Clinical trial NCT02625337: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Metastatic Melanoma
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-12-09
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Safety of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by SUSARs.
timeFrame: 18 weeks from baseline
measure: 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.
timeFrame: 18 weeks from baseline.
measure: The immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy
timeFrame: 18 weeks from baseline.
Secondary outcomes:
measure: To determine rates of response at week 6, 12, week 18.
timeFrame: Screening, week 6, 12 and 18
measure: To determine progression-free survival starting from randomization.
timeFrame: From randomisation until PD, median 10 months.
measure: Long-term toxicities of intermittent dabrafenib + trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy
timeFrame: From beyond week 18, up to 2 years follow-up.
Other outcomes:
measure: To describe time to progression beginning from week 12 (cohorts 2-4).
timeFrame: Randomisation until week 12.
measure: Changes of immune parameters within the tumor.
timeFrame: 18 weeks from baseline.
Locations:
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek ziekenhuis
state: NH
Study officials:
affiliation: Medical oncologist/researcher
name: Christian U. Blank, Prof.
role: PRINCIPAL_INVESTIGATOR
References: