Clinical trial NCT05767879: (Neo)Adjuvant BRAF/MEK Inhibition in pN1c Melanoma
Official title: Open Label Phase 2 Study Neo-Adjuvant BRAF/MEK Inhibition Followed by Surgery and Adjuvant BRAF/MEK Inhibition in In-transit Melanoma Metastases (NASAM)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Melanoma Stage III
In-Transit Metastasis of Cutaneous Melanoma
Keywords: Targeted therapy
In-transit
Melanoma
Neo-adjuvant
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Pierre Fabre Laboratories
First posted: 2023-03-14
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase 2 open-label single arm intervention study administering encorafenib/binimetinib in neo-adjuvant setting followed by surgery and subsequent adjuvant encorafenib/binimetinib in in-transit melanoma patients without lymph node and distant metastases.

Detailed description: 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 diagnosed solely with in-transit metastatic melanoma.

Primary objective is to determine the efficacy of neo-adjuvant encorafenib/binimetinib as measured by pathological response rate (partial-, complete- and 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 and complete response as 100% decrease of tumor cells, whereas no response is defined as more than 50% of viable tumor cells present.

Secondary objectives are to assess efficacy of adjuvant BRAF/MEK inhibition, measured as local recurrence free survival (LRFS), distant metastases-free survival (DFMS), recurrence free survival (local and/or distant recurrence, RFS) and overall survival (OS). Additionally, the toxicity of the administered regimen will be assessed by analyzing the frequency- and type of adverse events, and occurrences of therapy interruption, dose reduction and or therapy cessation. Moreover, an exploration of drug measurements and ctDNA in blood and additional research of biopsies / resections will be done.

Eligibility criteria: Inclusion Criteria:

* Age over 18 years old
* World Health Organization (WHO) Performance Status 0 or I
* Primary cutaneous melanoma or unknown primary melanoma with pathologically confirmed in-transit metastatic melanoma
* Patients must have undergone complete disease staging including: PET-CT scan and MRI scan
* Patients must be medically fit to undergo surgery
* Patients must be able to take oral medication
* No prior anticancer systemic treatment (including chemotherapy, immunotherapy, oncolytic viral therapy, other systemic therapies)
* No prior radiotherapy to site of interest (surgical therapy is allowed; in order to obtain pathological information of the melanoma)
* 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.
* Absence of additional severe and/or uncontrolled concurrent disease

Exclusion Criteria:

* Presence of regional lymph node metastases
* Presence of distant metastases
* Current treatment with antiretroviral drugs, herbal remedies and drugs that are strong inhibitors or inducers of CYP3A and CYP2C8
* Patients with active bacterial infections with systemic manifestations (malaise, fever, leukocytosis) are not eligible until completion of appropriate therapy
* 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
* 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.
* History of central serous retinopathy or retinal vein occlusion
* Active intestinal disease interfering with oral drug absorption
* Patients who are unable to be temporally removed from chronic anti-coagulation therapy for operation
* (Neo)Adjuvant BRAF/MEKi for pN1c melanoma, version 5, 31 October 2021
* Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
* 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
* Patient must not have any known history of acute or chronic pancreatitis
* 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
* Pregnancy or nursing

Primary outcomes:
measure: Efficacy of neo-adjuvant encorafenib/binimetinib
timeFrame: 8 weeks
Secondary outcomes:
measure: Evaluate efficacy of treatment related toxicity
timeFrame: 52 weeks
measure: Efficacy of adjuvant encorafenib/binimetinib - local recurrece free survival (LRFS)
timeFrame: 44 weeks
measure: Efficacy of adjuvant encorafeninb/binimetinib - distant metastases-free survival (DFMS)
timeFrame: 44 weeks
measure: Efficacy of adjuvant encorafeninb/binimetinib - overall survival
timeFrame: 44 weeks
measure: Efficacy of adjuvant encorafeninb/binimetinib - treatment related survival
timeFrame: 44 weeks
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid-Holland
Study officials:
References: