Non Small Cell Lung Cancer
Conditions
Keywords
Non small cell lung cancer (NSCLC), KRAS mutation
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).
Interventions
DRUGAZD6244
oral capsules, 75mg twice daily
DRUGdocetaxel
75mg/m2 iv on day 1 of every 21 day cycle
DRUGPlacebo
placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 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 | 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. |
| Progression Free Survival | 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. |
| Change From Baseline in Tumour Size at Week 12 | 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 | 6 months after first dose of treatment | Percentage of patients alive and progression-free at 6 months |
| Change From Baseline in Tumour Size at 6 Week. | 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. |
Countries
Belgium, Brazil, Bulgaria, Canada, Czechia, France, Hungary, Italy, Mexico, Peru, Spain, United States
Participant flow
Recruitment details
Selection of patients was in 2nd line patients with KRAS mutation positive locally advanced or metastatic NSCLC (Stage IIIB - IV).First patient enrolled: 20 April 2009.Last patient last visit: 30 June 2010.Data Cut Off (DCO): 01 May 2011
Participants by arm
| Arm | Count |
|---|---|
| AZD6244 + Docetaxel AZD6244 75 mg bd + Docetaxel 75 mg/m\^2 | 44 |
| Placebo + Docetaxel Placebo + Docetaxel 75 mg/m\^2 | 43 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Alive at data cut off (DCO) | 13 | 14 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo + Docetaxel | AZD6244 + Docetaxel | Total |
|---|---|---|---|
| Age, Continuous | 58.6 Years STANDARD_DEVIATION 8.38 | 58.2 Years STANDARD_DEVIATION 9.22 | 58.4 Years STANDARD_DEVIATION 8.77 |
| Age, Customized Age group : <=55 years | 15 Participants | 15 Participants | 30 Participants |
| Age, Customized Age group : >55 years | 28 Participants | 29 Participants | 57 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants | 7 Participants | 17 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 33 Participants | 37 Participants | 70 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 40 Participants | 41 Participants | 81 Participants |
| Sex: Female, Male Female | 23 Participants | 23 Participants | 46 Participants |
| Sex: Female, Male Male | 20 Participants | 21 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 44 | 42 / 42 |
| serious Total, serious adverse events | 26 / 44 | 13 / 42 |
Outcome results
Primary
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.
Time frame: At least 12 months since start of treatment.
Population: MITT
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD6244 + Docetaxel | Overall Survival | Withdrawn | 1 Participants |
| AZD6244 + Docetaxel | Overall Survival | Died | 29 Participants |
| AZD6244 + Docetaxel | Overall Survival | Alive at DCO | 13 Participants |
| Placebo + Docetaxel | Overall Survival | Alive at DCO | 13 Participants |
| Placebo + Docetaxel | Overall Survival | Withdrawn | 0 Participants |
| Placebo + Docetaxel | Overall Survival | Died | 27 Participants |
p-value: 0.206980% CI: [0.56, 1.14]Regression, Cox
Secondary
Alive and Progression-Free at 6 Months
Percentage of patients alive and progression-free at 6 months
Time frame: 6 months after first dose of treatment
Population: MITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD6244 + Docetaxel | Alive and Progression-Free at 6 Months | 37.1 percentage |
| Placebo + Docetaxel | Alive and Progression-Free at 6 Months | 15.8 percentage |
p-value: 0.015880% CI: [0.37, 0.78]Log Rank
Secondary
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.
Time frame: 6 weeks after first dose of treatment
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD6244 + Docetaxel | Change From Baseline in Tumour Size at 6 Week. | -16.98 Percentage change from baseline |
| Placebo + Docetaxel | Change From Baseline in Tumour Size at 6 Week. | 0.05 Percentage change from baseline |
p-value: 0.00480% CI: [-25.2, -8.86]ANCOVA
Secondary
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.
Time frame: 12 weeks
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD6244 + Docetaxel | Change From Baseline in Tumour Size at Week 12 | -19.38 Percent change from baseline |
| Placebo + Docetaxel | Change From Baseline in Tumour Size at Week 12 | 6.62 Percent change from baseline |
p-value: 0.00480% CI: [-38.34, -13.7]ANCOVA
Secondary
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.
Time frame: At least 12 months after start of treatment
Population: MITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD6244 + Docetaxel | Duration of Response | 193.4 Days | Standard Error 0.207 |
| Placebo + Docetaxel | Duration of Response | NA Days | — |
Secondary
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.
Time frame: At least 12 months after start of treatment
Population: MITT
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD6244 + Docetaxel | Objective Response Rate | Response | 16 Participants |
| AZD6244 + Docetaxel | Objective Response Rate | No response | 27 Participants |
| Placebo + Docetaxel | Objective Response Rate | Response | 0 Participants |
| Placebo + Docetaxel | Objective Response Rate | No response | 40 Participants |
p-value: <0.000195% CI: [23, 53]Fisher Exact
Secondary
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.
Time frame: At least 12 months after start of treatment
Population: MITT
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD6244 + Docetaxel | Progression Free Survival | Progression | 35 Participants |
| AZD6244 + Docetaxel | Progression Free Survival | Prog. after >2 missed or non-eval. assessments | 1 Participants |
| AZD6244 + Docetaxel | Progression Free Survival | No progression | 7 Participants |
| Placebo + Docetaxel | Progression Free Survival | Progression | 36 Participants |
| Placebo + Docetaxel | Progression Free Survival | Prog. after >2 missed or non-eval. assessments | 2 Participants |
| Placebo + Docetaxel | Progression Free Survival | No progression | 2 Participants |
p-value: 0.013880% CI: [0.42, 0.79]Regression, Cox