A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung

Sponsor

University Health Network, Toronto (Other)

Overall Status

Completed

CT.gov ID

NCT02185690

Collaborator

Novartis Pharmaceuticals (Industry)

Enrollment

Locations

Arm

17.7

Actual Duration (Months)

3.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients.

There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.

Condition or Disease	Intervention/Treatment	Phase
Lungcancer	Drug: Binimetinib Drug: Pemetrexed Drug: Carboplatin	Phase 1

Detailed Description

OBJECTIVES

1.1 Primary Objectives

To assess the safety of MEK162 administered in combination with carboplatin and pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).
To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a continuous dosing schedule together with pemetrexed and carboplatin administered on a 3-weekly schedule as first line treatment in advanced NSCLC.
To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.

1.2 Secondary Objectives

To characterize the population pharmacokinetics of MEK162 administered in combination with carboplatin and pemetrexed (Phase I).
To explore relationships between KRAS mutation (and sub-types) and additional genomic mutations and objective clinical response.

1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined in section 4.3) as measured with NCI CTC AE v4.

Phase Ib

• Objective response rate (ORR) as per RECIST v1.1.

Secondary Phase I • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs.

Phase Ib

Evaluation of response rate (RR), progression-free survival (PFS) and disease control rate (DCR) for patients with and without KRAS mutation in tumor tissue.
Exploratory analysis of KRAS mutation sub-type.

Exploratory end-points

• A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung

Actual Study Start Date :

Jan 11, 2018

Actual Primary Completion Date :

Jul 4, 2019

Actual Study Completion Date :

Jul 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Binimetinib efficacy/safety This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed. Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma. Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype. The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.	Drug: Binimetinib Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease. MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule. Other Names: MEK162 Drug: Pemetrexed 4-6 cycles given intravenously in combination with carboplatin as per standard therapy. Other Names: Alimta Drug: Carboplatin 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy. Other Names: Paraplatin AG

Arm

Intervention/Treatment

Other: Binimetinib efficacy/safety

This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed. Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma. Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype. The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.

Drug: Binimetinib

Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease. MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.

Other Names:

MEK162

Drug: Pemetrexed

4-6 cycles given intravenously in combination with carboplatin as per standard therapy.

Other Names:

Alimta

Drug: Carboplatin

4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.

Other Names:

Paraplatin AG

Outcome Measures

Primary Outcome Measures

Development of dose-limiting toxicity (DLT) in milligrams per day. [18 weeks of treatment]
To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.

Secondary Outcome Measures

Objective response rate (ORR) as per RECIST v1.1. [18 weeks of treatment & 30 days followup]
The size of tumours in centimetres before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.

Other Outcome Measures

Clearance (millilitres per minute)of MEK162 [18 weeks of treatment]
Exploratory end-points • A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.
Progression Free Survival measured in weeks. [18 weeks of treatment and 30 days of Follow up]
• Evaluation progression-free survival (PFS) for patients with and without KRAS mutation in tumor tissue. Number of weeks survived before progression or death.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects eligible for enrolment on the study must meet all of the following criteria:
Patients with histologically confirmed non-squamous EGFR wild-type, ALK-rearrangement negative carcinoma of lung. Patients with neuroendocrine carcinoma, mixed small and non-small cell carcinoma or squamous carcinoma are not eligible.
Tissue available for KRAS mutation status analysis.
Patients must have metastatic disease (Incurable stage IIIB/stage IV).
Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable by RECIST v1.1 as follows (Eisenhauer et al.):

CT-scan, physical exam ≥10 mm Chest X-ray ≥20 mm Lymph node short axis ≥15 mm

All radiology studies must be performed within 28 days prior to registration (35 days if negative).
Lesions in previously irradiated areas should not be selected unless there is clear evidence of progression in such lesions.
Patients may not have received any prior systemic treatment for metastatic NSCLC. Patients who have received adjuvant treatment or chemoradiation for stage III disease should have completed this ≥12 months prior to study enrollment.
Patients with stable CNS metastases are permitted if stability of disease is documented with imaging ≥28 days after treatment completion, are and off corticosteroids by day 1 of study treatment.
Patients may have had prior malignancy if definitively treated and/or, in the opinion of the investigator, the only active malignancy is NSCLC. Patients with mixed small cell lung cancer histology are excluded. Patients who have received radiotherapy to

30% bone marrow are excluded. Consult PI if unsure whether second malignancies meet requirements specified above.

In patients treated for other malignancy, all prior treatment-related toxicities must be CTCAE v4.0 ≤ Grade 1 (except alopecia) at the time of enrollment.
Able to swallow and retain oral medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
Patients receiving medications or substances that are inhibitors or inducers of CYP1A2, CYP2A19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs must be used with caution (Appendix C).

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx;

Patients must be aged ≥18 years.
Eastern Cooperative Oncology Group (ECOG) performance status ≤1
Adequate organ and laboratory parameters, defined below.
Laboratory Requirements - within 7 days prior to enrollment:

Haematology: absolute granulocytes ≥1.5 × 109/L platelets ≥100 × 109/L Biochemistry:

bilirubin ≤1.25 × institutional upper limit of normal AST(SGOT) ≤2.5 × institutional upper limit of normal /ALT(SGPT) or ≤5 × institutional upper limit of normal in the presence of liver metastases

creatinine clearance ≥45 mL/min/1.73 m2

-Patients must be able to provide Informed Consent based on the details below:

absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). Patients with prior deep venous thrombosis or pulmonary embolism are permitted.
Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR such as:
Evidence of new optic disc cupping
Evidence of new visual field defects on automated perimetry
Intraocular pressure >21mmHg as measured by tonography
Any serious and/or unstable pre-existing medical (aside from malignancy exception), psychiatric disorder, or other conditions that could interfere with subjects' safety, obtaining informed consent or compliance to the study procedures, in the opinion of the PI.
History of interstitial lung disease or pneumonitis.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal metabolic or cardiac disease).
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or baseline QTcB interval ≥480 msec.
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months or cardiac metastases.
History or evidence of current clinically significant uncontrolled arrhythmias.
History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association (NYHA).
Known positivity for Hepatitis B surface antigen or Hepatitis C antibody.
Known Human Immunodeficiency Virus (HIV) infection.
Treatment refractory hypertension defined as a blood pressure systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy.
Subjects with intra-cardiac defibrillators or permanent pacemakers.
Pregnant or nursing (lactating) women are excluded.
Female patient of child bearing potential must have a negative serum or urine pregnancy test.
Women of child-bearing potential must agree to use of appropriate contraceptive methods throughout the study and for 120 days after, These methods include
Total abstinence or 2 barrier methods or a barrier method plus hormonal method from visit 1 to 120 days after the last dose of treatment.
Men must agree to use an appropriate method of contraception starting with first dose of study drug through 120 days after the last dose of treatment (see above).
Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and should be followed by repeat audiograms prior to cycle

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G1Z2
2	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
3	The Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario	Canada	K1G 3Y9
4	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G2M9

Sponsors and Collaborators

University Health Network, Toronto
Novartis Pharmaceuticals

Investigators

Principal Investigator: Natasha Leighl, MD, UHN - Princess Margaret Cancer Centre
Study Director: Amit Oza, MD, Princess Margaret Cancer Centre Drug Development Program