AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of AZD6244 in combination with docetaxel versus docetaxel alone in patients with KRAS mutation positive locally advanced or metastatic non small cell lung cancer.

Detailed Description
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The primary objective of this study was to assess the efficacy in terms of overall survival (OS) of AZD6244 in combination with docetaxel, compared with docetaxel alone, in second-line patients with KRAS mutation-positive locally advanced or metastatic NSCLC. Amendment 4 of the CSP altered the primary objective and outcome variable from progression-free survival (PFS) to OS, and the secondary outcome variable changed from OS to PFS. The secondary objectives of the study were: To further assess the efficacy of AZD6244 in combination with docetaxel, compared with docetaxel alone, in second-line patients with KRAS mutation-positive locally advanced or metastatic NSCLC To assess the safety and tolerability profile of AZD6244 in combination with docetaxel To investigate the use of plasma and serum as a potential source of circulating free tumour DNA (cfDNA) for the analysis of KRAS mutation status To investigate the PK of AZD6244 and N-desmethyl AZD6244 and any other known metabolites when AZD6244 is administered in combination with docetaxel. The exploratory objectives of the study were: To assess the prevalence, severity and change over time of advanced NSCLC cancer specific symptoms in patients receiving AZD6244 in combination with docetaxel and docetaxel alone To explore potential biomarkers in residual tumour, plasma and/or serum taken for KRAS mutational analysis which may influence development of NSCLC (and associated clinical characteristics) and/or response (optional) To investigate the relationship between AZD6244 and/or N-desmethyl AZD6244 and any other known metabolite plasma concentrations or exposure and clinical outcomes, efficacy, AEs, and/or safety parameters if deemed appropriate To collect and store deoxyribonucleic acid (DNA), derived from a blood sample, for future exploratory research into genes that may influence response, eg, distribution, safety, tolerability, and efficacy of AZD6244 and/or agents used in combination and/or as comparators (optional).

Official Title
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Phase II, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy of AZD6244 in Combination With Docetaxel, Compared With Docetaxel Alone, in 2nd Line Patients With KRAS Mutation Positive Locally Advanced Metastatic NSCLC

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: AZD6244
* Drug: docetaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic non small cell lung cancer (IIIB-IV) Failure of first line anti-cancer therapy (either radiological documentation of disease progression or due to toxicity) in advanced disease or subsequent relapse of disease following first line therapy Tumour sample confirmed as KRAS mutation positive (Note: Sample must be available upon enrolment to ship to AZ appointed central laboratory, or mutation status confirmed locally at AstraZeneca agreed local laboratory using agreed methodology, or mutation status confirmed by an accredited (eg CLIA certified) commercial laboratory (eg Genzyme or Lab 21). Exclusion Criteria: Received >1 prior anti-cancer therapy for advanced or metastatic non small cell lung cancer (excluding radiotherapy) Prior treatment with a MEK inhibitor or any docetaxel containing regimen (prior treatment with paclitaxel is acceptable) Having received an investigational drug within 30 days of starting treatment, or have not recovered from side effects of an investigational drug Brain metastases or spinal cord compression unless asymptomatic, treated and stable off steroids and anti-convulsants for at least 1 month

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 |
| --- | --- |
| Active Comparator: AZD6244 + Docetaxel<br>AZD6244 75 mg bd + Docetaxel 75 mg/m^2 | Drug: AZD6244<br>* oral capsules, 75mg twice daily<br>* Other names: Selumetinib;Drug: docetaxel<br>* 75mg/m2 iv on day 1 of every 21 day cycle<br>* Other names: Taxotere;|
| Placebo Comparator: Placebo + Docetaxel<br>Placebo + Docetaxel 75 mg/m^2 | Drug: docetaxel<br>* 75mg/m2 iv on day 1 of every 21 day cycle<br>* Other names: Taxotere;Drug: Placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS was calculated as the interval from the date of randomisation to the date of patient death (any cause). Patients who had not died at the time of the final analysis, or who withdrew consent, were censored at the last date the patient was known to be alive. | At least 12 months since start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | PFS was defined as the interval between the date of randomisation and the earlier date of objective disease progression per RECIST criteria or death due to any cause in the absence of progression. Patients who did not progress or die at the time of analysis were censored at the time of their latest evaluable objective tumour assessment. This also included patients who withdrew consent. | At least 12 months after start of treatment | 
| Objective Response Rate | ORR is defined as the ratio of proportions, patients with at least one visit response of CR or PR in AZD6244 + Docetaxel vs Placebo + Docetaxel. | At least 12 months after start of treatment | 
| Duration of Response | Duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint. | At least 12 months after start of treatment | 
| Change From Baseline in Tumour Size at 6 Week. | Percentage change from baseline in tumour size at 6 week. Values calculated as tumour sizes at 6 weeks minus value at baseline. | 6 weeks after first dose of treatment | 
| Change From Baseline in Tumour Size at Week 12 | Percentage change from baseline in tumour size at Week 12. Values calculated as tumour sizes at 12 weeks minus value at baseline. | 12 weeks | 
| Alive and Progression-Free at 6 Months | Percentage of patients alive and progression-free at 6 months | 6 months after first dose of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non small cell lung cancer (NSCLC), KRAS mutation