Non-Small Cell Lung Cancer
Conditions
Brief summary
The purpose of this study is to find out what effects a new drug, selumetinib, has on lung cancer when receiving standard chemotherapy with pemetrexed and platinum-based chemotherapy.
Detailed description
This research is being done to see whether selumetinib improves the results of standard chemotherapy. The standard or usual treatment for this disease is treatment with chemotherapy alone.
Interventions
DRUGSelumetinib
DRUGPemetrexed
DRUGCisplatin
DRUGCarboplatin
Sponsors
AstraZeneca
Canadian Cancer Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically and/or cytologically confirmed non-squamous, KRAS wildtype or unknown, non-small cell lung cancer that is stage IIIB or IV, metastatic or unresectable and for which standard curative measures do not exist. * All patients must have a formalin fixed paraffin embedded tumour block (from primary or metastatic tumour) available for correlative studies and must have provided informed consent for the release of the block for correlative studies. * Patients must have at least one site of disease which is unidimensionally measurable as follows: * Measurable disease defined as at least one target lesion that has not been irradiated or has progressed after radiation and can be accurately measured in at least one dimension by RECIST 1.1 criteria. * Chest X-ray ≥ 20 mm * CT/MRI scan (with slice thickness of \< 5 mm) ≥ 10 mm --\> longest diameter * Physical exam (using calipers) ≥ 10 mm * Lymph nodes by CT scan ≥ 15 mm --\> measured in short axis * Presence of clinically and/or radiologically documented disease (marker positive only patients are not eligible). All radiology studies must be performed within 28 days prior to randomization (within 35 days if negative). * Age ≥ 18 years. * ECOG performance status 0 or 1 * Previous Therapy Surgery: Previous major surgery is permitted provided it has been at least 14 days prior to patient randomization and that wound healing has occurred. Radiation: Prior external beam radiation is permitted provided a minimum of 4 weeks has elapsed between the last dose and enrollment to the trial. Chemotherapy and systemic therapy: Prior therapy with ALK inhibitors is permissible. Patients may not have received prior MEK inhibitors or any other tyrosine kinase inhibitor (including EGFR inhibitors of any kind). Patients may have received vaccines, immunotherapy or other agents that are not MEK/tyrosine kinase inhibitors in the adjuvant setting or for advanced or metastatic disease. Prior adjuvant platinum-based chemotherapy or combined chemoradiotherapy with curative intent is permissible provided completed at least one year prior to enrollment. No prior cytotoxic chemotherapy for advanced / metastatic disease is permissible. \- Laboratory Requirements (must be done within 7 days prior to randomization) Neutrophils ≥ 1.5 x 10\^9/L Platelets ≥ 100 x 10\^9/L Biochemistry: Creatinine Clearance\* ≥ 50 ml/min Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN (if liver metastases ≤ 5x UNL permissible providing ALP also ≤ 6 x UNL) \* Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by appropriate formula below: Females: GFR = 1.04 x (140-age) x weight in kg/serum creatinine in μmol/L Males: GFR = 1.23 x (140-age) x weight in kg/serum creatinine in μmol/L * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate * Patients must be accessible for treatment and follow-up. Patients randomized on this trial must be treated and followed at the participating centre * In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization
Exclusion criteria
* Patients with a history of other untreated malignancies or malignancies which required therapy within the past 2 years * No symptomatic brain metastases or spinal cord compression. Patients with asymptomatic brain/spinal cord metastasis who are not planned for radiation, or who have been treated and are stable off steroids (or on a decreasing dose) and anticonvulsants are eligible. * Patients with significant cardiac disease, including: * any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age) or mean resting corrected QT interval (QTc) \> 470 msec * uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy) * acute coronary syndrome within 6 months prior to starting treatment * angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy) * symptomatic heart failure (NYHA II-IV) * prior or current cardiomyopathy * atrial fibrillation with a ventricular rate \> 100 bpm at rest * severe valvular heart disease Patients with cardiac disease, who do not meet the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 2 years and 5 months. | Defined as percentage of participants with objective response over all participants randomized. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 2 years 5 months | Defined as the time from randomization to the first objective documentation of disease progression, defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or death due to any cause with patients who had not progressed or died at the time of final analysis censored on the date of the last tumour assessment. |
Countries
Canada
Participant flow
Recruitment details
Subjects were recruited between February 2015 and May 2017 from cancer centres in Canada.
Participants by arm
| Arm | Count |
|---|---|
| Intermittent Oral Selumatinib With Pemetrexed and Platinum Selumetinib: 75mg/ bid PO given on days 2-19 Pemetrexed: 500mg/m\^2 & Cisplatin or Carboplatin\*: AUC6: 75mg/m\^2 given on day 1 Schedule = q 21 days
\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG
Selumetinib
Pemetrexed
Cisplatin
Carboplatin | 20 |
| Continuous Oral Selumatinib With Pemetrexed and Platinum Selumetinib: 75mg/ bid PO given on days 1-21 (continuous) Pemetrexed: 500mg/m\^2 & Cisplatin\*: 75mg/m\^2 or carboplatin AUC 6 given on day 1 Schedule = q 21 days
\*\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG
Selumetinib
Pemetrexed
Cisplatin
Carboplatin | 21 |
| Pemetrexed and Platinum Alone Selumetinib: NOT GIVEN Pemetrexed: 500mg/m\^2 & Cisplatin\*: 75mg/m\^2 or carboplatin AUC6 given on day 1 Schedule = q 21 days
\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG
Pemetrexed
Cisplatin
Carboplatin | 21 |
| Total | 62 |
Baseline characteristics
| Characteristic | Intermittent Oral Selumatinib With Pemetrexed and Platinum | Continuous Oral Selumatinib With Pemetrexed and Platinum | Pemetrexed and Platinum Alone | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 11 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 10 Participants | 33 Participants |
| Age, Continuous | 68 years | 66 years | 65 years | 66 years |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 16 Participants | 18 Participants | 18 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 21 Participants | 21 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Canada | 20 participants | 21 participants | 21 participants | 62 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 11 Participants | 32 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 20 | 15 / 21 | 9 / 21 |
| other Total, other adverse events | 20 / 20 | 21 / 21 | 21 / 21 |
| serious Total, serious adverse events | 14 / 20 | 14 / 21 | 9 / 21 |
Outcome results
Primary
Objective Response Rate
Defined as percentage of participants with objective response over all participants randomized. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR.
Time frame: 2 years and 5 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intermittent Oral Selumatinib With Pemetrexed and Platinum | Objective Response Rate | Not Responded | 14 Participants |
| Intermittent Oral Selumatinib With Pemetrexed and Platinum | Objective Response Rate | Responded | 6 Participants |
| Continuous Oral Selumatinib With Pemetrexed and Platinum | Objective Response Rate | Responded | 14 Participants |
| Continuous Oral Selumatinib With Pemetrexed and Platinum | Objective Response Rate | Not Responded | 7 Participants |
| Pemetrexed and Platinum Alone | Objective Response Rate | Not Responded | 16 Participants |
| Pemetrexed and Platinum Alone | Objective Response Rate | Responded | 5 Participants |
p-value: 0.7395% CI: [0.28, 7.01]Fisher Exact
p-value: 0.0195% CI: [1.65, 24.8]Fisher Exact
Secondary
Progression Free Survival
Defined as the time from randomization to the first objective documentation of disease progression, defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or death due to any cause with patients who had not progressed or died at the time of final analysis censored on the date of the last tumour assessment.
Time frame: 2 years 5 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intermittent Oral Selumatinib With Pemetrexed and Platinum | Progression Free Survival | 7.2 months |
| Continuous Oral Selumatinib With Pemetrexed and Platinum | Progression Free Survival | 6.9 months |
| Pemetrexed and Platinum Alone | Progression Free Survival | 4.0 months |
p-value: 0.5695% CI: [0.42, 1.6]Log Rank
p-value: 0.4495% CI: [0.4, 1.49]Log Rank