Melanoma Clinical Trial
E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma
This phase I tests the safety, side effects, and best dose of E6201 in combination with dabrafenib in treating patients with BRAF V600 mutated melanoma that has spread to the central nervous system (central nervous system metastases). E6201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Dabrafenib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving E6201 and dabrafenib together may work better in treating patients with BRAF V600 mutated melanoma that has spread to the central nervous system than either drug alone.
I. To determine the maximum tolerated dose of MEK-1/MEKK-1 inhibitor E6201 (E6201) in combination with dabrafenib in patients with central nervous system (CNS) metastases from BRAF V600- mutated metastatic melanoma.
I. To assess the time to first progression in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib.
II. To assess overall survival (OS) in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib.
III. To assess the adverse events profile of E6201 in combination with dabrafenib in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib.
CORRELATIVE RESEARCH OBJECTIVE:
I. To assess the impact of BRAF mutational status (e.g., type, heterozygosity or homozygosity) in archival tissue with clinical outcome.
OUTLINE: This is a dose-escalation study of MEK-1/MEKK-1 inhibitor E6201 followed by a dose-expansion study.
Patients receive MEK-1/MEKK-1 inhibitor E6201 intravenously (IV) over 2 hours on days 1, 4, 8, 11, 15, and 18, and dabrafenib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 2 years from time of registration.
Age >= 18 years
Histologically or cytologically confirmed stage IV metastatic BRAF V600-mutated melanoma
Documented metastasis of the primary tumor to the CNS
BRAF-mutation melanoma tumor status will be established prior to entry based on previous BRAF-gene analysis reports from a Clinical Laboratory Improvement Act (CLIA) qualified laboratory. If a report is not available, the mutation analysis will be performed at screening on archival tissue
At least one measurable brain metastasis 0.5 - 3.0 cm, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) with contrast =< 3 weeks prior to registration and does not require immediate local intervention (surgery or radiosurgery) NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible
Asymptomatic or symptomatic CNS metastasis
Other metastatic melanoma systemic disease is allowed, including leptomeningeal disease
Prior stereotactic radiosurgery and/or excision of up to 3 brain metastases is allowed > 3 weeks before initiation of study treatment, provided neurological sequelae have resolved completely and at least one measurable metastasis with documented disease progression is present on MRI
Prior immunotherapy for metastatic disease is allowed, if >= 2 weeks have elapsed between the end of therapy and initiation of study treatment
Prior treatment with BRAF/MEK inhibitor therapy is allowed, if >= 2 weeks have elapsed between the end of therapy and initiation of study treatment
Prior melanoma adjuvant immunotherapy is allowed, if >= 6 months has elapsed between the end of therapy and initiation of study treatment
Prior melanoma adjuvant BRAF/MEK inhibitor treatment is allowed if >= 12 months has elapsed between the end of therapy and initiation of study treatment
Able to swallow and retain oral medication with no clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels
Stable dose of corticosteroids for CNS metastasis is allowed if >= 7 days
Seizures due to CNS metastases must be controlled with stable anti-epileptic treatment for >= 14 days
Bisphosphonates and/or denosumab are allowed
Life expectancy >= 3 months
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Hemoglobin (Hb) >= 9 g/dL without ongoing transfusional support (obtained =< 15 days prior to registration)
Absolute neutrophil count (ANC) >= 1.0 x 10^9 cells/L without ongoing transfusional support (obtained =< 15 days prior to registration)
Platelets >= 75 x 10^9 cells/L without ongoing transfusional support (obtained =< 15 days prior to registration)
Creatinine =< 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance >= 50 mL/minute per the Cockcroft-Gault formula (obtained =< 15 days prior to registration)
Total bilirubin =< 2 times ULN unless due to Gilbert's disease (obtained =< 15 days prior to registration)
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 times ULN, or < 5 times ULN for subjects with liver metastases (obtained =< 15 days prior to registration)
Negative serum pregnancy test done =< 14 days prior to registration, for persons of childbearing potential only, defined as a female who has not undergone a hysterectomy or who has not been naturally post-menopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months)
Willing to use contraception
Sexually active persons of childbearing potential (PCBP) and persons able to father a child must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after the completion of study treatment
Provide written informed consent
Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
Ability to complete Patient Medication Diaries by themselves or with assistance
Willingness to have institution procure previous BRAF-gene analysis report(s) from a CLIA qualified laboratory, or if a report is not available, willingness to have institution procure archived tumor sample to establish BRAF-mutational melanoma tumor status prior to study
Ability to swallow
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Urgent need of treatment to prevent acute neurologic deterioration, including urgent neurosurgery or radiotherapy
Symptoms of uncontrolled intracranial pressure
Symptomatic or untreated spinal cord compression
Prior treatment with any chemotherapeutic or investigational agent for =< 4 weeks prior to registration
Prior treatment with > 2 lines of immunotherapy for metastatic disease
Prior treatment with > 1 line of a BRAF and/or MEK inhibitor for metastatic disease
Serious cardiac condition =< 6 months prior to registration, such as uncontrolled arrhythmia, myocardial infarction, unstable angina, or heart disease defined by the New York Heart Association (NYHA) class III or class IV
Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment
Uncontrolled intercurrent non-cardiac illness including, but not limited to:
Ongoing or active infection requiring IV antibiotic usage within the last week prior to study treatment
Any other conditions that would limit compliance with study requirements or confound the interpretation of study results
Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
Any of the following, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
Persons of childbearing potential who are unwilling to employ adequate contraception
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There are 3 Locations for this study
Scottsdale Arizona, 85259, United States More Info
Jacksonville Florida, 32224, United States More Info
Rochester Minnesota, 55905, United States More Info
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