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 (MEK162)

April 1, 2021 updated by: University Health Network, Toronto

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G1Z2
        • Cross Cancer Institute
    • Ontario
      • Hamilton, Ontario, Canada, L8V 5C2
        • Juravinski Cancer Centre
      • Ottawa, Ontario, Canada, K1G 3Y9
        • The Ottawa Hospital Regional Cancer Centre
      • Toronto, Ontario, Canada, M5G2M9
        • Princess Margaret Cancer Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 2.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Development of dose-limiting toxicity (DLT) in milligrams per day.
Time Frame: 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.
18 weeks of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR) as per RECIST v1.1.
Time Frame: 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.
18 weeks of treatment & 30 days followup

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clearance (millilitres per minute)of MEK162
Time Frame: 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.
18 weeks of treatment
Progression Free Survival measured in weeks.
Time Frame: 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.
18 weeks of treatment and 30 days of Follow up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 11, 2018

Primary Completion (Actual)

July 4, 2019

Study Completion (Actual)

July 4, 2019

Study Registration Dates

First Submitted

April 9, 2014

First Submitted That Met QC Criteria

July 3, 2014

First Posted (Estimate)

July 9, 2014

Study Record Updates

Last Update Posted (Actual)

April 2, 2021

Last Update Submitted That Met QC Criteria

April 1, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CMEK162ACA02T (Other Identifier: Novartis Pharmaceuticals Canada Inc)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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