Pembrolizumab and Trametinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer and KRAS Gene Mutations

• ClinicalTrials.gov Identifier: NCT03299088
• Recruitment Status: Active, not recruiting
• First Posted: October 2, 2017
• Last Update Posted: June 3, 2022
• Sponsor: University of California, Davis
• Collaborators: Merck Sharp & Dohme LLC; Novartis; National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of California, Davis

Study Description

Brief Summary:

This phase Ib trial studies the side effects of pembrolizumab and trametinib in treating patients with non-small cell lung cancer and KRAS gene mutations that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and trametinib may work better in treating patients with non-small cell lung cancer.

Condition or disease	Intervention/treatment	Phase
KRAS Gene Mutation; Metastatic Non-Squamous Non-Small Cell Lung Carcinoma; Recurrent Non-Squamous Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer AJCC v7	Biological: Pembrolizumab; Drug: Trametinib	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of pembrolizumab (MK-3475) when given in combination with trametinib in the proposed sequencing schemes in patients with advanced or metastatic non-small cell lung cancer with KRAS mutations.

SECONDARY OBJECTIVES:

To assess in a preliminary manner the clinical efficacy of these combinations with the proposed sequencing schemes including overall response rate and progression free survival.

TERTIARY OBJECTIVES:

To determine in an exploratory manner changes in PD-L1 expression as well as other immune correlates induced by mitogen-activated extracellular signal-regulated kinase (MEK) inhibition.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib Trial of Pembrolizumab (MK-3475) and Trametinib Focused on Advanced KRAS Mutant Non-small Cell Lung Cancer
• Actual Study Start Date: June 26, 2018
• Actual Primary Completion Date: January 28, 2021
• Estimated Study Completion Date: January 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (trametinib, pembrolizumab); Patients receive trametinib PO daily. Beginning on day 1 of course 2, patients also receive pembrolizumab IV over 30 minutes. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475; Drug: Trametinib; Given PO; Other Names: GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; Mekinist
Experimental: Arm B (pembrolizumab, trametinib); Patients receive pembrolizumab IV over 30 minutes on day 1. Beginning on day 1 of course 2, patients also receive trametinib PO daily. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475; Drug: Trametinib; Given PO; Other Names: GSK1120212; JTP-74057; MEK Inhibitor GSK1120212; Mekinist

Outcome Measures

Primary Outcome Measures :

1. Incidence of dose-limiting toxicity (DLT) of pembrolizumab and trametinib per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 6 weeks ]
   The occurrence of toxicities during the first two cycles (i.e. after completion of the lead in cycle and the first cycle where both pembrolizumab and trametinib are administered) will be considered a DLT, if judged by the Investigator to be possibly, probably or definitely related to study drug administration. Adverse events will be summarized descriptively by type and by severity, with number and relative frequency calculated for all non-zero occurrences.

Secondary Outcome Measures :

1. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
   Association with response rate will be summarized descriptively by presenting the mean, standard deviation (SD), and other characteristics of molecular and immune measures, stratified by response status. Will assess whether one arm has superior ORR, using logistic regression analysis to control for clinical covariates.
2. Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
   Associations of molecular and immune measures with PFS will be summarized descriptively by stratified Kaplan-Meier curves and, if numbers permit, by proportional hazards models with molecular and immune responses as predictors. Will assess whether one arm has superior PFS, using proportional hazards models to control for clinical covariates.

Other Outcome Measures:

1. Changes in PD-L1 expression assessed by immunohistochemistry and immunofluorescence [ Time Frame: Baseline up to 3 years ]
   Standard descriptive and graphical methods will be used to summarize the baseline levels and post-treatment changes for comparison, which will allow us to examine whether observed patterns are consistent with hypothesized mechanisms. The quantitative immune studies will be compared using a t-test to further inform the decision. Multiplicity of testing will not be considered since this considered an exploratory analysis. Association with response rate will be summarized descriptively by presenting the mean, SD, and other characteristics of molecular and immune measures, stratified by response s
2. Functional assessment of tumor infiltrating immune cells assessed by immunophenotyping [ Time Frame: Baseline up to 3 years ]
   Standard descriptive and graphical methods will be used to summarize the baseline levels and post-treatment changes for comparison of the three MEKi and pembrolizumab sequencing schemes, which will allow us to examine whether observed patterns are consistent with hypothesized mechanisms. The quantitative immune studies will be compared using a t-test to further inform the decision. Multiplicity of testing will not be considered since this considered an exploratory analysis. Association with response rate will be summarized descriptively by presenting the mean, SD, and other characteristics of
3. Local tumor cytokine/chemokine signatures assessed by Luminex [ Time Frame: Baseline up to 3 years ]
   Standard descriptive and graphical methods will be used to summarize the baseline levels and post-treatment changes for comparison of the three MEKi and pembrolizumab sequencing schemes, which will allow us to examine whether observed patterns are consistent with hypothesized mechanisms. The quantitative immune studies will be compared using a t-test to further inform the decision. Multiplicity of testing will not be considered since this considered an exploratory analysis. Association with response rate will be summarized descriptively by presenting the mean, SD, and other characteristics of
4. MEK target inhibition [ Time Frame: Baseline up to 3 years ]
   Standard descriptive and graphical methods will be used to summarize the baseline levels and post-treatment changes for comparison of the three MEKi and pembrolizumab sequencing schemes, which will allow us to examine whether observed patterns are consistent with hypothesized mechanisms. The quantitative immune studies will be compared using a t-test to further inform the decision. Multiplicity of testing will not be considered since this considered an exploratory analysis. Association with response rate will be summarized descriptively by presenting the mean, SD, and other characteristics of

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Stage IV or metastatic/recurrent non-small cell lung cancer; for expansion cohorts, patient's tumor must also harbor a KRAS mutation detected in a CLIA certified laboratory
• Have histologically or cytologically confirmed non-small cell lung cancer
• Have stage IV, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) with progressive disease after platinum containing chemotherapy (EGFR mutant, ALK, or ROS-1 rearranged NSCLC must have progressed on prior approved tyrosine kinase inhibitor [TKI]'s)
• For phase I dose expansion cohorts the patient's tumor must harbor a KRAS mutation detected by a CLIA certified laboratory
• Be willing and able to provide written informed consent/assent for the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; in the opinion of the investigator, the patient must have tumor accessible by CT or ultrasound guided core biopsy; subjects for whom newly-obtained samples cannot be provided may submit an archived specimen provided it was obtained after last systemic treatment, within 6 months of signing consent and that tissue is available for either 2 cell blocks or 20 uncut slides (core or excisional biopsy required, fine needle aspirate is not acceptable)
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Able to swallow and retain orally administered 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
• Absolute neutrophil count >= 1.5 x 10^9/L
• Hemoglobin >= 9 g/dL
• Platelets >= 100 x 10^9/L
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN)
• Albumin >= 2.5 g/dL
• Total bilirubin =< 1.5 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• Creatinine =< 1.5 ULN
• Calculated creatinine clearance >= 50 mL/min
• Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition (MUGA)
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication; note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy; note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; inhaled or topical steroids are allowed
• Has a known history of active tuberculosis (TB [Bacillus Tuberculosis])
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 3 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; note: subjects with =< grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study; note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis; history of radiation pneumonitis is allowed provided that it is not active and no corticosteroids were required for pneumonitis management
• Evidence of interstitial lung disease
• Has an active infection requiring systemic therapy
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO)
• History of retinal vein occlusion (RVO)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent for dose expansion; (patients in dose escalation may have received an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent)
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Has known active Hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid (RNA) [qualitative] is detected)
• LVEF < LLN on screening exam
• A QT interval corrected for heart rate using the Fridericia's formula (QTcF) >= 470 msec on screening exam
• History or evidence of current clinically significant uncontrolled arrhythmias
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment
• History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)
• Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
• Patients with intra-cardiac defibrillators
• Has received a live vaccine within 30 days of planned start of study therapy; note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Contacts and Locations

Locations

United States, California

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States, 95817

Sponsors and Collaborators

University of California, Davis

Merck Sharp & Dohme LLC

Novartis

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jonathan Riess; University of California, Davis

More Information

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT03299088
• Other Study ID Numbers: 1099442; UCDCC#259 ( Registry Identifier: UC Davis IRB ); UCDCC#259 ( Other Identifier: University of California Davis Comprehensive Cancer Center ); P30CA093373 ( U.S. NIH Grant/Contract ); NCI-2017-01633 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
• First Posted: October 2, 2017
• Last Update Posted: June 3, 2022
• Last Verified: June 2022

• 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.: No

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Trametinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action