E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma
Primary Purpose
Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Malignant Neoplasm in the Brain, Metastatic Malignant Neoplasm in the Central Nervous System
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Dabrafenib
MEK-1/MEKK-1 Inhibitor E6201
Sponsored by
About this trial
This is an interventional treatment trial for Clinical Stage IV Cutaneous Melanoma AJCC v8
Eligibility Criteria
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate contraception
Sites / Locations
- Mayo ClinicRecruiting
- Mayo Clinic in FloridaRecruiting
- Mayo ClinicRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (E6201, dabrafenib)
Arm Description
Patients receive MEK-1/MEKK-1 inhibitor E6201 IV over 2 hours on days 1, 4, 8, 11, 15, and 18, and dabrafenib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Maximum tolerated dose
Secondary Outcome Measures
Overall intracranial response rate
Defined as the number of patients who have achieved CR or PR per Response Assessment in Neuro-oncology (RANO) for brain metastases criteria during treatment with E6201 plus dabrafenib divided by total number of evaluable patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Overall extracranial response rate
Defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Systemic response by RECIST 1.1 criteria for extracranial disease will be estimated using systemic response rate (SRR) - where SRR is defined as the number of evaluable patients achieving a response (partial response or complete response per RECIST 1.1) during treatment with study therapy divided by the total number of evaluable patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Incidence of adverse events
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Time to first progression
Will be summarized descriptively.
Overall survival
Will be summarized descriptively.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05388877
Brief Title
E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma
Official Title
Phase 1 Study of E6201 Plus Dabrafenib for the Treatment of Central Nervous System (CNS) Metastases From BRAF V600-Mutated Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 30, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
PRIMARY OBJECTIVE:
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.
SECONDARY OBJECTIVES:
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Malignant Neoplasm in the Brain, Metastatic Malignant Neoplasm in the Central Nervous System, Metastatic Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (E6201, dabrafenib)
Arm Type
Experimental
Arm Description
Patients receive MEK-1/MEKK-1 inhibitor E6201 IV over 2 hours on days 1, 4, 8, 11, 15, and 18, and dabrafenib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Other Intervention Name(s)
BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
MEK-1/MEKK-1 Inhibitor E6201
Other Intervention Name(s)
E-6201, E6201
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose
Time Frame
Up to end of cycle 1 (1 cycle = 28 days)
Secondary Outcome Measure Information:
Title
Overall intracranial response rate
Description
Defined as the number of patients who have achieved CR or PR per Response Assessment in Neuro-oncology (RANO) for brain metastases criteria during treatment with E6201 plus dabrafenib divided by total number of evaluable patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Time Frame
Up to 2 years
Title
Overall extracranial response rate
Description
Defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Systemic response by RECIST 1.1 criteria for extracranial disease will be estimated using systemic response rate (SRR) - where SRR is defined as the number of evaluable patients achieving a response (partial response or complete response per RECIST 1.1) during treatment with study therapy divided by the total number of evaluable patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Time Frame
Up to 2 years
Title
Incidence of adverse events
Description
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Time Frame
Up to 2 years
Title
Time to first progression
Description
Will be summarized descriptively.
Time Frame
Up to 2 years
Title
Overall survival
Description
Will be summarized descriptively.
Time Frame
Up to 2 years
Other Pre-specified Outcome Measures:
Title
BRAF mutational status
Description
Correlations between BRAF mutational status (e.g., type, heterozygosity or homozygosity) and other outcome measures like response, and dose levels will be carried out in an exploratory manner. Descriptive statistics will form the basis of presentation of these data.
Time Frame
Up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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 brain metastasis, 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)
Asymptomatic or symptomatic CNS metastasis
Systemic, measurable metastatic melanoma disease is allowed; leptomeningeal disease is allowed.
Prior stereotactic radiosurgery and/or excision of brain metastases is allowed > 3 weeks before initiation of study treatment
Prior immunotherapy for adjuvant or metastatic disease is allowed provided there is documented progression of disease following 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 the upper limit of normal (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
Exclusion Criteria:
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:
Pregnant persons
Nursing persons
Persons of childbearing potential who are unwilling to employ adequate contraception
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hani M Babiker, M.D.
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Mahesh Seetharam, M.D.
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Hani M. Babiker, M.D.
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Svetomir Markovic, M.D.
12. IPD Sharing Statement
Links:
URL
https://www.mayo.edu/research/clinical-trials
Description
Mayo Clinic Clinical Trials
Learn more about this trial
E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma
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