Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02625337
Recruitment Status : Unknown
Verified September 2017 by The Netherlands Cancer Institute.
Recruitment status was:  Recruiting
First Posted : December 9, 2015
Last Update Posted : September 15, 2017
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Pembrolizumab Drug: Dabrafenib Drug: Trametinib Procedure: Biopsy Procedure: Blood taking Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study Comparing Pembrolizumab With Intermittent/Short-term Dual MAPK Pathway Inhibition Plus Pembrolizumab in Patients Harboring the BRAFV600 Mutation
Study Start Date : January 2016
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Active Comparator: Pembrolizumab mono
Pembrolizumab monotherapy
Drug: Pembrolizumab
Procedure: Biopsy
Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.

Procedure: Blood taking
Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.

Experimental: Pembrolizumab with dabrafenib+trametinib short
Pembrolizumab combined with a short scheme of dabrafenib+trametinib
Drug: Pembrolizumab
Drug: Dabrafenib
Drug: Trametinib
Procedure: Biopsy
Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.

Procedure: Blood taking
Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.

Experimental: Pembrolizumab with dabrafenib+trametinib intermediate
Pembrolizumab combined with an intermediate scheme of dabrafenib+trametinib
Drug: Pembrolizumab
Drug: Dabrafenib
Drug: Trametinib
Procedure: Biopsy
Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.

Procedure: Blood taking
Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.

Experimental: Pembrolizumab with dabrafenib+trametinib long
Pembrolizumab combined with a long scheme of dabrafenib+trametinib
Drug: Pembrolizumab
Drug: Dabrafenib
Drug: Trametinib
Procedure: Biopsy
Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.

Procedure: Blood taking
Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.




Primary Outcome Measures :
  1. 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 as measured by SUSARs during treatment week 0 till week 18.

  2. Feasibility of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by adherence to the timelines in the study protocol. [ Time Frame: 18 weeks from baseline. ]
    Feasibility as measured by adherence to the timelines in the study protocol (week 0 till week 18).

  3. The immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy [ Time Frame: 18 weeks from baseline. ]
    Readout will be the alterations in magnitude or breadth of the self-antigen specific T cell responses in the time interval pre-treatment to week 18 intrapatient, and interpatient, pembrolizumab only (cohort 1) versus pembrolizumab plus intermittent dabrafenib/ trametinib (cohorts 2-4). To this purpose, we will analyze melanoma antigen-specific T cells responses by HLA-A2-restricted MHC-tetramer staining.


Secondary Outcome Measures :
  1. To determine rates of response at week 6, 12, week 18. [ Time Frame: Screening, week 6, 12 and 18 ]
    Rates of response at week 6, week 12, week 18 according to RECIST 1.1 criteria

  2. To determine progression-free survival starting from randomization. [ Time Frame: From randomisation until PD, median 10 months. ]
    Progression-free survival (PFS) starting from randomization to progression using RECIST 1.1 criteria.

  3. 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. ]
    Rate and type of late adverse events


Other Outcome Measures:
  1. To describe time to progression beginning from week 12 (cohorts 2-4). [ Time Frame: Randomisation until week 12. ]
    As the short addition of dabrafenib+trametinib will induce for short time tumor regressions we will analyze cohorts 2-4 with a second baseline, namely the end of the targeted therapy at week 12, for progression free survival using to RECIST 1.1

  2. Changes of immune parameters within the tumor. [ Time Frame: 18 weeks from baseline. ]
    In addition to the primary readout (broadening of the melanoma-specific T cell response in peripheral blood), we will analyze the effect of the different therapy schemes on tumor immune cell infiltration (IHC for CD3, CD4, CD8, CD68, FoxP3, PD-L1, PD-L2, PD-1, CD11b, HLA).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02625337


Contacts
Layout table for location contacts
Contact: Christian U. Blank, Prof. +31205122570 c.blank@nki.nl

Locations
Layout table for location information
Netherlands
Antoni van Leeuwenhoek ziekenhuis Recruiting
Amsterdam, NH, Netherlands, 1066CX
Contact: Christian U. Blank, Prof.       c.blank@nki.nl   
Sponsors and Collaborators
The Netherlands Cancer Institute
Merck Sharp & Dohme Corp.
Investigators
Layout table for investigator information
Principal Investigator: Christian U. Blank, Prof. Medical oncologist/researcher
Layout table for additonal information
Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT02625337    
Other Study ID Numbers: N15IMP
First Posted: December 9, 2015    Key Record Dates
Last Update Posted: September 15, 2017
Last Verified: September 2017
Additional relevant MeSH terms:
Layout table for MeSH terms
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Trametinib
Dabrafenib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action