Phase III Study (Tarceva®) vs Chemotherapy to Treat Advanced Non-Small Cell Lung Cancer in Patients With Mutations in the TK Domain of EGFR

Study Overview
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Brief Summary
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A Phase III, multicenter, open-label, randomized trial of Erlotinib (Tarceva®) versus chemotherapy in patients with advanced NSCLC with mutations in the Tyrosine Kinase (TK) domain of the EGFR.

Detailed Description
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This is a multicenter, phase III, randomized, open-label clinical trial. 146 patients with a diagnosis of advanced (stage IIIB and stage IV), non-squamous-cell, non-small-cell pulmonary carcinoma not treated previously for their disease with chemotherapy who present mutation in the tyrosine kinase domain of the epidermal growth factor receptor, EGFR will be recluted. The primary objective is to compare the progression-free survival in both treatment arms of the study (conventional chemotherapy vs. erlotinib) in patients with non-squamous-cell, non-small-cell lung cancer (NSCLC) in advanced stage (stages IIIB and stage IV) who have not received previous chemotherapy for their disease and who present mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR).

Official Title
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Phase III, Multicenter, Open-label, Randomized Trial of Tarceva® vs Chemotherapy in Patients With Advanced NSCLC With Mutations in the TK Domain of the EGFR

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Carboplatin
* Drug: Gemcitabin
* Drug: Docetaxel
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Informed consent Histologically confirmed diagnosis of NSCLC, non epidermoid, stage IV or IIIB with pleural effusion, or N3 tumours not candidate for thoracic radiotherapy, harbouring deletions in the exon 19 or mutation in the exon 21 in the TK of the EGFR. Either measurable or evaluable disease. Age > 18 years. ECOG performance status < 2. Adequate bone marrow function Adequate renal function Adequate hepatic function Patients must be accessible for treatment and follow-up. Patients capable of following an adequate therapeutic compliance Women of child bearing potential: negative pregnancy test. Patients of both genders at a fertile age, including those women having their last menstruation within the two previous years, must follow effective contraceptive measures. Ability to swallow. Patients with asymptomatic brain metastasis and stable with medical treatment will be eligible for the study. Patients having received radiotherapy for their brain metastasis prior to the systemic treatment for the NSCLC will be also eligible. Absence of gastrointestinal tract problems Exclusion criteria: Pregnant or lactating women. Women of child bearing potential having a positive pregnancy test in the basal visit or not accomplishing the test. Patients of both genders sexually active (at a fertile age) not following contraceptive measures during the study. Prior chemotherapy for metastatic disease. Both prior neoadjuvant and adjuvant chemotherapy allowed provided that completed â‰¥ 6 months before entering the study. Prior treatment with EGFR targeted therapies. Patients may have received radiotherapy, provided that the irradiated lesion is not the only evaluable lesion for response and completed before entering the study. Prior experimental pharmacological agent within the 3 weeks prior to the inclusion of the study. Any significant ophthalmologic impairment of the eye surface. Use of contact lenses is not recommended. Pre-existing motor or sensorial neurotoxicity grade > 2, according to the NCI-CTC criteria. Evidence of spinal cord compression. Inability to take oral medication and surgical procedures affecting the absorption or implying intravenous or parenteral feeding. Any other severe disease or clinical conditions, as, but not only: Unstable cardiopathy despite treatment, myocardial infarction within the 6 months before entering the study History of significant neurological or psychiatric disorders, including dementia and epileptic seizures. Uncontrolled active infection. Uncontrolled peptic ulcer. Unstable diabetes mellitus or any other contraindication for treatment with corticosteroids. AST and/or ALT > 1.5 x UNL associated to alkaline phosphatase > 2.5 x UNL. Any other underlying severe process affecting the ability to take part in the study. Absolute contraindication for steroids. Dementia or significant mental disorder interfering the understanding and giving the informed consent. History of other malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, radically treated prostatic carcinoma with good prognostic (Gleason = 6). History of other curatively treated malignancy and no evidence of disease within the past 5 years.

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 |
| --- | --- |
| Experimental: A<br>Erlotinib (Tarceva)150 mg /day Patients will receive treatment until disease progression or unacceptable toxicity. For all practical effects a treatment cycle will be defined as three weeks of continuous treatment with erlotinib | Drug: Erlotinib<br>* 150 mg/day Patients will receive treatment until disease progression or unacceptable toxicity. For all practical effects a treatment cycle will be defined as three weeks of continuous treatment with erlotinib<br>* Other names: Tarceva;|
| Active Comparator: B<br>4 cycles of Chemotherapy: Cisplatin / Gemcitabine; Cisplatin /Docetaxel; Carboplatin / Gemcitabine; Carboplatin / Docetaxel. - Cisplatin plus docetaxel: cisplatin 75 mg/m2 i.v. day 1 and docetaxel 75 mg/m2 i.v. day 1. Repeat cycles every 3 weeks. - Cisplatin plus gemcitabine: Cisplatin 75 mg/m2 i.v. on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8. Repeat cycles every 3 weeks. In the case of patients not eligible for treatment with cisplatin, cisplatin can be replaced by carboplatin. The schedules will be the following: Docetaxel 75 mg/m2 day 1 and carboplatin AUC = 6 day 1, every 21 days. Gemcitabine 1000 mg/m2 days 1 and 8 and carboplatin AUC = 5 day 1, every 21 days. Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given. | Drug: Carboplatin<br>* Gemcitabine 1000 mg/m2 days 1 and 8 and Carboplatin AUC = 5 day 1, every 21 days. Docetaxel (75 mg/m2) /carboplatin (AUC=6); Gemcitabine (1000 mg/m2; day 1 and 8) / Carboplatin (AUC=5) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.<br>* Other names: Paraplatin;Drug: Gemcitabin<br>* Cisplatin (75 mg/m2) / Gemcitabine (1250 mg/m2; day 1 and 8) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.<br>* Other names: Gemzar;Drug: Docetaxel<br>* Cisplatin (75 mg/m2) / Docetaxel (75 mg/m2) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.<br>* Other names: Taxotere;Drug: Cisplatin<br>* Cisplatin (75 mg/m2) / Docetaxel (75 mg/m2) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free-survival | The time from enrollment in the study to tumor progression or death from any cause (whichever occurs first) | From the date of randomization to the date of last follow up, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response | The objective response rate is defined as the percentage of patients who attain complete response (CR) or partial response (PR); response will be evaluated following RECIST criteria. | From the date of randomization to the date of last follow up, assessed up to 24 months | 
| One year survival | Proportion of patients who are still alive one year after enrollment in the study. | From the date of randomization to the one year after initiation of treatment. | 
| Overall survival | Overall survival will be assessed from the date of enrollment in the study until the date of death from any cause. Patients lost to follow-up will be censured on the date of the last follow-up visit. | From the date of randomization to the date of last follow up, assessed up to 24 months | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Occurrence and severity of adverse events, with severity determined by NCI CTCAE v3.0 criteria | From the subject's written consent to participate in the study through 30 days after the final administration of the drug | 
| Life quality | Changes in the scores obtained with the LCSS validated questionnaire throughout the course of the study will be analyzed to assess change in the patient's quality of life. | At baseline, every 3 weeks during treatment period, end of treatment visit and every 3 months during follow up period. | 
| Molecular markers related to EGFR and study pathology | The study of mutations in serum (serum DNA) | At baseline, after 6 months of inclusion and at progression. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erlotinib, Lung, cancer, EGFR, Epidermal Growth Factor Receptor, tyrosine kinase, Tarceva®