- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02015117
Trametinib With or Without Whole Brain Radiation Therapy in Treating Patients With Brain Metastases
A Phase 1 Study of Trametinib in Combination With Radiation Therapy for Brain Metastases
Study Overview
Status
Conditions
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. (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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Ohio
-
Columbus, Ohio, United States, 43210
- Ohio State University Comprehensive Cancer Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
- 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
- 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
Exclusion Criteria:
- 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:
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Cohort A (trametinib, whole-brain radiation therapy)
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.
|
Correlative studies
Correlative studies
Given PO
Other Names:
Undergo whole-brain radiation therapy
Other Names:
|
Experimental: Cohort B (trametinib, surgery)
Patients receive trametinib PO QD on days 1-14 followed by surgical resection of the tumor.
|
Correlative studies
Correlative studies
Given PO
Other Names:
Undergo surgical resection of the tumor
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
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)
Time Frame: Up to day 28
|
Trametinib quantification will also be completed in brain margin, arachnoid, and cerebrospinal fluid.
|
Up to day 28
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
Time Frame: Up to 8 weeks
|
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.
|
Up to 8 weeks
|
Objective response rate per Response Evaluation Criteria in Solid Tumors
Time Frame: Up to 3 years
|
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.
|
Up to 3 years
|
Local control rate
Time Frame: Up to 2 years
|
Local control rate will be measured from time of study enrollment until the time of progression within the irradiated site.
|
Up to 2 years
|
Neurologic progression-free survival
Time Frame: Time from study entry to the time of progression within the brain or until time of death, assessed up to 2 years
|
Described graphically and quantitatively using the methods of Kaplan and Meier.
|
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 Frame: Time from study entry to the time of death due to any cause, assessed up to 2 years
|
Described graphically and quantitatively using the methods of Kaplan and Meier.
|
Time from study entry to the time of death due to any cause, assessed up to 2 years
|
Proportion of patients who complete treatment per protocol
Time Frame: Up to 4 weeks
|
Assessed as a measure of tolerability.
|
Up to 4 weeks
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Quantification of cyclin D1, p27, pERK-1/2, pAKT, PTEN, pMTOR, pS6K, and pS6 of resected metastatic brain lesions via immunohistochemistry
Time Frame: Up to day 14
|
Will be assessed using immunohistochemistry.
|
Up to day 14
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Joshua D Palmer, Ohio State University Comprehensive Cancer Center
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NCI-2013-02343 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- P30CA016058 (U.S. NIH Grant/Contract)
- UM1CA186712 (U.S. NIH Grant/Contract)
- U01CA076576 (U.S. NIH Grant/Contract)
- OSU 13197
- 2013C0115
- 9458 (Other Identifier: CTEP)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Metastatic Malignant Neoplasm in the Brain
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingAdvanced Malignant Solid Neoplasm | Metastatic Malignant Solid Neoplasm | Metastatic Malignant Neoplasm in the Liver | Metastatic Malignant Neoplasm in the LungUnited States
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingMalignant Solid Neoplasm | Metastatic Malignant Neoplasm in the BrainUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)CompletedMalignant Neoplasm | Metastatic Malignant Neoplasm in the BrainUnited States
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingMetastatic Malignant Solid Neoplasm | Metastatic Malignant Neoplasm in the BrainUnited States
-
Sameek RoychowdhuryNational Cancer Institute (NCI)WithdrawnLocally Advanced Malignant Solid Neoplasm | Metastatic Malignant Solid Neoplasm | ALK Gene Mutation | Metastatic Malignant Neoplasm in the Brain | Advanced Malignant Neoplasm | ALK Fusion Protein Expression | Metastatic Malignant Neoplasm in the Central Nervous System | ROS1 Gene Mutation | ALK Gene... and other conditionsUnited States
-
National Cancer Institute (NCI)Active, not recruitingAdvanced Malignant Solid Neoplasm | Metastatic Malignant Solid Neoplasm | Metastatic Malignant Neoplasm in the Liver | Unresectable Solid NeoplasmUnited States, Canada
-
Northwestern UniversityNational Cancer Institute (NCI)WithdrawnBreast Carcinoma | Metastatic Malignant Neoplasm in the Brain | Metastatic Malignant Neoplasm in the LeptomeningesUnited States
-
M.D. Anderson Cancer CenterActive, not recruitingAdvanced Malignant Solid Neoplasm | Metastatic Malignant Solid Neoplasm | Metastatic Carcinoma in the Liver | Metastatic Carcinoma in the Lung | Metastatic Malignant Neoplasm in the Thoracic CavityUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI); California Institute for Regenerative Medicine...RecruitingBreast Cancer | HER2-positive Breast Cancer | Malignant Neoplasm | Metastatic Malignant Neoplasm in the Brain | Metastatic Malignant Neoplasm in the LeptomeningesUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingMetastatic Malignant Neoplasm in the Bone | Metastatic Malignant NeoplasmUnited States
Clinical Trials on Laboratory Biomarker Analysis
-
Children's Oncology GroupNational Cancer Institute (NCI)Completed
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Active, not recruitingLeukemia | Acute Lymphoblastic Leukemia | Acute Promyelocytic LeukemiaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedUntreated Adult Acute Lymphoblastic Leukemia | Untreated Childhood Acute Lymphoblastic LeukemiaUnited States, Canada, Australia, New Zealand, Puerto Rico, Switzerland
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Lymphoblastic Leukemia in Remission | Recurrent Childhood Acute Lymphoblastic LeukemiaUnited States
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)CompletedLung CancerUnited States
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Completed
-
Children's Oncology GroupNational Cancer Institute (NCI)WithdrawnClear Cell Renal Cell Carcinoma | Rhabdoid Tumor of the Kidney | Congenital Mesoblastic Nephroma | Childhood Kidney NeoplasmUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)WithdrawnBreast Carcinoma | BRCA1 Mutation Carrier | BRCA2 Mutation CarrierUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedWilms Tumor and Other Childhood Kidney TumorsUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Monoblastic Leukemia (M5a) | Childhood Acute Monocytic Leukemia (M5b) | Childhood Acute Myeloblastic Leukemia Without Maturation (M1) | Childhood Acute Myelomonocytic Leukemia (M4) | Childhood Acute Myeloid Leukemia/Other Myeloid MalignanciesUnited States