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

NCT02015117 | Active Not Recruiting Phase 1

• 7 other identifiers: NCI-2013-02343OSU 131972013C01159458P30CA016058U01CA076576UM1CA186712
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Metastatic Malignant Neoplasm in the Brain

Outcome Measures

Primary Outcomes (2)

• 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.

  Up to 8 weeks

• 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.

  Up to day 28

Secondary Outcomes (6)

• 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

  Up to 8 weeks

• Objective response rate per Response Evaluation Criteria in Solid Tumors

  Up to 3 years

• Local control rate

  Up to 2 years

• Neurologic progression-free survival

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

• Overall survival

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

Other Outcomes (1)

• Quantification of cyclin D1, p27, pERK-1/2, pAKT, PTEN, pMTOR, pS6K, and pS6 of resected metastatic brain lesions via immunohistochemistry

  Up to day 14

Study Arms (2)

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.

Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Trametinib; Radiation: Whole-Brain Radiotherapy

Cohort B (trametinib, surgery)

EXPERIMENTAL

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

Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery; Drug: Trametinib

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Cohort A (trametinib, whole-brain radiation therapy); Cohort B (trametinib, surgery)

Whole-Brain Radiotherapy RADIATION

Undergo whole-brain radiation therapy

Also known as: WBRT, whole-brain radiation therapy

Cohort A (trametinib, whole-brain radiation therapy)

Pharmacological Study OTHER

Correlative studies

Cohort A (trametinib, whole-brain radiation therapy); Cohort B (trametinib, surgery)

Therapeutic Conventional Surgery PROCEDURE

Undergo surgical resection of the tumor

Cohort B (trametinib, surgery)

Trametinib DRUG

Given PO

Also known as: GSK 1120212, GSK 212, GSK-1120212, GSK-212, GSK1120212, GSK212, JTP 74057, JTP-74057, JTP74057, MEK Inhibitor GSK1120212

Cohort A (trametinib, whole-brain radiation therapy); Cohort B (trametinib, surgery)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (1)

• 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.

  PMID: 35367525 DERIVED

MeSH Terms

Conditions

Brain Neoplasms

Interventions

trametinib; omipalisib

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Joshua D Palmer

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: December 19, 2013
• Study Start: April 28, 2014
• Primary Completion: July 10, 2020
• Study Completion (Estimated): October 8, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-03

Locations

US (1)