Clinical Trials /

Trametinib With or Without Whole Brain Radiation Therapy in Treating Patients With Brain Metastases

NCT02015117

Description:

This phase I trial studies the side effects and best dose of trametinib with or without whole brain radiation therapy in treating patients with brain metastases. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs, such as trametinib, may make tumor cells more sensitive to radiation therapy. Giving trametinib with whole brain radiation therapy may be a better treatment for brain metastases.

Related Conditions:
  • Cancer
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Trametinib</span> With or Without Whole Brain <span class="go-doc-concept go-doc-intervention">Radiation</span> Therapy in Treating Patients With Brain Metastases

Title

  • Brief Title: Trametinib With or Without Whole Brain Radiation Therapy in Treating Patients With Brain Metastases
  • Official Title: A Phase 1 Study of Trametinib in Combination With Radiation Therapy for Brain Metastases From KRAS-, BRAF-, NRAS- or HRAS- Mutant Malignancies
  • Clinical Trial IDs

    NCT ID: NCT02015117

    ORG ID: NCI-2013-02343

    NCI ID: NCI-2013-02343

    Trial Conditions

    Metastatic Malignant Neoplasm in the Brain

    Trial Interventions

    Drug Synonyms Arms
    Trametinib GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist, TRAMETINIB Cohort A (trametinib, whole-brain radiation therapy), Cohort B (trametinib, surgery)

    Trial Purpose

    This phase I trial studies the side effects and best dose of trametinib with or without
    whole brain radiation therapy in treating patients with brain metastases. Trametinib may
    stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
    Radiation therapy uses high energy x rays to kill tumor cells. Drugs, such as trametinib,
    may make tumor cells more sensitive to radiation therapy. Giving trametinib with whole brain
    radiation therapy may be an effective treatment for brain metastases.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To identify the maximally tolerated dose of trametinib to be used in combination with
    whole brain radiation therapy in patients with brain metastases from primary cancers
    harboring v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma
    viral oncogene homolog B1 (BRAF), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS),
    or HRAS mutations to be used in a phase II trial. (Cohort A) II. To quantify trametinib in
    resected brain metastatic lesions utilizing high performance liquid chromatography/tandem
    mass spectrometry (LC/MS/MS) and compare to quantification of adjacent tissues: brain
    margin, arachnoid, and cerebrospinal fluid (CSF). (Cohort B)

    SECONDARY OBJECTIVES:

    I. To evaluate the tolerability and feasibility of the combination of trametinib and
    radiation therapy to brain for brain metastases.

    II. To evaluate the objective response rate per Response Evaluation Criteria in Solid Tumors
    (RECIST) criteria of combination trametinib and radiation therapy.

    III. To evaluate the local control rate, as measure from the time of study enrollment until
    the time of death.

    IV. To evaluate the neurologic progression-free survival, as measured from the time of study
    enrollment until the time of progression within the brain or death.

    V. To evaluate overall survival, as measured from the time of study enrollment until the
    time of death.

    TERTIARY OBJECTIVES:

    I. To quantify cyclin D1, p27, phosphorylated mitogen-activated protein kinase 1 (pERK)-1/2,
    phosphorylated v-akt murine thymoma viral oncogene homolog 1 (pAKT), phosphatase and tensin
    homolog gene (PTEN), phosphorylated mammalian target of rapamycin (pMTOR), phosphorylated
    ribosomal protein S6 kinase (pS6K), and ribosomal protein S6 (pS6) of resected metastatic
    brain lesions via quantitative immunohistochemistry (IHC) and compare to the IHC profile of
    the primary tumor.

    OUTLINE: This is a dose-escalation study of trametinib. Patients are assigned to 1 of 2
    treatment cohorts.

    COHORT A: Patients receive trametinib orally (PO) once daily (QD) for 4 weeks. Beginning in
    week 2, patients undergo whole brain radiation therapy five days a week for 3 weeks.
    Treatment continues for 4 weeks in the absence of disease progression or unacceptable
    toxicity.

    COHORT B: Patients receive trametinib PO QD on days 1-14 followed by surgical resection of
    the tumor.

    After completion of study treatment, patients are followed up for 4 weeks, every 2 months
    for 1 year, every 3 months for 3 years, and then every 6 months thereafter.

    Trial Arms

    Name Type Description Interventions
    Cohort A (trametinib, whole-brain radiation therapy) Experimental Patients receive trametinib PO QD for 4 weeks. Beginning in week 2, patients undergo whole brain radiation therapy five days a week for 3 weeks. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity. Trametinib
    Cohort B (trametinib, surgery) Experimental Patients receive trametinib PO QD on days 1-14 followed by surgical resection of the tumor. Trametinib

    Eligibility Criteria

    Inclusion Criteria:

    - Histologically confirmed cancer with measurable or evaluable brain metastases by
    computed tomography (CT) or magnetic resonance imaging (MRI); MRI is preferred, but a
    CT scan is acceptable for patients that are unable to have an MRI

    - Presence of a KRAS gene mutation (at codon 12,13, 61) , a BRAF gene mutation (V600E
    or V600K), an NRAS mutation (at codon 12, 13, 61), or HRAS mutation (at codon 12, 13,
    61) (for Cohort A only); this testing should be performed in a Clinical Laboratory
    Improvement Amendments (CLIA)-certified pathology laboratory; a copy of the pathology
    report documenting the presence of a KRAS, BRAF, HRAS, or NRAS mutation is required
    for enrollment on Cohort A

    - Eastern Cooperative Oncology Group (ECOG) performance status 0 -1

    - All prior treatment- related toxicities must be Common Terminology Criteria for
    Adverse Events (CTCAE) (version 4.0) =< grade 1 (except alopecia) at the time of
    enrollment

    - Absolute neutrophil count >= 1.5 10^9/L

    - Hemoglobin >= 9 g/dL

    - Platelets >= 100 x10^9/L

    - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
    time (PTT) =< 1.5 x upper limit of normal (ULN) unless using warfarin for therapeutic
    anti-coagulation

    - Albumin >= 2.5 g/dL

    - Total bilirubin =< 1.5 x ULN

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ULN

    - Creatinine =< 1.5 ULN or calculated creatinine clearance >= 50 mL/min or 24-hour
    urine creatinine clearance >= 50 mL/min; calculated by the Cockcroft-Gault formula

    - Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram (ECHO) or
    multigated acquisition scan (MUGA); same method as used at baseline must be use
    throughout the study, ECHO is the preferred method

    - Life expectancy of at least 3 months in the opinion of investigator

    - 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

    - Ability to provide written informed consent obtained prior to participation in the
    study and any related procedures being performed

    - Women of child-bearing potential (WOCBP) must have a negative pregnancy test within
    14 days prior to registration, and counseled on contraception/abstinence while
    receiving the study treatment; urine or serum human chorionic gonadotropin (HCG) is
    an acceptable pregnancy assessment; women of child-bearing potential and men must
    agree to use adequate contraception (hormonal or barrier method of birth control;
    abstinence) prior to study entry and for the duration of study participation; women
    of child-bearing potential must have a negative serum or urine pregnancy test within
    14 days prior to registration; should a woman become pregnant or suspect she is
    pregnant while she or her partner is participating in this study, she should inform
    her treating physician immediately; men treated or enrolled on this protocol must
    also agree to use adequate contraception prior to the study, for the duration of
    study participation, and 4 months after completion of trametinib administration)

    Exclusion Criteria:

    - Prior radiation therapy to the whole brain (prior stereotactic radiosurgery or
    fractionated stereotactic radiation therapy to focal areas is allowed)

    - Prior treatment with a selective inhibitor of v-RAF-1 murine leukemia viral oncogene
    homolog (RAF) or mitogen-activated protein kinase kinase (MEK) (trametinib,
    dabrafenib, vemurafenib, etc.)

    - Evidence of leptomeningeal metastases

    - Urgent need of treatment to prevent acute neurologic deterioration

    - Radiosensitive primary tumor such as small cell lung cancer, germ cell tumors,
    lymphoma, leukemia, or multiple myeloma

    - History of another malignancy that makes determination of the source of the brain
    metastases uncertain

    - History of interstitial lung disease or pneumonitis

    - Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
    biologic therapy, or immunotherapy within 14 days prior to enrollment and/or daily or
    weekly chemotherapy with the potential for delayed toxicity within 14 days prior to
    enrollment

    - Use of other anti-cancer therapies within five half-lives from the previous dose of
    the prior anti-cancer therapy preceding enrollment and during the study

    - Symptomatic or untreated spinal cord compression

    - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
    chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO)

    - Current use of a prohibited medication; the following medications or non-drug
    therapies are prohibited:

    - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if
    used as an appetite stimulant is allowed)

    - Concurrent treatment with bisphosphonates is permitted; however, treatment must
    be initiated prior to enrollment; prophylactic use of bisphosphonates in
    patients without bone disease is not permitted, except for the treatment of
    osteoporosis

    - Concurrent use of all herbal supplements is prohibited during the study
    (including, but not limited to, St. John's wort, kava, ephedra [ma huang],
    gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

    - In vitro studies suggest that the metabolism of trametinib is mediated predominantly
    by non-cytochrome (CYP)-mediated processes and possibly by cytochrome P450, family 3,
    subfamily A, polypeptide 4 (CYP3A4); therefore, drugs that potently inhibit or induce
    CYP3A4 should be administered with caution, as they may alter exposure to trametinib;
    below are a few examples of the agents:

    - Drugs that may increase exposure of trametinib (CYP3A4 inhibitors):

    - Antivirals: Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,
    nelfinavir, ritonavir, saquinavir

    - Antibiotics: Clarithromycin, erythromycin, telithromycin, troleandomycin

    - Antifungals: Fluconazole, itraconazole, ketoconazole, voriconazole

    - Antidepressants: Nefazodone

    - Calcium channel blockers: Mibefradil, diltiazem, verapamil

    - Miscellaneous: Aprepitant

    - Drugs that may decrease exposure of trametinib (CYP3A4 inducers)

    - Antivirals: Efavirenz, nevirapine

    - Antibiotic: Rifampin

    - Anticonvulsants: Carbamazepine, phenobarbital, phenytoin

    - Trametinib may be an inhibitor of cytochrome P450, family 2, subfamily C,
    polypeptide 8 (CYP2C8) in vivo; caution should be exercised when dosing
    trametinib concurrently with medications with narrow therapeutic windows that
    are substrates of CYP2C8; below are a few examples of the agents

    - Drug metabolism potentially affected by trametinib resulting in increased
    exposure of these substrates

    - 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA)-reductase inhibitors:
    Cerivastatin

    - Thiazolidinediones: Rosiglitazone, pioglitazone

    - Miscellaneous: Chloroquine, zopiclone, repaglinide

    - As part of the enrollment/informed consent procedures, the patient will be
    counseled on the risk of interactions with other agents, and what to do if new
    medications need to be prescribed or if the patient is considering a new
    over-the-counter medicine or herbal product

    - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment
    epithelial detachment (RPED):

    - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g.,
    uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such
    as hypertension, diabetes mellitus, or history of hyperviscosity or
    hypercoagulability syndromes)

    - Visible retinal pathology as assessed by ophthalmic exam that is considered a
    risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence
    of new visual field defects, and intraocular pressure > 21 mm Hg

    - History or evidence of cardiovascular risk including any of the following:

    - LVEF < lower limit of normal (LLN)

    - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480
    msec

    - History or evidence of current clinically significant uncontrolled arrhythmias
    (exception: patients with controlled atrial fibrillation for > 30 days prior to
    registration are eligible)

    - History of acute coronary syndromes (including myocardial infarction and
    unstable angina), coronary angioplasty, or stenting within 6 months prior to
    registration

    - History or evidence of current >= class II congestive heart failure as defined
    by the New York Heart Association (NYHA) functional classification system

    - Treatment-refractory hypertension defined as a blood pressure of systolic > 140
    mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive
    therapy

    - Patients with intra-cardiac defibrillators

    - Known cardiac metastases

    - Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the
    exception of chronic or cleared HBV and HCV infection, which will be allowed);
    patients with human immunodeficiency virus (HIV) are not eligible if on
    anti-retroviral medications

    - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
    arrhythmia, or psychiatric illness/social situations that would limit compliance with
    study requirements

    - Pregnancy or breastfeeding (women of childbearing potential should be advised to
    avoid pregnancy and use effective methods of contraception; men with a female partner
    of childbearing potential must have either had a prior vasectomy or agree to use
    effective contraception; if a female patient or a female partner of a patient becomes
    pregnant while the patient receives trametinib, the potential hazard to the fetus
    should be explained to the patient and partner (as applicable); radiation therapy is
    also contraindicated in pregnancy

    - Unable to reliably be immobilized for safe administration of whole brain radiation
    therapy

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Frequency of dose-limiting toxicities (DLT), defined as the maximum dose level of trametinib where at most 1 of 6 patients experience DLT, assessed according to the National Cancer Institute (NCI) CTCAE v4.0 (Cohort A)

    Quantification of trametinib in resected brain metastatic lesions utilizing high performance LC/MS/MS (Cohort B)

    Secondary Outcome Measures

    Local control rate

    Neurologic progression-free survival

    Objective response rate per RECIST

    Overall survival

    Overall tolerability and toxicity of the regimen, as assessed by adverse events and their grade and attribution for each dose level, graded according to the NCI CTCAE v4.0

    Proportion of patients who complete treatment per protocol

    Trial Keywords