Locally Advanced or Metastatic Non Small Cell Lung Cancer Stage IIIb - IV
Conditions
Keywords
Mitogen-Activated Protein Kinase Kinase inhibitor, Non Small Cell Lung Cancer, Metastatic, Second line treatment for Non Small Cell Lung Cancer
Brief summary
The purpose of this study is to treat patients with locally advanced or metastatic NSCLC with a combination therapy of selumetinib and two different doses of docetaxel 75mg/m2 or 60 mg/m2 vs placebo and compare how well each dose affects how their cancer responds. It will also help us to understand the tolerability profile of the different dosing regimens in these patients
Detailed description
A Phase II, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy and Safety of Selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) in Combination with Docetaxel, Compared with Placebo in Combination with Docetaxel, in Patients receiving second line treatment for Locally Advanced or Metastatic Non Small Cell Lung Cancer (Stage IIIB - IV)
Interventions
DRUGSelumetinib 75 mg
Three selumetinib capsules (Hyd-Sulfate) 25 mg will be administered orally, twice daily, (75 mg dose bd) on an uninterrupted schedule.
Docetaxel 75 mg/m2 will be administered intravenously on day 1 of each 21 day cycle.
Docetaxel 60 mg/m2 will be administered intravenously on day 1 of each 21 day cycle.
DRUGPlacebo
Three placebo capsules will be administered orally uninterrupted twice daily.
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
* Provision of signed, written and dated informed consent prior to any study specific procedures * Male or female, aged 18 years or older * Histological or cytological confirmation of locally advanced or metastatic NSCLC (IIIB-IV) * Prospective confirmation of KRAS mutation negative status as determined via an AZ approved laboratory * Failure of 1st line anti-cancer therapy due to radiological documentation of disease progression in advanced disease or subsequent relapse of disease following 1st line therapy
Exclusion criteria
* Mixed small cell and non-small cell lung cancer histology * Received \>1 prior anti-cancer drug regimen for advanced or metastatic NSCLC. Patients who develop disease progression while on switch maintenance therapy (maintenance using an agent not in the first-line regimen) will not be eligible. * Other concomitant anti-cancer therapy agents except steroids * Prior treatment with a MEK (Mitogen-Activated Protein Kinase) inhibitor or any docetaxel-containing regimen (prior treatment with paclitaxel is acceptable) * The last radiation therapy within 4 weeks prior to starting study treatment, or limited field of radiation for palliation within 7 days of the first dose of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline and then every 6 weeks after randomization until objective disease progression, up to 29 months (at the time of the analysis) | Median time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours (RECIST v1.1): \>= 20% increase in the sum of diameters of Target Lesions (TL) and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of Non TLs or a new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Following progression, survival status was collected every 8 weeks until death, withdrawal of consent, or end of study, whichever occurred first, up to 29 months (at the time of the analysis) | The time from 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 |
Countries
Brazil, Bulgaria, France, Germany, Hungary, Netherlands, Poland, United States
Participant flow
Recruitment details
Initially the study protocol allowed patients with KRASm (KRAS mutation positive), KRAS NMD (No mutation detected) and KRAS mutation status unknown. Recruitment was put on hold after the 77th patient was randomised in September 2013, to allow a protocol amendment to include only patients with centrally confirmed KRAS NMD NSCLC to be enrolled.
Pre-assignment details
The Protocol Section Enrolment Number of 466 includes 1 patient who was pre-screened twice. Of the 465 unique pre-screened patients, 337 gave informed consent and of these, 212 were randomised. 211 received at least 1 dose of treatment and were included in the safety analysis set. Patients received selumetinib (AZD6244; ARRY-142886) or Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Docetaxel 75 mg/m^2 Oral placebo BD and intravenous docetaxel on day 1 of every 21 day cycle | 43 |
| Selumetinib 75 mg BD + Docetaxel 60 mg/m^2 Oral selumetinib BD and intravenous docetaxel on day 1 of every 21 day cycle | 85 |
| Selumetinib 75 mg BD + Docetaxel 75 mg/m^2 Oral selumetinib BD and intravenous docetaxel on day 1 of every 21 day cycle | 84 |
| Total | 212 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Did not receive treatment | 0 | 1 | 0 |
| Overall Study | Discontinued Selumetinib/Placebo | 37 | 77 | 75 |
| Overall Study | Ongoing Selumetinib/Pbo at data cut-off | 6 | 7 | 9 |
Baseline characteristics
| Characteristic | Placebo + Docetaxel 75 mg/m^2 | Selumetinib 75 mg BD + Docetaxel 60 mg/m^2 | Selumetinib 75 mg BD + Docetaxel 75 mg/m^2 | Total |
|---|---|---|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 7.75 | 62.4 Years STANDARD_DEVIATION 8.53 | 60.4 Years STANDARD_DEVIATION 9.35 | 61.8 Years STANDARD_DEVIATION 8.77 |
| KRAS Mutation Status at Baseline KRAS mutation positive | 10 Participants | 15 Participants | 19 Participants | 44 Participants |
| KRAS Mutation Status at Baseline KRAS mutation unknown | 3 Participants | 8 Participants | 11 Participants | 22 Participants |
| KRAS Mutation Status at Baseline KRAS no mutation detected (NMD) | 30 Participants | 62 Participants | 54 Participants | 146 Participants |
| Race/Ethnicity, Customized Black Or African American | 0 Participants | 5 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 41 Participants | 80 Participants | 78 Participants | 199 Participants |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 26 Participants | 61 Participants |
| Sex: Female, Male Male | 27 Participants | 66 Participants | 58 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 43 | 80 / 84 | 83 / 84 |
| serious Total, serious adverse events | 16 / 43 | 40 / 84 | 38 / 84 |
Outcome results
Primary
Progression Free Survival (PFS)
Median time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours (RECIST v1.1): \>= 20% increase in the sum of diameters of Target Lesions (TL) and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of Non TLs or a new lesion.
Time frame: Baseline and then every 6 weeks after randomization until objective disease progression, up to 29 months (at the time of the analysis)
Population: Full Analysis Set (All randomised patients). Progression events that do not occur within 14 weeks of the last evaluable assessement are censored and therefore excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Docetaxel 75 mg/m^2 | Progression Free Survival (PFS) | 4.3 Months |
| Selumetinib 75 mg BD + Docetaxel 60 mg/m^2 | Progression Free Survival (PFS) | 3.0 Months |
| Selumetinib 75 mg BD + Docetaxel 75 mg/m^2 | Progression Free Survival (PFS) | 4.2 Months |
p-value: 0.58490% CI: [0.8, 1.61]Cox Proportional Hazards
p-value: 0.6990% CI: [0.65, 1.31]Cox Proportional Hazards
Secondary
Overall Survival (OS)
The time from 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
Time frame: Following progression, survival status was collected every 8 weeks until death, withdrawal of consent, or end of study, whichever occurred first, up to 29 months (at the time of the analysis)
Population: Full Analysis Set (All randomised patients)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Docetaxel 75 mg/m^2 | Overall Survival (OS) | 11.5 Months |
| Selumetinib 75 mg BD + Docetaxel 60 mg/m^2 | Overall Survival (OS) | 5.7 Months |
| Selumetinib 75 mg BD + Docetaxel 75 mg/m^2 | Overall Survival (OS) | 7.7 Months |
p-value: 0.48590% CI: [0.8, 1.78]Cox Proportional Hazards
p-value: 0.12690% CI: [0.97, 2.13]Cox Proportional Hazards