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

• ClinicalTrials.gov Identifier: NCT00890825
• Recruitment Status: Completed
• First Posted: April 30, 2009
• Results First Posted: June 20, 2018
• Last Update Posted: June 20, 2018
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 29, 2009
• First Posted Date: April 30, 2009
• Results First Submitted Date: June 14, 2017
• Results First Posted Date: June 20, 2018
• Last Update Posted Date: June 20, 2018
• Actual Study Start Date: April 20, 2009
• Actual Primary Completion Date: May 11, 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 22, 2018)

Overall Survival [ Time Frame: At least 12 months since start of treatment. ]

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.

• Original Primary Outcome Measures (submitted: April 29, 2009): To assess the efficacy in terms of Progression Free Survival (PFS) of AZD6244 in combination with docetaxel compared with docetaxel alone, in 2nd line patients with KRAS mutation positive locally advanced or metastatic non small cell lung cancer [ Time Frame: PFS will be assessed using RECIST measurements. RECIST assessments to be carried out at baseline, week 6, week 12 and every 12 weeks thereafter relative to randomisation ]

Current Secondary Outcome Measures (submitted: May 22, 2018)

• Progression Free Survival [ Time Frame: At least 12 months after start of treatment ]
  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.
• Objective Response Rate [ Time Frame: At least 12 months after start of treatment ]
  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.
• Duration of Response [ Time Frame: At least 12 months after start of treatment ]
  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.
• Change From Baseline in Tumour Size at 6 Week. [ Time Frame: 6 weeks after first dose of treatment ]
  Percentage change from baseline in tumour size at 6 week. Values calculated as tumour sizes at 6 weeks minus value at baseline.
• Change From Baseline in Tumour Size at Week 12 [ Time Frame: 12 weeks ]
  Percentage change from baseline in tumour size at Week 12. Values calculated as tumour sizes at 12 weeks minus value at baseline.
• Alive and Progression-Free at 6 Months [ Time Frame: 6 months after first dose of treatment ]
  Percentage of patients alive and progression-free at 6 months

Original Secondary Outcome Measures (submitted: April 29, 2009)

• To further assess the efficacy in terms of:- Overall Survival (OS)- Objective Response Rate (ORR)- Duration of Response (DoR)- Change in tumour size at 12 weeks- Alive and Progression Free at 6 months (APF6) [ Time Frame: ORR, DoR, APF6 and change in tumour size at 12 weeks will be assessed using RECIST measurements. RECIST assessments to be carried out at baseline, week 6, week 12 and every 12 weeks thereafter relative to randomisation ]
• To assess the safety and tolerability profile of AZD6244 in combination with docetaxel [ Time Frame: At every visit (ie weekly for the first 6 weeks and then every 3 weeks) ]
• To investigate the pharmacokinetics of AZD6244 [ Time Frame: At Day 1 and Day 22 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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).

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non Small Cell Lung Cancer

Intervention

• Drug: AZD6244
  oral capsules, 75mg twice daily
  Other Name: Selumetinib
• Drug: docetaxel
  75mg/m2 iv on day 1 of every 21 day cycle
  Other Name: Taxotere
• Drug: Placebo
  placebo

Study Arms

• Active Comparator: AZD6244 + Docetaxel
  AZD6244 75 mg bd + Docetaxel 75 mg/m^2
  Interventions:

  • Drug: AZD6244
  • Drug: docetaxel
• Placebo Comparator: Placebo + Docetaxel
  Placebo + Docetaxel 75 mg/m^2
  Interventions:

  • Drug: docetaxel
  • Drug: Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 22, 2018): 88
• Original Estimated Enrollment (submitted: April 29, 2009): 80
• Actual Study Completion Date: November 2, 2016
• Actual Primary Completion Date: May 11, 2011 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, Bulgaria, Canada, Czechia, France, Hungary, Italy, Mexico, Peru, Spain, United States
• Removed Location Countries: Czech Republic, Denmark, Luxembourg

Administrative Information

• NCT Number: NCT00890825
• Other Study ID Numbers: D1532C00016
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: AstraZeneca, MSD
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Dr. Pasi Janne; Dana-Farber Cancer Institute, Boston, USA
• Study Director: Dr. Gabriella Mariani; AstraZeneca, Hertfordshire, UK

• PRS Account: AstraZeneca
• Verification Date: May 2018