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Metastatic Malignant Neoplasm in the BrainPhase 1NCT02015117

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

A Phase 1 study testing Laboratory Biomarker Analysis, Pharmacological Study and Therapeutic Conventional Surgery in people with Metastatic Malignant Neoplasm in the Brain, run by National Cancer Institute (NCI) at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Pharmacological Study and Therapeutic Conventional Surgery
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
1 siteUnited States
Study dates
28 Apr 2014to 23 Sep 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 -1
  • All prior treatment- related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) =< grade 1 (except alopecia) at the time of enrollment
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100 x10^9/L
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  • 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 x 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 start of study treatment, and counselled 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 randomization; 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

Who cannot join

  • Prior radiation therapy to the whole brain (prior stereotactic radiosurgery or fractionated stereotactic radiation therapy to focal areas is allowed)
  • 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
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  • 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)
  • Drugs that potently inhibit or induce CYP3A4 should be administered with caution; 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
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

Other trials in United States

About this study

Official title: A Phase 1 Study of Trametinib in Combination With Radiation Therapy for Brain Metastases

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To identify the maximally tolerated dose of trametinib to be used in combination with whole brain radiation therapy in patients with brain metastases. (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:

  1. 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.

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

TERTIARY OBJECTIVES:

  1. 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.

Being tested
Laboratory Biomarker Analysis, Pharmacological Study, Therapeutic Conventional Surgery, Trametinib, Whole-Brain Radiotherapy
Medical subject headings
Brain Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo surgical resection of the tumor

  • TrametinibDrug

    Also called GSK 1120212, GSK 212, GSK-1120212, GSK-212

    Given PO

  • Whole-Brain RadiotherapyRadiation

    Also called WBRT, whole-brain radiation therapy

    Undergo whole-brain radiation therapy

Study groups in NCT02015117
Study groupRoleWhat they receive
Cohort A (trametinib, whole-brain radiation therapy)ExperimentalPatients 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.
Receives: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Trametinib; Radiation: Whole-Brain Radiotherapy
Cohort B (trametinib, surgery)ExperimentalPatients receive trametinib PO QD on days 1-14 followed by surgical resection of the tumor.
Receives: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery; Drug: Trametinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Frequency of dose-limiting toxicities (DLT), defined as the maximum dose level of trametinib where at most 1 of 6 patients experience DLT (Cohort A)

    Frequency of DLTs will be assessed by assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse (CTCAE) version 5.0. DLTs will be summarized by dose level.

    Measured: Up to 8 weeks

  2. Quantification of trametinib in resected brain metastatic lesions utilizing high performance liquid chromatography/tandem mass spectrometry (Cohort B)

    Trametinib quantification will also be completed in brain margin, arachnoid, and cerebrospinal fluid.

    Measured: Up to day 28

Secondary outcomes (6)

  1. 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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse (CTCAE) version 5.0

    Will summarize observed adverse events and their grade and attribution for each dose level, and patterns reflecting tolerability of the regimen explored through graphical analysis and descriptive summaries. In addition, overall tolerability and toxicity of the regimen will also be evaluated, including reasons for treatment discontinuation as well as the number of patients who successfully complete treatment will be summarized by dose level.

    Measured: Up to 8 weeks

  2. Objective response rate per Response Evaluation Criteria in Solid Tumors

    The overall response rate will be assessed as the number of patients who achieve a partial or complete response to therapy divided by the total number of evaluable patients. Assuming that this measure is binomially distributed, the proportion will be estimated and corresponding 95% binomial confidence intervals generated.

    Measured: Up to 3 years

  3. Local control rate

    Local control rate will be measured from time of study enrollment until the time of progression within the irradiated site.

    Measured: Up to 2 years

  4. Neurologic progression-free survival

    Described graphically and quantitatively using the methods of Kaplan and Meier.

    Measured: Time from study entry to the time of progression within the brain or until time of death, assessed up to 2 years

  5. Overall survival

    Described graphically and quantitatively using the methods of Kaplan and Meier.

    Measured: Time from study entry to the time of death due to any cause, assessed up to 2 years

  6. Proportion of patients who complete treatment per protocol

    Assessed as a measure of tolerability.

    Measured: Up to 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Dec 2013 (estimated)
  2. Study start28 Apr 2014
  3. Primary completion10 Jul 2020
  4. Study completion23 Sep 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02015117
Sponsor's protocol ID
NCI-2013-02343
Other IDs
NCI-2013-02343, OSU 13197, 2013C0115, 9458, 9458, P30CA016058, U01CA076576, UM1CA186712
Status last verified
Sep 2026
First submitted
16 Dec 2013
Last updated
25 Sep 2026
Results posted
No
Data monitoring committee
No

Publications

  • Palmer JD, Prasad RN, Fabian D, Wei L, Yildiz VO, Tan Y, Grecula J, Welliver M, Williams T, Elder JB, Raval R, Blakaj D, Haglund K, Bazan J, Kendra K, Arnett A, Beyer S, Liebner D, Giglio P, Puduvalli V, Chakravarti A, Wuthrick E. Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. Radiother Oncol. 2022 May;170:21-26. doi: 10.1016/j.radonc.2022.03.016. Epub 2022 Mar 31.

    PubMed 35367525

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Laboratory Biomarker Analysis, Pharmacological Study and Therapeutic Conventional Surgery in people with Metastatic Malignant Neoplasm in the Brain, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 48 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 25 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Frequency of dose-limiting toxicities (DLT), defined as the maximum dose level of trametinib where at most 1 of 6 patients experience DLT (Cohort A) (time frame: Up to 8 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02015117, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2026.

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