A Study of IRESSA Treatment Beyond Progression in Addition to Chemotherapy Versus Chemotherapy Alone

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of gefitinib in patients who have progressed on first line gefitinib, comparing continuing gefitinib in addition to cisplatin plus pemetrexed combination chemotherapy versus cisplatin plus pemetrexed combination chemotherapy alone.

Detailed Description
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A Phase III Randomised, Double blind, Placebo controlled, Parallel, Multicentre Study to Assess the Efficacy and Safety of continuing IRESSA 250 mg in addition to Chemotherapy versus Chemotherapy alone in Patients who have Epidermal Growth Factor Receptor (EGFR) Mutation Positive Locally advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) and have progressed on First Line IRESSA.

Official Title
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A Phase III Randomised, Double Blind, Placebo Controlled, Parallel, Multicentre Study to Assess the Efficacy and Safety of Continuing IRESSA 250 mg in Addition to Chemotherapy Versus Chemotherapy Alone in Patients Who Have Epidermal Growth Factor Receptor (EGFR) Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) and Have Progressed on First Line IRESSA

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Placebo
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 years or older (For Japan only- male or female patients aged 20 years or older) Cytological or histological confirmation of NSCLC other than predominantly squamous cell histology with an activating EGFR TK mutation as determined locally Patients with documented 'acquired resistance' on first line gefitinib Patients suitable to start cisplatin based pemetrexed combination chemotherapy. Provision of informed consent prior to any study specific procedures. Exclusion Criteria: Prior chemotherapy or other systemic anti-cancer treatment (excluding gefitinib). Palliative bone radiotherapy must be completed at least 2 weeks before start of study treatment with no persistent radiation toxicity). Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease Other co-existing malignancies or malignancies diagnosed within the last 5 years, with the exception of basal cell carcinoma or cervical cancer in situ or completely resected intramucosal gastric cancer Any evidence of severe of uncontrolled systemic disease Treatment with an investigational drug within 4 weeks before randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefitinib<br>Gefitinib and cisplatin plus pemetrexed combination chemotherapy | Drug: Gefitinib<br>* Investigational Drug<br>Drug: Pemetrexed<br>* Chemotherapy (concomitant therapy)<br>Drug: Cisplatin<br>* Chemotherapy (concomitant therapy)<br>|
| Placebo Comparator: Placebo<br>Placebo and cisplatin plus pemetrexed combination chemotherapy. | Drug: Placebo<br>* Matching placebo as comparator<br>Drug: Pemetrexed<br>* Chemotherapy (concomitant therapy)<br>Drug: Cisplatin<br>* Chemotherapy (concomitant therapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (Site Read, Investigator Assessment) | PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. | Radiologic evaluations were carried out every 6 weeks from randomization until documented progression, withdrawal of consent, loss to follow up, death or the primary data cut off (DCO) for the analysis, assessed up to 50 weeks | 
| Median Progression-Free Survival (Site Read, Investigator Assessment) | PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. | Radiologic evaluations were carried out every 6 weeks from randomization until documented progression, withdrawal of consent, loss to follow up, death or the primary data cut off (DCO) for the analysis, assessed up to 50 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive. | Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first. | 
| Median Overall Survival (OS) at Time of PFS Analysis |  | Baseline and then every 6 weeks after randomization until objective disease progression. OS is then assessed 8 weekly following PFS progression up to PFS analysis data cut off. | 
| Objective Response Rate (ORR) (Site Read Data) | ORR rate is defined as the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) , as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions. Data obtained up until progression, or last evaluable assessment in the absence of progression, was included in the assessment of ORR. | Radiologic evaluations were carried out every 6 weeks from randomization until documented progression, withdrawal of consent, loss to follow up, death or the primary data cut off (DCO) for the analysis. | 
| Disease Control Rate (DCR) | DCR is the percentage of patients who achieve disease control at 6 weeks following randomisation. DCR is defined as a Best Objective Response (BOR) of Complete Response, Partial Response or Stable Disease, as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions; SD, neither sufficient shrinkage to qualify for PR not sufficient increase to qualify for Progressive Disease (PD); PD, ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, and the sum must have shown an absolute increase of ≥5mm | Radiologic evaluations were carried out every 6 weeks from randomization until documented progression, withdrawal of consent, loss to follow up, death or the primary data cut off (DCO) for the analysis. | 
| Improvement in Trial Outcome Index | An improvement is defined as a change from baseline of ≥ +6 (0-84 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire. | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 
| Time to Worsening in Trial Outcome Index | A worsening is defined as a change from baseline of ≤ -6 (0-84 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 
| Improvement in FACT-L Total Score | An improvement is defined as a change from baseline of ≥ +6 (0-136 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 
| Time to Worsening in FACT-L Total Score | A worsening is defined as a change from baseline of ≤ -6 (0-136 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 
| Improvement in Lung Cancer Subscale | An improvement is defined as a change from baseline of ≥ +2 (0-28 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 
| Time to Worsening in Lung Cancer Subscale | A worsening is defined as a change from baseline of ≤ -2 (0-28 score range). Measured by the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire | At visits 2-8, then every 6 weeks until progression, at progression or treatment discontinuation, and every 8 weeks after progression until PFS analysis data cut off. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Small Cell Lung Cancer, Gefitinib, Pemetrexed, Treatment Beyond Progression