Clinical trial NCT00890825: AZD6244 in Combination With Docetaxel Versus Docetaxel Alone in KRAS Mutation Positive NSCLC Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Keywords: Non small cell lung cancer (NSCLC)
KRAS mutation
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2009-04-30
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: At least 12 months since start of treatment.
Secondary outcomes:
measure: Progression Free Survival
timeFrame: At least 12 months after start of treatment
measure: Objective Response Rate
timeFrame: At least 12 months after start of treatment
measure: Duration of Response
timeFrame: At least 12 months after start of treatment
measure: Change From Baseline in Tumour Size at 6 Week.
timeFrame: 6 weeks after first dose of treatment
measure: Change From Baseline in Tumour Size at Week 12
timeFrame: 12 weeks
measure: Alive and Progression-Free at 6 Months
timeFrame: 6 months after first dose of treatment
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Brussels
country: Belgium
facility: Research Site
city: Charleroi
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Belo Horizonte
country: Brazil
facility: Research Site
city: Ijuí
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio de Janeiro
country: Brazil
facility: Research Site
city: Santo André
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Oshawa
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Ostrava
country: Czechia
facility: Research Site
city: Praha 8
country: Czechia
facility: Research Site
city: Znojmo
country: Czechia
facility: Research Site
city: Brest Cedex
country: France
facility: Research Site
city: Clermont Ferrand
country: France
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: Lyon Cedex 08
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Rennes Cedex 9
country: France
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Györ
country: Hungary
facility: Research Site
city: Mosdós
country: Hungary
facility: Research Site
city: Székesfehérvár
country: Hungary
facility: Research Site
city: Törökbálint
country: Hungary
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Perugia
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Rozzano
country: Italy
facility: Research Site
city: Mexico
country: Mexico
facility: Research Site
city: Morelia
country: Mexico
facility: Research Site
city: Zacatecas
country: Mexico
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Badalona(Barcelona)
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
Study officials:
affiliation: Dana-Farber Cancer Institute, Boston, USA
name: Dr. Pasi Janne
role: PRINCIPAL_INVESTIGATOR
affiliation: AstraZeneca, Hertfordshire, UK
name: Dr. Gabriella Mariani
role: STUDY_DIRECTOR
References:
citation: Janne PA, Smith I, McWalter G, Mann H, Dougherty B, Walker J, Orr MC, Hodgson DR, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios CH, Franke FA, Crino L, Smith P. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J Cancer. 2015 Jul 14;113(2):199-203. doi: 10.1038/bjc.2015.215. Epub 2015 Jun 30.
citation: Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crino L. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013 Jan;14(1):38-47. doi: 10.1016/S1470-2045(12)70489-8. Epub 2012 Nov 28.