Selumetinib in Patients Receiving Pemetrexed and Platinum-based Chemotherapy in Advanced or Metastatic KRAS Wildtype or Unknown Non-Squamous NSCLC

Phase 2

Completed

Conditions: Non-Small Cell Lung Cancer

Interventions: Drug: Selumetinib
Drug: Pemetrexed
Drug: Cisplatin
Drug: Carboplatin

Registration Number: NCT02337530

Lead Sponsor: Canadian Cancer Trials Group

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

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 exclusion criteria above, must have a baseline LVEF ≥ 50%.
Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
Patients who have neuropathy > grade 1 or other conditions precluding treatment with the standard chemotherapy regimen planned. Consult CCTG for patients with localised neuropathies as such patients may be eligible.
Patients who have significant gastrointestinal disease and who are unable to swallow capsules.
Patients on potent inhibitors or inducers of CYP3A4/5, CYP2C19 and CYP1A2 (must have discontinued within 2 weeks prior to randomization or 3 weeks for St. John's Wort). Patients who do not agree to avoid the ingestion of large amounts of grapefruit and Seville oranges (and other products containing these fruits, e.g. grapefruit juice or marmalade) and not take vitamin E supplements or multivitamin supplements.

Patients who require oral anticoagulants (Coumadin) are eligible provided there is increased vigilance with respect to INR monitoring upon initiation of dosing with selumetinib. If medically appropriate and treatment available, the investigator should consider switching these patients to LMW heparin.

Patients with current or past history of central serous retinopathy or retinal vein occlusion, high intraocular pressure (≥ 21mm) or uncontrolled glaucoma (irrespective of IOP). Patients with visual symptoms should undergo ophthalmologic examination prior to randomization.
Pregnant or lactating women. Women of childbearing potential must have a urine pregnancy test proven negative within 7 days prior to randomization. Men and women of childbearing potential must agree to use adequate contraception
Patients who do not agree to avoid excessive sun exposure and use adequate sunscreen protection.
Selumetinib-specific precautions for patients of Asian ethnicity:

Plasma exposure of selumetinib (Cmax and AUC) is higher, at a population level, in subjects of Asian descent by approximately 1.5- to 2-fold in non-Japanese Asians and Japanese subjects, compared with Western subjects. However, there is overlap in the range of exposure experienced by Asian and Western subjects and the higher average plasma exposure was not associated with a change in the tolerability profile of single dose selumetinib.

Investigators should make a clinical judgment as to whether the potential risk of experiencing higher selumetinib plasma exposure and potential adverse events outweighs the potential benefit of treatment with selumetinib.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	Pemetrexed	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
Arm A	Selumetinib	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
Arm A	Cisplatin	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
Arm A	Carboplatin	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
Arm B	Selumetinib	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
Arm B	Pemetrexed	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
Arm B	Cisplatin	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
Arm B	Carboplatin	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
Arm C	Pemetrexed	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
Arm C	Cisplatin	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
Arm C	Carboplatin	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

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (12): Mount Sinai Hospital
🇨🇦
Toronto, Ontario, Canada
CHUM - Hopital Notre-Dame
🇨🇦
Montreal, Quebec, Canada
Tom Baker Cancer Centre
🇨🇦
Calgary, Alberta, Canada
Cross Cancer Institute
🇨🇦
Edmonton, Alberta, Canada
BCCA - Vancouver Cancer Centre
🇨🇦
Vancouver, British Columbia, Canada
Ottawa Hospital Research Institute
🇨🇦
Ottawa, Ontario, Canada
Juravinski Cancer Centre at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Cancer Centre of Southeastern Ontario at Kingston
🇨🇦
Kingston, Ontario, Canada
Lakeridge Health Oshawa
🇨🇦
Oshawa, Ontario, Canada
University Health Network
🇨🇦
Toronto, Ontario, Canada
BCCA - Abbotsford Centre
🇨🇦
Abbotsford, British Columbia, Canada
Regional Health Authority B, Zone 2
🇨🇦
Saint John, New Brunswick, Canada