Clinical Trials /

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

NCT02902042

Description:

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 pembrolizumab 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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Encorafenib + Binimetinib + Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
  • Official Title: A Randomized Phase I / II Open Label, Multicentre Study of Encorafenib Plus Binimetinib and PD-1 Antibody Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Clinical Trial IDs

  • ORG STUDY ID: IST-818-201X
  • NCT ID: NCT02902042

Conditions

  • Malignant Melanoma

Interventions

DrugSynonymsArms
EncorafenibBraftoviArm A: Triple therapy
BinimetinibMektoviArm A: Triple therapy
PembrolizumabKeytrudaArm A: Triple therapy
Pembrolizumab aloneKeytrudaArm B: Pembrolizumab alone

Purpose

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 pembrolizumab 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Triple therapyExperimentalEncorafenib, binimetinib and pembrolizumab. Doses as determined in phase I
  • Encorafenib
  • Binimetinib
  • Pembrolizumab
Arm B: Pembrolizumab aloneExperimentalPembrolizumab with a dose of 200 mg every 3 weeks.
  • Pembrolizumab alone

Eligibility Criteria

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability of the triple combination treatment]
Time Frame:42 days
Safety Issue:
Description:Dose limiting toxicities (DLT) will be determined within 42 days of therapy start (first pembrolizumab injection) and are defined as all ≥ grade 4 hematological toxicities and certain non-hematological toxicities ≥ CTCAE grade 3.

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:24 months
Safety Issue:
Description:All adverse events (AEs) / serious adverse events (SAEs) NCI CTCEA (Common Terminology Criteria for Adverse Events) Grade ≥ 3
Measure:Objective response rate
Time Frame:24 months
Safety Issue:
Description:Number of patients with complete response (CR), partial response (PR) and stable disease (SD) as best response.
Measure:Overall survival time
Time Frame:24 months
Safety Issue:
Description:Time from the date of first administration of study drug to the date of death due to any cause.
Measure:1-year survival rate
Time Frame:12 months
Safety Issue:
Description:Number of patients alive in the time period from date of first administration of study drug until 1 year after date of first administration
Measure:2-year survival rate
Time Frame:24 months
Safety Issue:
Description:Number of patients alive in the time period from date of first administration of study drug until 2 years after date of first administration

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Prof. Dr. med. Dirk Schadendorf

Trial Keywords

  • Unresectable or metastatic BRAF V600 mutant melanoma
  • Encorafenib, binimetinib, pembrolizumab

Last Updated

October 29, 2019