Primary objectives: To explore the safety, feasibility, and the immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapySecondary…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Safety and feasibility as measured by SUSARs and adherence to the timelines
of the study protocol (week 0 till week 18).
- Alterations in percentage of tumor infiltrating CD8+ T cells and in
percentage of PD-1+CD8+ T cells in peripheral blood samples 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).
Secondary outcome
Secondary endpoints:
- Rates of response at week 6, week 12, week 18, and best overall response,
according to RECIST 1.1 criteria
- Progression-free survival (PFS) starting from randomization to progression
using RECIST 1.1 criteria.
- Rate and type of late adverse events (beyond week 18, for up to 2 years)
Exploratory endpoints:
- 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
- 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).
Background summary
Targeting the PD-1/PD-L1 immune checkpoint pathway by e.g. pembrolizumab
(MK-3475, Keytruda) is currently one of the most promising immunotherapeutic
approaches in late stage melanoma with a response rate of 34% and long-term
responses. In contrast to immunotherapies that are characterized by (so far)
lower response rates, but long-term benefit, targeted therapies (BRAF or MEK
inhibitors), can induce high response rates, but only of short duration, even
when combined. These contrasting response patterns have early led to the idea
of combining immune- and targeted therapy. However, initial attempts of
combining vemurafenib or dabrafenib + trametinib with ipilimumab failed due to
toxicity. Combination of BRAF+MEK inhibition with PD-L1 blockade, however,
seems to be feasible and might induce prolonged tumor control.
In line with these observations, we observed in a patient treated with
pembrolizumab within the MK-3475-006 study, who switched after 4 courses
pembrolizumab 10mg/kg within one (respectively two weeks for trametinib) weeks
to dabrafenib 150mg bid (+trametinib 2mg qd), strong immune activation, as
manifested by fever up to 41°C, immune related meningitis (recovering fast
after steroid substitution). Interestingly, this patient, who suffered from
fast progression of omental cake, ascites, and pleural effusion after the 4
courses of pembrolizumab, stayed in near CR after stopping all treatment for
several months. The clinical response in this patient was already observed one
week after start of dabrafenib, when pembrolizumab can be assumed to be still
active and at relevant dose levels in the patient at that timepoint (MSD,
internal data). Thus, we postulate that combined BRAF+MEK inhibition can
synergize (by antigen retrieval and modulation of intratumoral immune
infiltrates) with pembrolizumab. In line with this clinical observation, we
found in our mouse model of human melanoma, short-term BRAF+MEK inhibition (7
days) to induce the highest intratumoral CD8/Treg ratios, when comparing
different targeted therapy combinations (Blank et al., manuscript in
preparation).
In summary, preclinical data, and our clinical observation, indicate that
intermittent short-term BRAF+MEKi can synergize with pembrolizumab treatment.
Study objective
Primary objectives:
To explore the safety, feasibility, and the immune-activating capacity of
different schemes of continuous/intermittent dabrafenib+trametinib during
treatment with pembrolizumab as compared to pembrolizumab monotherapy
Secondary objectives:
- To determine rates of response at week 6, 12, week 18, and best overall
response.
- To determine progression-free survival starting from randomization.
- To determine long-term toxicities of intermittent dabrafenib + trametinib
during treatment with pembrolizumab as compared to pembrolizumab monotherapy
Study design
This is a phase 2 feasibility trial consisting of 32 patients randomizing
between 3 combinations of dabrafenib + trametinib + pembrolizumab and
pembrolizumab monotherapy.
Intervention
Irresectable stage III or stage IV BRAFV600E/K mutation positive melanoma
patients, naïve for CTLA4/PD-1/PD-L1 blockade, will be treated with
pembrolizumab 200mg q3wk. After 6 weeks pembrolizumab monotherapy, depending on
the randomiztion outcome the patients will receive in addition 2x intermittent
dabrafenib + trametinib or pembrolizumab monotherapy and continue with
pembrolizumab for up to 2 years in case of confirmed clinical benefit at week
18. Each group will consist of 8 patients. Lab testing (incl. PBMC, serum
collection) will be performed during screening, at baseline, at the indicated
time points until week 18, and subsequently every three months. Tumor
biopsies/material preservations are required at baseline, at week 6, week 8 and
at week 12. CT scans will be required at baseline, week 6, week 12, week 18,
and subsequently every 3 months up to 2 years. Another PBMC, serum collection
and tumor biopsies will be performed at the timepoint of progression.
Study burden and risks
Pembrolizumab monotherapy and the combination of dabrafenib and trametinib have
both been tested as safe and effective treatment options in melanoma patients,
and have become approved standard therapies for late stage melanoma. The
combination of dabrafenib+trametinib with anti-PD-L1 (MEDI4736, durvalumab) has
been declared to be safe and induced increased tumor T cell infiltration (Ribas
et al., abstract #3003, ASCO 2015). Nevertheless, adding an anti-PD-1 instead
of anti-PD-L1 antibody could have another toxicity profile, despite their
similarities in adverse events as monotherapies.
In contrast to Ribas et al. we will apply dabrafenib+trametinib for shorter
time. This will expose the patients to less triple therapy, but might be more
immunostimulatory, as we assume that continuous application reduces the initial
tumor immune infiltration again. Thus a burden for the patients could be more
frequent immune-related adverse events. Therefore we have included safety as
primary readout into this study, despite the strong indication that the triple
treatment is safe.
Additional burden for the patients participating in this trial (as compared to
pembrolizumab monotherapy outside the study) are additional tumor biopsies that
will be taken from easy accessible lesions (lymph node or subcutaneous lesions,
which is an inclusion criterion), and more blood drawing.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
• Adults at least 18 years of age
• World Health Organization (WHO) Performance Status 0-2
• Histologically/cytologically confirmed irresectable stage III or 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 CTLA-4, PD-1 or PD-L1
• 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.
Exclusion criteria
• 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 CTLA4/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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003120-31-NL |
| CCMO | NL54421.031.15 |