlotinib<br>* Erlotinib, 150 mg, QD will be administered orally on a continuous schedule (Phase 2 only)<br>|
| Experimental: Erlotinib + PF-02341066<br> | Drug: Erlotinib<br>* For Phase 1 - escalating doses of erlotinib will be administered orally on a continuous schedule. The planned doses to be evaluated are 100 and 150 mg QD. The dose determined in Phase 1 will be used in Phase 2<br>Drug: PF-02341066<br>* For Phase 1 - escalating doses of PF-02341066 will be administered orally on a continuous schedule. The planned doses to be evaluated are 200 and 250 mg BID. The dose determined in Phase 1 will be used in Phase 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLT) (Phase 1) | Phase 1, first cycle DLT includes Grade (Gr) ≥4 hematologic possible drug-related toxicities and Gr ≥3 possible drug-related febrile neutropenia. Gr ≥3 non-hematological possible drug-related toxicities (except asymptomatic lab value elevation). Gr 3/4 nausea, vomiting or diarrhea. Gr 3 hypertension considered DLT if event unmanageable by approved pharmacologic agents or symptomatic sequelae despite medical intervention. Diagnosis of interstitial lung disease. Inability to deliver at least 80 percent (%) of planned dose during cycle 1 due to possible drug-related adverse events (AEs). | Baseline up to Day 28 | 
| Progression-Free Survival (Phase 2) | Time in weeks from phase 2 study randomization to first documentation of objective disease progression or death due to any cause. Progression-Free Survival was calculated as (first event date minus randomization date plus 1) divided by 7.02. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from AE data (where the outcome was Death; date of death reported in notice of death was used). | Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PF-02341066 (Crizotinib) Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1) | AUCtau is a measure of the plasma exposure to PF-02341066. In this study, it is used to characterize PF-02341066 exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle1 Day 15) of PF-02341066 were administered in combination of Erlotinib. | Cycle 1 (C1) Day 1 (D1) i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| PF-02341066 (Crizotinib) Maximum Observed Plasma Concentration (Cmax) (Phase 1) | Cmax is a measure of the plasma exposure to PF-02341066. In this study, it is used to characterize PF-02341066 exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib | C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| PF-02341066 (Crizotinib) Apparent Oral Clearance (CL/F) (Phase 1) | Apparent oral Clearance is a measure of combination of the rate at which a drug is removed from the blood (CL) and the bioavailability (F) after oral dose. In this study, It is used to characterize PF-02341066 CL/F after multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib. | C1D15 i.e., 15 days of giving crizotinib and erlotinib | 
| PF-06260182 Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1) | AUCtau is a measure of the plasma exposure to PF-06260182, a PF-02341066 metabolite. In this study, it is used to characterize the metabolite exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib. | C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| PF-06260182 Maximum Observed Plasma Concentration (Cmax) (Phase 1) | Cmax is a measure of the plasma exposure to PF-06260182, a PF-02341066 metabolite. In this study, it is used to characterize the metabolite exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib. | C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| Molecular Weight Adjusted PF-06260182-to-PF-02341006 Ratio of AUCtau (Phase 1) | Molecular weight adjusted PF-06260182-to-PF-02341006 ratio of AUCtau is a measure of how much PF-02341066 (parent drug) was converted to the metabolite PF-06260182 after PF-02341066 dosing. In this study, it is used to characterize the metabolite-to-parent ratio exposure after a single dose (Cycle 1 Day 1) and multiple doses (Cycle 1 Day 15) of PF-02341066 were administered in combination of Erlotinib. | C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| Erlotinib Area Under the Concentration-Time Curve During Dosing Interval (AUCtau) (Phase 1) | AUCtau is a measure of the plasma exposure to erlotinib. In this study, it is used to characterize erlotinib exposure after multiple doses of erlotinib were administered alone (Day -1) and in combination of PF-02341066 (Cycle 1 Day 1 and Day 15). | C1D-1 i.e., 1 day prior to initiation of continuous dosing of crizotinib; C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| Erlotinib Maximum Observed Plasma Concentration (Cmax) (Phase 1) | Cmax is a measure of the plasma exposure to erlotinib. In this study, it is used to characterize erlotinib exposure after multiple doses of erlotinib were administered alone (Day -1) and in combination of PF-02341066 (Cycle 1 Day 1 and Day 15). | C1D-1 i.e., 1 day prior to initiation of continuous dosing of crizotinib; C1D1 i.e., 1 day of giving crizotinib and erlotinib; and C1D15, i.e., 15 days of giving crizotinib and erlotinib | 
| Erlotinib Apparent Oral Clearance (CL/F) (Phase 1) | Apparent oral Clearance is a measure of combination of the rate at which a drug is removed from the blood (CL) and the bioavailability (F) after oral dose. In this study, it is used to characterize erlotinib CL/F after multiple doses in combination with PF-02341066 (Cycle 1 Day 15). | C1D15 i.e., 15 days of giving crizotinib and erlotinib | 
| Ratio of Adjusted Means of Erlotinib AUCtau (Crizotinib + Erlotinib / Erlotinib Alone) (Phase 1) | Ratio of adjusted means of Erlotinib AUCtau (Crizotinib + Erlotinib / Erlotinib Alone) is a measure of the plasma exposure to erlotinib after erlotinib dosing with crizotinib compared with that after erlotinib dosing alone. In this study, it is used to characterize the effect magnitude of crizotinib on the erlotinib exposure after combinational use of crizotinib and erlotinib. | C1D-1 (i.e., 1 day prior to initiation of continuous dosing of crizotinib) to C1D15 (i.e., 15 days of giving crizotinib and erlotinib) | 
| Ratio of Adjusted Means of Erlotinib Cmax (Crizotinib + Erlotinib / Erlotinib Alone) (Phase 1) | Ratio of adjusted means of Erlotinib Cmax (Crizotinib + Erlotinib / Erlotinib Alone) is a measure of the plasma exposure to erlotinib after erlotinib dosing with crizotinib compared with that after erlotinib dosing alone. In this study, it is used to characterize the effect magnitude of crizotinib on the erlotinib exposure after combinational use of crizotinib and erlotinib. | C1D-1 (i.e., 1 day prior to initiation of continuous dosing of crizotinib) to C1D15 (i.e., 15 days of giving crizotinib and erlotinib) | 
| Progression-Free Survival (Phase 1) | Time in weeks from phase 1 randomization to first documentation of objective disease progression or death due to any cause. Progression-Free Survival was calculated as (first event date minus randomization date plus 1) divided by 7.02. Tumor progression was determined from oncologic assessment data (where data meet the criteria for PD), or from AE data (where the outcome was Death; date of death reported in notice of death was used). | Baseline, every 42 days until disease progression or unacceptable toxicity | 
| Duration of Response (Phase 1) | Median duration (50 percent [%]) of tumor response. Duration of response (DR) defined as time from start of first documented objective tumor response [Complete Response (CR) or Partial Response (PR)] to first documented objective tumor progression or death due to any cause, whichever occurs first. DR calculated as (Weeks) = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR: disappearance of a target lesions. PR: at least 30% decrease in the sum of diameters of target lesions. | Baseline, every 42 days until disease progression or unacceptable toxicity | 
| Percentage of Participants With Objective Response (Phase 1) | Percentage of participants during phase 1 with objective response based assessment of confirmed CR or confirmed PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Confirmed responses: persist on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions. | Baseline, every 42 days until disease progression or unacceptable toxicity | 
| Plasma Level of Soluble Marker: c-Met Ectodomain (Phase 1) | Levels of soluble protein biomarker c-MET was analyzed at Baseline and at Day 50. | Baseline and Day 50 (Cycle 3, Day 1) | 
| Plasma Level of Soluble Marker: Hepatocyte Growth Factor (HGF) Scatter Factor (Phase 1) |  | Baseline and Day 50 (Cycle 3, Day 1) | 
| Plasma Level of Soluble Marker: c-Met Ectodomain (Phase 2) |  | Baseline and Day 50 (Cycle 3, Day 1) | 
| Plasma Level of Soluble Marker: HGF Scatter Factor (Phase 2) |  | Baseline and Day 50 (Cycle 3, Day 1) | 
| Duration of Response (Phase 2) | Median duration (50%) of tumor response. DR defined as time from start of first documented objective tumor response (CR or PR) to first documented objective tumor progression or death due to any cause, whichever occurs first. DR calculated as (Weeks) = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions. | Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity | 
| Percentage of Participants With Confirmed CR, PR or Stable Disease (SD) at Phase 2 | Percentage of participants during phase 2 with confirmed CR, confirmed PR or SD according to RECIST 1.1. Also known as Disease Control Rate (DCR). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions. SD: neither sufficient shrinkage or increase to qualify for PR or PD. | Week 6 and Week 12 | 
| Percentage of Participants With Objective Response (Phase 2) | Percentage of participants during phase 2 with objective response based assessment of confirmed CR or confirmed PR according to RECIST (1.1). Confirmed responses: persist on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of nontarget disease. No new lesions. | Baseline, every 42 days up to 20 months, disease progression, or unacceptable toxicity | 
| Overall Survival (OS) at Phase 2 | Time in months from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 30.4. | Baseline until death, up to 20 months | 
| European Organization for Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire (QLQ-C30) Score at Phase 2 | Phase 2 EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. | Baseline and every 21 days, up to 20 months | 
| EORTC Quality of Life Questionnaire -Lung Cancer 13 (QLQ-LC13) Score at Phase 2 | QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, neuropathy, alopecia, and medicine for pain). Recall period: past week; response range: not at all to very much. Scale score range: 0 to 100. Higher symptom score = greater degree of symptoms. | Baseline and every 21 days, up to 20 months | 
| Plasma Concentration of PF-02341066 and Erlotinib (Phase 2) | Plasma concentration of PF-02341066 and erlotinib when administered in combination during phase 2 | Day 1 of cycles 1, 3, and 5 (i.e., up to 15 weeks) at 0 (pre-dose) and 2 to 6 hours post dose | 
| Plasma Concentration of Erlotinib (Phase 2) | Plasma concentration of erlotinib when administered as a single agent during phase 2 | Day 1 of cycles 1, 3, and 5 (i.e., up to 15 weeks) at 0 hours (pre-dose) | 
| Percentage of Participants With Mutations in Tumor Tissue (Phase 2) | Tumor tissue samples collected for molecular profiling were to be analyzed to assess Kirsten rat sarcoma (KRAS) mutations, mutations, amplification and expression of Epidermal Growth Factor Receptor (EGFR) and c-Met, and echinoderm microtubule-associated protein-like 4-anaplastic large cell receptor kinase (EML4-ALK) fusion in tumors. | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Neoplasms, Crizotinib