E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)
Condition: Malignant Melanoma; Brain Metastases
MeSH terms: Melanoma; Neoplasm Metastasis; Brain Neoplasms
Intervention: E6201; E6201 plus dabrafenib
Intervention description: E6201 formulated in cyclodextrin for IV administration.; E6201 formulated in cyclodextrin for IV administration. Dabrafenib capsules for oral administration.
Intervention MeSH terms: Dabrafenib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: 4 subjects were treated in the E6201 Monotherapy Safety Run-in Phase. A total of 6-12 subjects are anticipated in the E6201 plus dabrafenib Combination Safety Run-in Phase. Once an MTD of the combination is determined, a total of 6 subjects will be treated at the combined MTD before the Expansion Phase will begin. In the Expansion Phase, an additional cohort of up to N=18 subjects will be treated at the combined E6201 plus dabrafenib MTD. Subjects treated at the MTD in the Combination Safety Run-in Phase will count towards accrual in the Expansion Phase.
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; CNS metastases; BRAF V600 mutation; E6201; Dabrafenib

Summary:

      This is a Phase 1 study of E6201 plus dabrafenib for the treatment of CNS metastases in BRAF
      V600-mutated metastatic melanoma. A total of up to N=28-34 subjects with melanoma
      metastasized to the CNS will be included.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males and females ≥ 18 years of age

          -  Histologically or cytologically confirmed BRAFV600-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 or MEK pathway mutation reports from a CLIA qualified
             laboratory. If a report is not available, the mutation analysis will be performed at
             Screening on archival tissue

          -  Other metastatic melanoma systemic disease allowed

          -  At least one measurable brain metastasis, 0.5 - 3.0 cm, as assessed by MRI ≤ 3 weeks
             prior to 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 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

          -  One prior line of immunotherapy for metastatic disease is allowed, if ≥ 2 weeks has
             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 therapy 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 (Combination Safety Run-in and
             Expansion Phases of the study only)

          -  Asymptomatic or symptomatic CNS metastasis is allowed

          -  Stable dose of corticosteroids for CNS metastasis for ≥ 7 days allowed

          -  Patients with seizures due to CNS metastases must be controlled with stable
             anti-epileptic treatment for ≥ 14 days

          -  Bisphosphonates and/or denosumab are allowed

          -  Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2

          -  Life expectancy of ≥ 3 months

          -  Adequate hematologic parameters without ongoing transfusional support:

               -  Hemoglobin (Hb) ≥ 9 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9 cells/L

               -  Platelets ≥ 75 x 10^9 cells/L

          -  Adequate renal and hepatic function:

               -  Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine
                  clearance ≥ 50 mL/minute x 1.73 m^2

               -  Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's
                  disease

               -  ALT/AST ≤ 2.5 times ULN, or < 5 times ULN for subjects with liver metastases

          -  Negative serum pregnancy test within 14 days prior to the first dose of study therapy
             for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects
             must agree to use adequate methods to avoid pregnancy throughout the study and for 28
             days after the completion of study treatment.

          -  Ability to provide written informed consent

        Exclusion Criteria:

          -  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

          -  Prior treatment with any BRAF and/or MEK inhibitor for metastatic disease

          -  Prior treatment with > 1 line of immunotherapy for metastatic disease

          -  Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia,
             myocardial infarction, unstable angina or heart disease defined by the New York Heart
             Association (NYHA) Class III or Class IV

          -  QT interval corrected for rate (QTc) > 480 msec for on the ECG obtained at Screening
             using Fridericia method for QTc calculation

          -  Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
             hepatitis C virus (HCV) requiring systemic antiviral treatment within the last week
             prior to study treatment

          -  Other active infection requiring IV antibiotic usage within the last week prior to
             study treatment

          -  Any other medical intervention or other condition which, in the opinion of the
             Principal Investigator, could compromise adherence to study requirements or confound
             the interpretation of study results

          -  Pregnant or breast-feeding