Clinical Trials /

Study Comparing Pembrolizumab With Dual MAPK Pathway Inhibition Plus Pembrolizumab in Melanoma Patients

NCT02625337

Description:

This is a Phase 2 trial consisting of 24 patients receiving the combination of dabrafenib + trametinib + pembrolizumab in 3 different dosing schemes and 8 patients receiving pembrolizumab standard monotherapy. All patients start with pembrolizumab standard therapy for 6 weeks and will then be randomized to continue pembrolizumab monotherapy or to receive additional intermitted/short-term dabrafenib + trametinib. Stratification will be baseline LDH level and baseline PD-L1 expression.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study Comparing Pembrolizumab With Dual MAPK Pathway Inhibition Plus Pembrolizumab in Melanoma Patients
  • Official Title: Phase 2 Study Comparing Pembrolizumab With Intermittent/Short-term Dual MAPK Pathway Inhibition Plus Pembrolizumab in Patients Harboring the BRAFV600 Mutation

Clinical Trial IDs

  • ORG STUDY ID: N15IMP
  • NCT ID: NCT02625337

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
PembrolizumabPembrolizumab mono
DabrafenibPembrolizumab with dabrafenib+trametinib short
TrametinibPembrolizumab with dabrafenib+trametinib short

Purpose

This is a Phase 2 trial consisting of 24 patients receiving the combination of dabrafenib + trametinib + pembrolizumab in 3 different dosing schemes and 8 patients receiving pembrolizumab standard monotherapy. All patients start with pembrolizumab standard therapy for 6 weeks and will then be randomized to continue pembrolizumab monotherapy or to receive additional intermitted/short-term dabrafenib + trametinib. Stratification will be baseline LDH level and baseline PD-L1 expression.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab monoActive ComparatorPembrolizumab monotherapy
  • Pembrolizumab
Pembrolizumab with dabrafenib+trametinib shortExperimentalPembrolizumab combined with a short scheme of dabrafenib+trametinib
  • Pembrolizumab
  • Dabrafenib
  • Trametinib
Pembrolizumab with dabrafenib+trametinib intermediateExperimentalPembrolizumab combined with an intermediate scheme of dabrafenib+trametinib
  • Pembrolizumab
  • Dabrafenib
  • Trametinib
Pembrolizumab with dabrafenib+trametinib longExperimentalPembrolizumab combined with a long scheme of dabrafenib+trametinib
  • Pembrolizumab
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Adults at least 18 years of age

          -  World Health Organization (WHO) Performance Status 0-2

          -  Histologically/cytologically confirmed stage IV BRAF V600E or K metastatic melanoma

          -  Measurable disease according to RECIST 1.1

          -  At least one easy accessible lesion (s.c., lymph node) that can be repeatedly biopsied

          -  Patient willing to undergo triple tumor biopsies during screening, at week 6, week 8
             (cohorts 2-4 only), week 12, at week 18, and in case of disease progression.

          -  No prior immunotherapy targeting PD-1 or PD-L1 (CTLA-4 targeting therapy is allowed)

          -  No prior BRAF and/or MEK targeting therapy

          -  No immunosuppressive medications

          -  Screening laboratory values must meet the following criteria:

        WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L
        Creatinine ≤ 2x ULN AST, ALT ≤ 2.5 x ULN (≤5 x ULN for patients with liver metastases)
        Bilirubin ≤2 X ULN

          -  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. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

          -  Women of child bearing potential must agree to use a reliable form of contraceptive
             during the study treatment period and for at least 120 days following the last dose of
             study drug

          -  Men must agree to the use of male contraception during the study Treatment Period and
             for at least 180 days after the last dose of study drug.

        Exclusion Criteria:

        A potential subject who meets any of the following criteria will be excluded from this
        study:

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          -  Presence of symptomatic brain or leptomeningeal metastases; patients with asymptomatic
             brain metastases detected during screening for this study are allowed to participate
             in this study

          -  Prior PD-1/PD-L1 targeting immunotherapy

          -  Has an active automimmune disease requiring systemic treatment within the past 3
             months or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule. Subjects that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjorgen's syndrome will not be excluded from the study.

          -  Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not
             recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

          -  Known history of Human Immunodeficiency Virus;

          -  Active infection requiring therapy, positive tests for Hepatitis B surface antigen or
             Hepatitis C ribonucleic acid (RNA);

          -  Has active tuberculosis

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.
             Patients that have had another malignancy, but are free of tumor for more than 2 years
             are allowed for inclusion.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by SUSARs.
Time Frame:18 weeks from baseline
Safety Issue:
Description:Safety as measured by SUSARs during treatment week 0 till week 18.

Secondary Outcome Measures

Measure:To determine rates of response at week 6, 12, week 18.
Time Frame:Screening, week 6, 12 and 18
Safety Issue:
Description:Rates of response at week 6, week 12, week 18 according to RECIST 1.1 criteria
Measure:To determine progression-free survival starting from randomization.
Time Frame:From randomisation until PD, median 10 months.
Safety Issue:
Description:Progression-free survival (PFS) starting from randomization to progression using RECIST 1.1 criteria.
Measure:Long-term toxicities of intermittent dabrafenib + trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy
Time Frame:From beyond week 18, up to 2 years follow-up.
Safety Issue:
Description:Rate and type of late adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:The Netherlands Cancer Institute

Last Updated

September 14, 2017