Open Label Phase 2 Study Neo-Adjuvant BRAF/MEK Inhibition Followed by Surgery and Adjuvant BRAF/MEK Inhibition in In-transit Melanoma Metastases (NASAM)

Phase 2

Recruiting

Conditions: in transit metastases melanoma
10040900

Registration Number: NL-OMON52356

Lead Sponsor: Academisch Medisch Centrum

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 28

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

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary study endpoint is to determine efficacy of neo-adjuvant BRAF/MEK<br /><br>inhibition with encorafenib/binimetinib in patients with histologically<br /><br>confirmed in-transit melanoma metastases, measured as partial-, complete- or no<br /><br>response. In the biopsy at week 0 the viability will be judged and will be<br /><br>graded according to the amount of tumor necrosis: >50% tumor necrosis with <50%<br /><br>viable tumor cells, <50% necrosis with >50% viable tumor cells and 100%<br /><br>necrosis without viable tumor cells. Partial response is defined as a decrease<br /><br>of at least 50% of the viable tumor cells, compared to the baseline<br /><br>measurement, week 0, and complete response as 100% decrease of tumor cells,<br /><br>whereas no response is defined as more than 50% of viable tumor cells present. </p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary endpoints/parameters are: toxicity according to CTCAE v 5.0,<br /><br>recurrence free survival (RFS); defined as the time from inclusion into the<br /><br>study to recurrence of disease (local and/or distant), distant metastasis free<br /><br>survival (DMS) defined as the moment from inclusion into the study to<br /><br>recurrence event (distant) and overall survival (OS); defined as moment of<br /><br>inclusion into the study up to the last moment alive. </p><br>