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.
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
Interventions
Drug | Synonyms | Arms |
---|
Pembrolizumab | | Pembrolizumab mono |
Dabrafenib | | Pembrolizumab with dabrafenib+trametinib intermediate |
Trametinib | | Pembrolizumab with dabrafenib+trametinib intermediate |
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
Name | Type | Description | Interventions |
---|
Pembrolizumab mono | Active Comparator | Pembrolizumab monotherapy | |
Pembrolizumab with dabrafenib+trametinib short | Experimental | Pembrolizumab combined with a short scheme of dabrafenib+trametinib | - Pembrolizumab
- Dabrafenib
- Trametinib
|
Pembrolizumab with dabrafenib+trametinib intermediate | Experimental | Pembrolizumab combined with an intermediate scheme of dabrafenib+trametinib | - Pembrolizumab
- Dabrafenib
- Trametinib
|
Pembrolizumab with dabrafenib+trametinib long | Experimental | Pembrolizumab 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: | Unknown status |
Lead Sponsor: | The Netherlands Cancer Institute |
Last Updated
September 15, 2017