Study Comparing Pembrolizumab With Dual MAPK Pathway Inhibition Plus Pembrolizumab in Melanoma Patients
IMPemBra
Phase 2 Study Comparing Pembrolizumab With Intermittent/Short-term Dual MAPK Pathway Inhibition Plus Pembrolizumab in Patients Harboring the BRAFV600 Mutation
1 other identifier
interventional
32
1 country
1
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Jan 2016
Typical duration for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
December 1, 2015
CompletedFirst Posted
Study publicly available on registry
December 9, 2015
CompletedStudy Start
First participant enrolled
January 1, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 1, 2018
CompletedStudy Completion
Last participant's last visit for all outcomes
December 1, 2018
CompletedSeptember 15, 2017
September 1, 2017
2.4 years
December 1, 2015
September 14, 2017
Conditions
Outcome Measures
Primary Outcomes (3)
Safety of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by SUSARs.
Safety as measured by SUSARs during treatment week 0 till week 18.
18 weeks from baseline
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.
Feasibility as measured by adherence to the timelines in the study protocol (week 0 till week 18).
18 weeks from baseline.
The immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy
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.
18 weeks from baseline.
Secondary Outcomes (3)
To determine rates of response at week 6, 12, week 18.
Screening, week 6, 12 and 18
To determine progression-free survival starting from randomization.
From randomisation until PD, median 10 months.
Long-term toxicities of intermittent dabrafenib + trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy
From beyond week 18, up to 2 years follow-up.
Other Outcomes (2)
To describe time to progression beginning from week 12 (cohorts 2-4).
Randomisation until week 12.
Changes of immune parameters within the tumor.
18 weeks from baseline.
Study Arms (4)
Pembrolizumab mono
ACTIVE COMPARATORPembrolizumab monotherapy
Pembrolizumab with dabrafenib+trametinib short
EXPERIMENTALPembrolizumab combined with a short scheme of dabrafenib+trametinib
Pembrolizumab with dabrafenib+trametinib intermediate
EXPERIMENTALPembrolizumab combined with an intermediate scheme of dabrafenib+trametinib
Pembrolizumab with dabrafenib+trametinib long
EXPERIMENTALPembrolizumab combined with a long scheme of dabrafenib+trametinib
Interventions
Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.
Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- The Netherlands Cancer Institutelead
- Merck Sharp & Dohme LLCcollaborator
Study Sites (1)
Antoni van Leeuwenhoek ziekenhuis
Amsterdam, North Holland, 1066CX, Netherlands
Related Publications (1)
Rozeman EA, Versluis JM, Sikorska K, Hoefsmit EP, Dimitriadis P, Rao D, Lacroix R, Grijpink-Ongering LG, Lopez-Yurda M, Heeres BC, van de Wiel BA, Flohil C, Sari A, Heijmink SWTPJ, van den Broek D, Broeks A, de Groot JWB, Vollebergh MA, Wilgenhof S, van Thienen JV, Haanen JBAG, Blank CU. IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation. J Immunother Cancer. 2023 Jul;11(7):e006821. doi: 10.1136/jitc-2023-006821.
PMID: 37479483DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Christian U. Blank, Prof.
Medical oncologist/researcher
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
December 1, 2015
First Posted
December 9, 2015
Study Start
January 1, 2016
Primary Completion
June 1, 2018
Study Completion
December 1, 2018
Last Updated
September 15, 2017
Record last verified: 2017-09