Encorafenib + Binimetinib + Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

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.

Inclusion criteria

• 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 melanoma AJCC (2017) Stage IIIB, IIIC, IIID or IV with no active brain metastasis. All known CNS lesions must have been only treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline); there is no evidence of new or enlarging brain metastases, and the patient must not have used steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment.
• Treatment naive patient for locally advanced unresectable or metastatic melanoma. Prior adjuvant or neoadjuvant systemic therapy is permitted (in stage II, III and IV with no evidence of disease) if all related adverse events have either returned to baseline or stabilized.

(i) Anti-PD-1, anti-CTLA-4, BRAF/MEK inhibitor therapy with at least 6 months between the last dose and date of recurrence.

(ii) Interferon therapy and chemotherapy with the last dose at least 6 weeks prior to registration.

(iii) Radiotherapy with the last radiation at least 28 days prior to registration. Participants must have recovered from all radiation-related toxicities. Note: radiated lesions cannot be used as measurable lesions unless there is clear evidence of progression.

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 V600 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 ECOG Performance Scale.
• Adequate organ function: ANC ≥1,500 /mcL, Platelets ≥100,000 / mcL, Hemoglobin ≥9 g/dL OR ≥5.6 mmol/L, Serum creatinine OR Measured or calculated CrCl ≤1.5 X 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, AST and ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.
• Adequate cardiac function:

• LVEF ≥ 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram
• Corrected QT (QTc) interval ≤ 480ms
• All treatment-related toxicities of prior adjuvant or neoadjuvant systemic therapy (except alopecia) must be ≤ Grade 1 according to the CTCAE version 4.03:
• Able to take oral medications.
• Female subject of childbearing potential should have a negative urine or serum pregnancy test 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 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 in dosing exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
• Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon given as adjuvant or neoadjuvant therapy for melanoma).
• Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib) and / or MEK inhibitor (including but not limited to trametinib, AZD6244, binimetinib, cobimetinib).
• Any previous anti-cancer treatment, extensive radiotherapy or investigational agent for locally advanced unresectable or metastatic melanoma.
• Known additional malignancy that is progressing or required active treatment within 3 years prior to the study.
• Known active CNS metastases and/or carcinomatous meningitis.
• Presence of uveal melanoma.
• History of leptomeningeal metastases.
• History or current evidence of CSR or 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 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 or history of (non-infectious) pneumonitis that required steroids.
• 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 until up to 120 days after the last dose of trial treatment.
• Positive test for HIV.
• Positive test for Hep B or Hep 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.
• Medical, psychiatric, cognitive or other conditions, including known alcohol or drug abuse that would not permit the subject to complete the study or sign informed consent.
• Patients taking non-topical medication known to be a strong inhibitor of CYP3A4.
• History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) or kinase inhibition (e.g. BRAF and/or MEK inhibitor) except those that are unlikely to re-occur with standard countermeasures (e.g. hormone replacement after adrenal crisis).