Encorafenib/binimetinb combination therapy can possibly reduce tumor size and thus making surgical treatment less comprehensive. In addition, the treatment can potentially improve recurrence-free survival, overall survival, and distant metastases-…
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Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint is to determine efficacy of neo-adjuvant BRAF/MEK
inhibition with encorafenib/binimetinib in patients with histologically
confirmed in-transit melanoma metastases, measured as partial-, complete- or no
response. In the biopsy at week 0 the viability will be judged and will be
graded according to the amount of tumor necrosis: >50% tumor necrosis with <50%
viable tumor cells, <50% necrosis with >50% viable tumor cells and 100%
necrosis without viable tumor cells. Partial response is defined as a decrease
of at least 50% of the viable tumor cells, compared to the baseline
measurement, week 0, and complete response as 100% decrease of tumor cells,
whereas no response is defined as more than 50% of viable tumor cells present.
Secondary outcome
Secondary endpoints/parameters are: toxicity according to CTCAE v 5.0,
recurrence free survival (RFS); defined as the time from inclusion into the
study to recurrence of disease (local and/or distant), distant metastasis free
survival (DMS) defined as the moment from inclusion into the study to
recurrence event (distant) and overall survival (OS); defined as moment of
inclusion into the study up to the last moment alive.
Background summary
In-transit metastases of cutaneous melanoma is a unique form of locoregional
disease occurrence in the dermal and subdermal tissue[1]. The clinical
presentation of in-transit metastases can vary largely, with involvement of 1
to 100 subcutaneous metastatic nodules, and nodules too can differ
significantly in size, ranging from 1mm to 5cm[2]. In-transit melanoma
metastases occurring without lymph node and or distant metastases involvement
is classified as stage IIIB or IIIC, depending on primary tumor
characteristics, according to the American Joint Committee on Cancer (AJCC) 8th
Edition[3]. Interestingly, patients diagnosed solely with in-transit melanoma
metastases, so called N1c positive patients, have similar overall survival
rates as compared to stage IIIA melanoma patients, however with a lower quality
of life due to a relatively high tumor burden, which poses the significant
impact this disease can have[4].
Primary therapy for in-transit melanoma is complete resection of the tumor.
However, patients who have undergone complete resection of in-transit
metastases have a high rate of locoregional disease recurrence, which justifies
the need for additional adjuvant therapy[1, 5, 6]. Even though adjuvant therapy
is warranted, no consensus exists on adjuvant therapy for these patients, as
only a small subgroup of pN1c patients were included in adjuvant trials
investigating the efficacy of nivolumab and dabrafenib/trametinib[7, 8].
Currently, FDA approved adjuvant approaches for resected in-transit metastases
include anti-programmed death 1 agent nivolumab and adjuvant BRAF/MEK
inhibition with dabrafenib/trametinib, a therapy eligible for patients
harboring the oncogenic BRAFV600E/K mutation[9].
Since the disease can be widespread, complete surgical excision of the tumor
can become challenging and form a heavy burden for the patient. Neo-adjuvant
therapy can be of aid in in reducing tumor size and thus making surgical
intervention less comprehensive[10]. Recently conducted studies investigating
the combination therapy of nivolumab and ipilimumab, an anti-cytotoxic
T-lymphocyte-associated antigen 4 monoclonal antibody, in neo-adjuvant setting
for in-transit melanoma have achieved radiological and pathological disease
responses, despite limitations in sample size[11, 12]. As for targeted therapy,
neo-adjuvant BRAF/MEK inhibition with dabrafenib/trametinib, has shown to
decrease tumor size and induce pathological responses in patients with
resectable stage III melanoma, however conducted studies included few
in-transit metastases patients[13, 14]. An equivalent therapy to
dabrafenib/trametinib is the combination therapy encorafenib/binimetinib with a
more favorable toxicity profile, which is FDA and EMA approved as systemic
therapy for advanced melanoma[15]. Despite this, encorafenib/binimetinib has
not been studied in the (neo)adjuvant setting yet.
Since dabrafenib/trametinib and encorafenib/binimetinib have a similar working
mechanism but with a more favorable toxicity profile for
encorafenib/binimetinib, we propose the following trial: Neo-Adjuvant
encorafenib/binimetinib in patients with in-transit melanoma metastases,
followed by Surgical excision and subsequently Adjuvant encorafenib/binimetinib
(NASAM).
Furthermore, a pooled data analysis from the Neoadjuvant Melanoma Consortium
Group observed a (near) complete pathological response in 33% in neo-adjuvant
immunotherapy treated patients and 47% in patients who received neoadjuvant
BRAF/MEK inhibition. The one-year recurrence free survival was 96% in the
neoadjuvant immunotherapy cohort and 88% in the neoadjuvant BRAF/MEK-treated
patients. Interestingly, in patients with a partial response, the two-year
recurrence free survival was significantly higher in the neoadjuvant treated
immunotherapy group as compared to the neoadjuvant BRAF/MEK cohort with 13%
versus 64%, respectively. This underlines the importance of attaining a
pathologic (near) complete response in targeted therapy treated patients,
whereas partial response to immunotherapy might be sufficient to achieve
improved recurrence free survival.
Rresults of the NeoAdjuvant melanoma Consortium has demonstrated that patients
who develop a (near) complete pathological response to BRAF/MEK inhibition have
an improved recurrence free survival. This underlines the potential of
neoadjuvant BRAF/MEK inhibition in patients with locoregional in-transit
disease, especially as response to therapy can be fast and might come with less
therapy related adverse events. More specifically, trials investigating the
efficacy of neo-adjuvant BRAF/MEK inhibition with dabrafenib/trametinib, showed
to significantly improve event-free survival versus standard of care in
patients with high-risk surgically resectable clinical stage III-IV
melanoma[13, 14]. Moreover, the NeoCombi study demonstrated promising results:
35 stage IIIB/IIIC BRAFV600E/V600K mutated of which 7 (20%) stage patients with
in-transit metastases only, received neo- adjuvant BRAF/MEK inhibition with
dabrafenib/trametinib, followed by surgical resection leading to a pathological
response in 30 (86%) patients[14]. In addition, a study conducted by Ameria
and colleagues, revealed that 9 (75%) patients with stage III or
oligometastatic stage IV melanoma, treated with neo-adjuvant BRAF/MEK
inhibition achieved a pathological response[13]. Taken these promising study
results together, we hypothesize that neo- adjuvant BRAF/MEK inhibition can
contribute to reducing locoregional tumor burden, consequently surgery will
become less comprehensive, thus forming a smaller burden for the patient.
Study objective
Encorafenib/binimetinb combination therapy can possibly reduce tumor size and
thus making surgical treatment less comprehensive. In addition, the treatment
can potentially improve recurrence-free survival, overall survival, and distant
metastases-free survival, implying the benefit the study potentially has.
Study design
Phase 2 open-label single arm intervention study administering
encorafenib/binimetinib in neo-adjuvant setting followed by surgery and
subsequent adjuvant encorafenib/binimetinib in patients with a (near) complete
pathological response to neo-adjuvant encorafenib/binimetinib.
Patient with partial respons or no respons to neo-adjuvant BRAF/MEKi will
receive adjuvant anti-PD-1 therapy.
Intervention
Patients diagnosed with in-transit melanoma metastases will receive
encorafenib/binimetinib in the neo-adjuvant setting for 8 weeks according to
the schedule depicted below. Additionally, patients will undergo extra blood
drawings in the context of translational research. Upon completion of
neo-adjuvant therapy, patients will undergo surgery. Patients with a (near)
complete response will receive adjuvant encorafenib/binimetinib for 44 weeks.
Patients with a partial respons or no respons to neo-adjuvant
encorafenib/binimetinib, will receive adjuvant anti-PD-1 (nivolumab) for 52
weeks.
Study burden and risks
The combination of encorafenib/binimetinib has been FDA and EMA approved as
standard therapy for BRAF V600E/V600K mutated cutaneous melanoma in the
advanced setting, based on progression free survival and overall survival
results from the randomized phase 3 trial COLUMBUS[15]. In addition, the
COLUMBUS trial demonstrated that encorafenib/binimetinib has a favorable
side-effect profile as compared to other BRAF/MEK inhibition therapies such as
dabrafenib/trametinib and vemurafenib/cobimetinib[16, 17]. Important to outline
is, that encorafenib/binimetinib has not been investigated yet in the
neo-adjuvant nor in the adjuvant setting for melanoma.
Despite the current lack of information regarding the efficacy of
encorafenib/binimetinib in both neo-adjuvant and adjuvant setting, we
hypothesize that encorafenib/binimetinib is effective in the neo-adjuvant
setting, since this regimen has shown to be effective in treating melanoma in
the advanced setting, and encorafenib/binimetinib has a similar working
mechanism as FDA and EMA approved adjuvant BRAF/MEK inhibition with
dabrafenib/trametinib.
Patients who will enroll in our study, are at risk of receiving an ineffective
therapy for the treatment of in-transit metastases, despite available evidence
regarding the systematic efficacy of encorafenib/binimetinib in the metastatic
setting. Furthermore, patients will be at risk of developing treatment related
adverse events. An additional burden in this trial is extra blood drawings that
will be performed at the beginning, during and at the end of treatment.
Considered as standard care, the mandated 4-monthly PET-CT and MRI scan at
start with hospital visit is a burden for the patient. Patients are mandated to
undergo surgery upon completing neo-adjuvant treatment, and surgery can
potentially have complications, such as uncontrolled bleeding, infection,
thrombosis, nerve damage and shock.
Despite the named burdens of this trial, important is to underline the benefit
the trial potentially has for the patients. Encorafenib/binimetinb combination
therapy can possibly reduce tumor size and thus making surgical treatment less
comprehensive. In addition, the treatment can potentially improve
recurrence-free survival, overall survival, and distant metastases-free
survival, implying the benefit the study potentially has.
Albinusdreef 2 Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2 Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
1. Age over 18 years old
2. World Health Organization (WHO) Performance Status 0 or I
3. Primary cutaneous melanoma or unknown primary melanoma with pathologically
confirmed in-transit metastatic melanoma
4. Histologically confirmed presence of BRAFV600E/K mutation in primary tumor
tissue
5. Patients must have undergone complete disease staging including: PET-CT scan
and MRI scan
6. Patients must be medically fit to undergo surgery
7. Patients must be able to take oral medication
8 No prior anticancer systemic treatment (including chemotherapy,
immunotherapy, oncolytic viral therapy, other systemic therapies)
9. No prior radiotherapy to site of interest (surgical therapy is allowed; in
order to obtain pathological information of the melanoma)
10. Screening laboratory values must meet the following criteria: WBC >=
2.0x109/L, Neutrophils >= 1.0x109/L, Platelets >= 100 x109/L, Hemoglobin >= 6.5
mmol/L, AST <= 2.5 x ULN, ALT <= 2.5 x ULN, Total bilirubin <= 1.5 X ULN, INR and
PTT in normal range, LDH < 2xULN. Serum creatinine <= 1.5 × ULN; or
calculated creatinine clearance >= 50 mL/min by Cockcroft-Gault formula; or
estimated glomerular filtration rate > 50 mL/min/1.73m2.
11. Absence of additional severe and/or uncontrolled concurrent disease
12. Patients known to be human immunodeficiency virus (HIV) positive are
eligible if they have undetectable HIV viral load and stable and adequate CD4
counts (>= 500 mm^3) on screening labs provided they meet all other protocol
criteria for participation and that there are no high-risk drug interactions
Exclusion criteria
1. Presence of regional lymph node metastases
2. Presence of distant metastases
3. Current treatment with antiretroviral drugs, herbal remedies and drugs that
are strong inhibitors or inducers of CYP3A and CYP2C8
4. Patients with active bacterial infections with systemic manifestations
(malaise, fever, leukocytosis) are not eligible until completion of appropriate
therapy
5. Underlying medical conditions that, in the Investigator's opinion, will make
the administration of study treatment hazardous or obscure the interpretation
of toxicity determination or adverse events
6. History of congestive heart failure, active cardiac conditions, including
unstable coronary syndromes (unstable or severe angina, recent myocardial
infarction), significant arrhythmias and severe valvular disease must be
evaluated for risks of undergoing general anesthesia. Furthermore, enlarged QTc
interval, uncontrolled hypertension, poor left ventricular function (< 50%,
as determined by MUGA scan) and recent thromboembolic or cerebral event.
7. History of central serous retinopathy or retinal vein occlusion
8. Active intestinal disease interfering with oral drug absorption
9. Patients who are unable to be temporally removed from chronic
anti-coagulation therapy
10. Other malignancy within 2 years prior to entry into the study, except for
treated non-melanoma skin cancer and in situ cervical carcinoma
11. Patient must not have active hepatitis B, and/or active hepatitis C
infection given concerns for drug interactions or increased toxicities. Testing
is not required
12. Patient must not have any known history of acute or chronic pancreatitis
13. Patient must not have any concurrent neuromuscular disorder that is
associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies,
muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy
14. Pregnancy or nursing
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR2021-002285-40-NL |
| CCMO | NL77905.058.21 |