An Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-mutant Melanoma Brain Metastasis
Condition: Brain Metastases
MeSH terms: Melanoma; Neoplasm Metastasis; Brain Neoplasms
Intervention: encorafenib; binimetinib
Intervention description: taken orally; taken orally
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BRAFV600-mutant; melanoma; brain metastasis

Summary:

      This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and
      pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in
      patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will
      be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a
      Screening Period, treatment will be administered in 28-day cycles and will continue until
      disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent
      anticancer therapy, death.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.

          -  Presence of B-RAF proto-oncogene, V600 mutant (BRAFV600) mutation in tumor tissue
             previously determined by a local PCR or NGS-based assay at any time prior to Screening
             or by a central laboratory during Screening.

          -  Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as a
             magnetic resonance imaging (MRI) contrast-enhancing lesion that may be accurately
             measured in at least 1 dimension. (Measurable intracranial lesions that have been
             previously irradiated and have not been shown to be progressing following irradiation
             should not be considered as target lesions).

          -  Patients may have received the following prior therapies:

               1. Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have received
                  prior local therapy for brain metastases including but not restricted to brain
                  surgery, whole brain radiotherapy, stereotactic radiotherapy or stereotactic
                  radiosurgery. Multiple local (brain) therapies or combinations of local therapies
                  are allowed. For patients receiving local therapy to all brain lesions (including
                  WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in
                  longest diameter on baseline scan) or new measurable lesions are required. For
                  patients receiving local therapy for some but not all lesions, disease
                  progression based on RECIST 1.1 is not required as long as there are remaining
                  brain lesions that are measurable and not previously treated.

               2. Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery,
                  craniotomy, SRS or SRT) for brain metastases.

               3. All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy.

               4. All patients (Safety Lead-In and Phase 2): If receiving concomitant
                  corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior
                  to first dose of study treatment (up to a total daily dose of 4mg of
                  dexamethasone or equivalent).

          -  An Eastern Cooperation Oncology Group Performance Status (ECOG PS) of 0 or 1 and
             Karnofsky score ≥ 80

          -  Adequate bone marrow, organ function and laboratory parameters

        Key Exclusion Criteria:

          -  Patients with symptomatic brain metastasis.

          -  Uveal or mucosal melanoma.

          -  History of or current leptomeningeal metastases.

          -  Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or
             treatment with whole-brain radiation within 28 days prior to study treatment. Patients
             who received local therapy should have complete recovery with no neurological
             sequelae.

          -  Either of the following:

               1. Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start
                  of study treatment;

               2. Continuous or intermittent small-molecule therapeutics or investigational agents
                  within 5 half-lives of the agent (or within 4 weeks prior to start of study
                  treatment, when half-life is unknown).

          -  Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months
             prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic
             setting are excluded.

          -  Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before
             starting study treatment.