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; KRAS mutation
Brief summary
The purpose of this study is to assess the efficacy of selumetinib in combination with docetaxel (75mg/m2) vs placebo in combination with docetaxel (75mg/m2) in patients with locally advance or metastatic NSCLCs that harbor mutations of KRAS. This study will also assess the PK, safety, patient reported outcomes (PRO) and tolerability profile of the selumetinib/docetaxel combination, compared to placebo in combination with docetaxel
Detailed description
A Phase III, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy and Safety of Selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) in Combination with Docetaxel, in Patients receiving second line treatment for KRAS Mutation-Positive Locally Advanced or Metastatic Non Small Cell Lung Cancer (Stage IIIB - IV) (SELECT-1)
Interventions
DRUGSelumetinib
Three 25 mg selumetinib capsules (Hyd-Sulfate) be administered orally, twice daily, (total dose 75 mg dose bd) on an uninterrupted schedule.
DRUGDocetaxel
Docetaxel 75 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 in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle.
DRUGPegylated G-CSF
All patients will receive pegylated Granulocyte Colony Stimulating Factor (G-CSF) at least 24 hours after administration of every docetaxel dose and not within 14 days prior to the next docetaxel administration.
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) * KRAS mutation positive tumour sample as determined by the designated testing 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. * Receiving or have received systemic anti-cancer therapy within 30 days prior to starting study treatment * Other concomitant anti-cancer therapy agents excepts steroids * Prior treatment with a Mitogen-Activated protein Kinase (MEK) inhibitor or any docetaxel-containing regimen (prior treatment with paclitaxel is acceptable). * Last radiation therapy within 4 weeks prior 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) | Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI) | Progression free survival is defined as the time from randomisation until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Measured at baseline until date of death due to any cause. Estimated final completion : approximately 3.5 years after FSI | Overall Survival is defined as the time from the date of randomisation until death due to any cause. |
| Objective Response Rate (ORR) | Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI) | ORR is defined as the number (%) of subjects with at least one overall visit response of complete response (CR) or partial response (PR). Per RECIST v1.1 for target lesions and assessed by CT/MRI: CR - disappearance of all target lesions; PR - \>=30% decrease in the sum of the longest diameter of target lesion. (Non-target lesion and new lesion results are also taken into account for the overall visit result) |
| Duration of Response (DoR) | Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI) | Duration of response is defined as the time from the date of first documented response until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression) |
| Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI) | The symptom improvement rate will be defined as the number (%) of patients with two consecutive assessments at least 18 days apart (ie 21 days allowing a visit window of 3 days) which showed a clinically meaningful improvement in symptoms from baseline (defined as a decrease in the ASBI from baseline ≥10). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index. |
| Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI) | Time to symptom progression will be defined as the time from randomization until the date of first clinically meaningful symptom deterioration (defined as an increase in the ASBI from baseline ≥10), or death (by any cause). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Peru, Poland, Portugal, Romania, Russia, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_CHAIRGabriella Mariani, MD
AstraZeneca UK, MSD
PRINCIPAL_INVESTIGATORPasi Jänne, MD
Dana-Faber Cancer Institute, USA
Participant flow
Recruitment details
This study started with an assessment visit where a tumour KRAS mutation assessment was performed, eligibility assessments were performed and informed consent obtained. Eligible patients were randomised at the next visit. Patients then received double-blinded study treatment, were seen and assessments performed until objective disease progression.
Pre-assignment details
Eligible patients randomised in a ratio of 1:1 to receive selumetinib (AZD6244; ARRY-142886) 75 mg bd in combination with docetaxel 75 mg/m2 or placebo in combination with docetaxel 75 mg/m2. They were stratified based on their WHO performance status and tumour histology. 510 patients enrolled and 510 randomised.
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib + Docetaxel Three 25mg selumetinib capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle | 254 |
| Placebo + Docetaxel Three placebo capsules will be administered orally uninterrupted twice daily in combination with docetaxel 75 mg/m2 intravenously administered on day 1 of each 21 day cycle. | 256 |
| Total | 510 |
Baseline characteristics
| Characteristic | Selumetinib + Docetaxel | Placebo + Docetaxel | Total |
|---|---|---|---|
| Age, Continuous | 61.9 Years STANDARD_DEVIATION 8.48 | 60.9 Years STANDARD_DEVIATION 8.08 | 61.4 Years STANDARD_DEVIATION 8.3 |
| Age, Customized <65 years | 157 Participants | 173 Participants | 330 Participants |
| Age, Customized >=65 years | 97 Participants | 83 Participants | 180 Participants |
| Ethnic group Hispanic or Latino | 14 Participants | 15 Participants | 29 Participants |
| Ethnic group Not Hispanic or Latino | 240 Participants | 241 Participants | 481 Participants |
| Race American Indian or Alaska Native | 3 Participants | 2 Participants | 5 Participants |
| Race Asian | 1 Participants | 4 Participants | 5 Participants |
| Race Black or African American | 5 Participants | 1 Participants | 6 Participants |
| Race Other | 4 Participants | 6 Participants | 10 Participants |
| Race White | 241 Participants | 243 Participants | 484 Participants |
| Sex: Female, Male Female | 96 Participants | 111 Participants | 207 Participants |
| Sex: Female, Male Male | 158 Participants | 145 Participants | 303 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 235 / 254 | 244 / 251 |
| serious Total, serious adverse events | 82 / 254 | 124 / 251 |
Outcome results
Primary
Progression-Free Survival (PFS)
Progression free survival is defined as the time from randomisation until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)
Time frame: Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)
Population: Full analysis set (FAS) population comprised of all randomised patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib + Docetaxel | Progression-Free Survival (PFS) | 3.9 Months |
| Placebo + Docetaxel | Progression-Free Survival (PFS) | 2.8 Months |
p-value: 0.435595% CI: [0.77, 1.12]Log Rank
Secondary
Duration of Response (DoR)
Duration of response is defined as the time from the date of first documented response until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression)
Time frame: Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)
Population: Full analysis set (FAS) population comprised of all randomised patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib + Docetaxel | Duration of Response (DoR) | 88.0 Days |
| Placebo + Docetaxel | Duration of Response (DoR) | 136.0 Days |
Secondary
Objective Response Rate (ORR)
ORR is defined as the number (%) of subjects with at least one overall visit response of complete response (CR) or partial response (PR). Per RECIST v1.1 for target lesions and assessed by CT/MRI: CR - disappearance of all target lesions; PR - \>=30% decrease in the sum of the longest diameter of target lesion. (Non-target lesion and new lesion results are also taken into account for the overall visit result)
Time frame: Measured at baseline until the date of first documented objective disease progression. Estimated final completion : approximately 3 years after first subject in (FSI)
Population: Full analysis set (FAS) population comprised of all randomised patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib + Docetaxel | Objective Response Rate (ORR) | 51 Number of responders |
| Placebo + Docetaxel | Objective Response Rate (ORR) | 35 Number of responders |
p-value: 0.051595% CI: [1, 2.62]Regression, Logistic
Secondary
Overall Survival (OS)
Overall Survival is defined as the time from the date of randomisation until death due to any cause.
Time frame: Measured at baseline until date of death due to any cause. Estimated final completion : approximately 3.5 years after FSI
Population: Full analysis set (FAS) population comprised of all randomised patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib + Docetaxel | Overall Survival (OS) | 8.7 Months |
| Placebo + Docetaxel | Overall Survival (OS) | 7.9 Months |
p-value: 0.643195% CI: [0.85, 1.3]Log Rank
Secondary
Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS)
The symptom improvement rate will be defined as the number (%) of patients with two consecutive assessments at least 18 days apart (ie 21 days allowing a visit window of 3 days) which showed a clinically meaningful improvement in symptoms from baseline (defined as a decrease in the ASBI from baseline ≥10). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.
Time frame: Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)
Population: Full analysis set (FAS) patients who have a baseline ASBI score \>= 10
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib + Docetaxel | Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | 49 Number of patients with improvements |
| Placebo + Docetaxel | Symptom Improvement Rate Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | 46 Number of patients with improvements |
p-value: 0.500795% CI: [0.74, 1.86]Regression, Logistic
Secondary
Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS)
Time to symptom progression will be defined as the time from randomization until the date of first clinically meaningful symptom deterioration (defined as an increase in the ASBI from baseline ≥10), or death (by any cause). LCSS-Lung Cancer Symptom Scale; ASBI-Average symptom burden index.
Time frame: Measured from date of randomisation until 30 days post treatment discontinuation or 30 days post progression (if study treatment is discontinued before progression). Estimated final completion : approximately 3 years after first subject in (FSI)
Population: Full analysis set (FAS) patients who have a baseline ASBI score \<= 90
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selumetinib + Docetaxel | Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | 1.6 Months |
| Placebo + Docetaxel | Time to Symptom Progression Using Average Symptom Burden Index (ASBI) of the Lung Cancer Symptom Scale (LCSS) | 1.3 Months |
p-value: 0.343895% CI: [0.74, 1.11]Log Rank