Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Open Label, Multicentre Study of Encorafenib + Binimetinib + PD (Programmed Cell Death Protein) -1 Antibody Pembrolizumab

Summary: This study will investigate the influence of maintenance therapy on progression-free survival (PFS) and overall survival (OS) after combination therapy with BRAF/MEK (MAP-ERK kinase) inhibitors and PD-1 antibody pembrolizumab.
  In the safety phase I part the optimal dose of pembrilizumab in combination with BRAF inhibitor and MEK inhibitor and the safety of this three-drugs-combination regime will be determined.
  In the randomized part 2 different maintenance therapies will be tested for toxicity and efficacy. Patients with disease control after 6 months of triple therapy will be randomized to receive 2 different maintenance therapies further on, either continuation of triple therapy or administration of pembrolizumab alone.

Detailed description: There is growing interest to understand the best strategies to use targeted therapies and novel immunotherapy for the treatment of advanced melanoma. This study will explore the combination of encorafenib plus binimetinib with the PD-1 antibody pembrolizumab in patients with BRAF mutant melanoma. Combination of two clinically effective approaches, targeting the mutant BRAF pathway by BRAF/MEK inhibition and modulating immunological checkpoint control by administration of a PD-1 antibody, should prolong PFS and OS even further. This study will investigate the influence of maintenance therapy on PFS and OS after triple therapy. Patients with disease control after 6 months of triple therapy will be randomized to receive 2 different maintenance therapies further on to investigate if administration of pembrolizumab only is sufficient for maintenance of disease control. For reasons of safety a phase I study is performed to determine the optimal dosing and schedule of the combination therapy (encorafenib, binimetinib, pembrolizumab).
  In the phase ii-part, patient will receive triple therapy with the doses defined in phase I for a 6 months induction period. Patients with complete or partial response or stable disease after the 6 months period will be randomized for maintenance therapy:
  Arm A: Therapy as in induction period. Arm B: Therapy with pembrolizumab only with a dose of 200 mg every 3 weeks.

Eligibility: Inclusion Criteria:
  -  Be willing and able to provide written informed consent/assent for the trial.
  -  Being ≥ 18 years of age on day of signing informed consent.
  -  Histologically confirmed diagnosis of locally advanced, unresectable or metastatic, treatment naive, cutaneous melanoma AJCC (American Joint Committee on Cancer) Stage IIIB, IIIC or IV with no active brain metastasis.
  -  Naïve untreated patient for locally advanced or metastatic melanoma. Prior adjuvant therapy is permitted (e.g. interferon [IFN], (interleukin-2 [IL-2]-therapy, chemo- or radiotherapy). Patients who are in follow-up period of a clinical trial in adjuvant setting may be enrolled.
  -  Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
  -  Presence of BRAF mutation (V600E or V600K) in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrollment.
  -  Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  -  Adequate organ function: Absolute neutrophil count (ANC) ≥1,500 /mcL, Platelets ≥100,000 / mcL, Hemoglobin ≥9 g/dL OR ≥5.6 mmol/L, Serum creatinine OR Measured or calculated creatinine clearance ≤1.5 X upper limit of normal (ULN) OR ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN, Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.
  -  Adequate cardiac function:
  -  Left ventricular ejection fraction (LVEF) ≥ 50% as determined by multigated acquisition (MUGA) scan or echocardiogram
  -  Corrected QT (QTc) interval ≤ 480ms
  -  Able to take oral medications.
  -  Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication.
  -  Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to Clinical Trials Facilitation Group (CTFG) starting with the first dose of study therapy during the course of this study and for at least 120 days after the last dose of study medication
  Exclusion Criteria:
  -  Currently participating in or having participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
  -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
  -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  -  Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or MEK inhibitor (including but not limited to trametinib, AZD6244, binimetinib).
  -  Any previous anti-cancer treatment, extensive radiotherapy or investigational agent for locally advanced unresectable or metastatic melanoma.
  -  Known additional malignancy that is progressing or requires active treatment within 5 years prior to the study.
  -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  -  Non-cutaneous melanoma.
  -  History of leptomeningeal metastases.
  -  History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
  -  History of retinal degenerative disease.
  -  History of allogeneic bone marrow transplantation or organ transplantation.
  -  History of Gilbert's syndrome.
  -  Uncontrolled arterial hypertension despite medical treatment.
  -  Patients who have neuromuscular disorders that are associated with elevated creatine kinase (e. g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  -  Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection).
  -  Evidence of interstitial lung disease or active, non-infectious pneumonitis.
  -  Active infection requiring systemic therapy.
  -  Pregnancy or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  -  Positive test for Human Immunodeficiency Virus.
  -  Positive test for Hepatitis B or Hepatitis C.
  -  Receiving a live vaccine within 30 days prior to the first dose of trial treatment.
  -  Known hypersensitivity reaction to any of the components of study treatment.

Relevance to patient case: not relevant