A Phase I/IB Trial of MEK162 in Combination With Erlotinib in NSCLC Harboring KRAS or EGFR Mutation

A Phase I/IB Trial of MEK162 in Combination With Erlotinib in Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS or EGFR Mutation

The main purpose of this study is to find out if the drugs MEK162 and erlotinib (Tarceva) given in combination are safe and have beneficial effects in patients who have NSCLC.

The U.S. Food and Drug Administration (FDA) has not approved MEK162 for use to treat NSCLC. Erlotinib is an FDA approved drug for the treatment of Non-Small Cell Lung Cancer.

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer; Lung Cancer
• Intervention / Treatment: Drug: MEK162; Drug: Erlotinib

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eligible patients will have a histologic or cytologic diagnosis of NSCLC of the advanced stage (IV), with no known curative treatment options.
• Have a tissue or blood proven KRAS or EGFR mutation confirmed in a Clinical Laboratory Improvement Amendments (CLIA)certified lab (only required in the Phase IB expansion cohort).
• For Phase I/Ib enrollment, Patients with a CLIA confirmed EGFR mutation may be treatment naïve. All other patients must have received at least one previous line of therapy. There will be no limits to prior lines of treatment for the Phase 1 portion.
• Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1
• There will be no limits to prior lines of treatment.
• At least one measurable site of disease (as defined by Response Evaluation Criteria in Solid Tumors), or other disease specific response assessment criteria, as appropriate (RECIST 1.1).
• Have discontinued all previous systemic therapies and recovered from side effects due to systemic treatment for more than 14 days prior to starting on treatment.
• Have discontinued all previous biologic therapies and recovered from side effects due to biologic treatment for more than 14 days prior to starting on treatment.
• Have discontinued all previous external beam radiation therapy and recovered from side effects due to radiation therapy for more than 14 days prior to starting on treatment.
• Have archival tissue sample (if available) or be willing to undergo a repeat biopsy (if feasible).
• Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential (WOCBP).
• Adequate organ function and lab parameters
• Prior to any screening or invasive procedure, written informed consent must be obtained.

Exclusion Criteria:

• Does not have adequate cardiac function
• Patients with documented central nervous system or leptomeningeal metastasis (brain metastasis) at time of study entry. Patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic.
• Any other serious uncontrolled medical disorder or active infection that would impair the patient's ability to receive study treatment
• Prior use of MEK162 or concurrent use of other approved anticancer or investigational agents. Patients treated with prior EGFR TKI therapy (including erlotinib) are allowed to enroll.
• Gastrointestinal disease that precludes absorption
• History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO)
• Any ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO by the ophthalmologist
• History of another malignancy within 2 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix
• Patients who have received prior anti-cancer treatment within the following time frames: systemic therapies less than 14 days prior to starting on treatment; radiation therapy less than 14 days prior to starting on treatment; biologic therapy less than 14 days prior to starting on treatment.
• Patients who have not recovered from side effects of prior anti-cancer treatment to less than or equal to grade 1 toxicity according to Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 within the following time frames: Received previous systemic therapy and has not recovered from side effects for more than 14 days prior to starting on treatment; Received previous radiation therapy and has not recovered from side effects for more than 14 days prior to starting on treatment; Received previous biologic therapy and has not recovered from side effects for more than 14 days prior to starting on treatment
• Have undergone major surgery < 4 weeks of initiation of study medication or who have not recovered from side effects of such procedure
• Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data
• Women who are pregnant or nursing
• Women of child-bearing potential (WOCBP) and males who have not been sterilized by vasectomy or other means with partners who are WOCBP, UNLESS the women are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method.
• Unwilling or unable to comply with the protocol
• Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection
• History of Gilbert's syndrome
• Neuromuscular disorders that are associated with elevated creatinine kinase (CK)
• Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment.
• Previous treatment with any substrate of CYP2B6 enzyme < 14 days prior to initiation of investigational products

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I - Dose Escalation; For the Phase I portion, patients will start MEK162 by mouth (p.o.) on cycle 1, day 1 and erlotinib on cycle 1, day 2. The MEK162 will be dosed once daily (QD) or twice (b.i.d.), and erlotinib will be dosed daily (QD) on a 28-day cycle. Phase I will be followed by an expansion Phase Ib.	Drug: MEK162; Treatment as outlined in study arms.; Other Names: ARRY-162; ARRY-438162; Mitogen Activated Kinase (MEK) inhibitor; Drug: Erlotinib; Treatment as outlined in study arms.; Other Names: Tarceva; OSI-774; CP-358,774; Reversible tyrosine kinase inhibitor; Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
Experimental: Arm A: Dose Expansion; Phase Ib Arm A: EGFR Mutant Tumor Status. In the phase IB expansion cohort study there are 2 arms based on the presence of the EGFR (Arm A) or KRAS (Arm B) mutation. The treatments for each arm are the same: MEK162 (2 time a day) and erlotinib (once) daily on 28 day cycles.	Drug: MEK162; Treatment as outlined in study arms.; Other Names: ARRY-162; ARRY-438162; Mitogen Activated Kinase (MEK) inhibitor; Drug: Erlotinib; Treatment as outlined in study arms.; Other Names: Tarceva; OSI-774; CP-358,774; Reversible tyrosine kinase inhibitor; Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
Experimental: Arm B: Dose Expansion; Phase Ib Arm B: KRAS Mutant Tumor Status. In the phase IB expansion cohort study there are 2 arms based on the presence of the EGFR (Arm A) or KRAS (Arm B) mutation. The treatments for each arm are the same: MEK162 (2 time a day) and erlotinib (once) daily on 28 day cycles.	Drug: MEK162; Treatment as outlined in study arms.; Other Names: ARRY-162; ARRY-438162; Mitogen Activated Kinase (MEK) inhibitor; Drug: Erlotinib; Treatment as outlined in study arms.; Other Names: Tarceva; OSI-774; CP-358,774; Reversible tyrosine kinase inhibitor; Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose (MTD)	To evaluate the safety of MEK162 plus erlotinib in patients with advanced NSCLC by evaluating toxicities of therapy and establish a recommended phase IB dosing of MEK162 and erlotinib. Safety population: consists of all patients who received at least one dose of study drug and had at least one post-baseline safety assessment.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Progression Free Survival (PFS)	PFS is defined as the duration of time from the time of randomization to time of disease progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).	6 months
Number of Participants with Overall Survival (OS)	OS, defined as the time from study enrollment to death from any cause during the study duration.	3 years

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Array BioPharma
• Investigators: Principal Investigator: Jhanelle Gray, M.D., H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

Helpful Links

• Moffitt Cancer Center Clinical Trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2013
• Primary Completion (Actual): August 22, 2019
• Study Completion (Actual): August 22, 2019

Study Registration Dates

• First Submitted: May 17, 2013
• First Submitted That Met QC Criteria: May 17, 2013
• First Posted (Estimate): May 21, 2013

Study Record Updates

• Last Update Posted (Estimate): January 19, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: KRAS mutation; Non-Small Cell Lung Cancer (NSCLC); EGFR mutation; Epidermal growth factor receptor (EGFR); Kirsten rat sarcoma 2 viral oncogene homolog(KRAS); Advanced-stage IV
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Mitosis Modulators; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Mitogens
• Other Study ID Numbers: MCC-17361

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No