Clinical Trials /

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

NCT03299088

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Trametinib in Treating Patients With Stage IV Non-Small Cell Lung Cancer and KRAS Gene Mutations
  • Official Title: A Phase Ib Trial of Pembrolizumab (MK-3475) and Trametinib Focused on Advanced KRAS Mutant Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 1099442
  • SECONDARY ID: UCDCC#259
  • SECONDARY ID: UCDCC#259
  • SECONDARY ID: P30CA093373
  • SECONDARY ID: NCI-2017-01633
  • NCT ID: NCT03299088

Conditions

  • 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

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A (trametinib, pembrolizumab)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistArm A (trametinib, pembrolizumab)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (trametinib, pembrolizumab)ExperimentalPatients 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.
  • Pembrolizumab
  • Trametinib
Arm B (pembrolizumab, trametinib)ExperimentalPatients 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.
  • Pembrolizumab
  • Trametinib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Overall response rate (ORR)
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, Davis

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