A Phase II Clinical Trial on Neo-adjuvant Pembrolizumab in Patients With pT3b-T4a/b cN0M0 Melanoma.

A Phase 2 Clinical Trial on Neoadjuvant Pembrolizumab in Patients Diagnosed With High-risk Melanoma Without Clinical Evidence of Metastatic Dissemination.

This study, called NeoSenti, is exploring whether giving one dose of the immunotherapy drug pembrolizumab before surgery can help the immune system fight melanoma more effectively. The study includes adults with high-risk melanoma who do not show any signs of the cancer having spread on scans. Participants receive a single infusion of pembrolizumab six weeks before their scheduled sentinel lymph node biopsy. The goal is to see if this early treatment can reduce or eliminate tiny cancer cells that might already be in the lymph nodes but are too small to detect.

After surgery, patients whose melanoma stage normally requires further treatment will continue with standard immunotherapy for one year. Others will move directly into follow-up care. All participants are monitored closely for five years with regular scans, blood tests, and check-ups to watch for any signs of recurrence and to ensure their safety.

The NeoSenti study is a clinical trial exploring whether giving one dose of the immunotherapy drug pembrolizumab before surgery can help improve outcomes for people with high-risk melanoma. Pembrolizumab is a treatment that strengthens the immune system so it can better recognize and attack cancer cells. It is already used after surgery for certain melanoma stages, but this study aims to find out whether giving it earlier-before the sentinel lymph node biopsy-can reduce the chance that melanoma has already spread microscopically.

Adults with high-risk primary melanoma who do not show any signs of cancer spread on physical examination or scans may be eligible to participate. Before joining, patients undergo blood tests, a PET/CT scan, an ultrasound of the lymph node area, and a review of their melanoma features. Some patients will also have a Merlin™ genetic test to determine whether their tumor carries a high risk of spreading.

Participants who qualify receive a single infusion of pembrolizumab six weeks before their planned surgery. This "pre-surgery" (neoadjuvant) treatment is intended to give the immune system time to attack melanoma cells that may be in the lymph nodes but are too small to detect. About six weeks later, patients undergo surgery, including a sentinel lymph node biopsy-used to check whether melanoma has started to spread-and, if needed, a wide local excision to remove additional tissue around the original melanoma.

The results of the surgery determine the next steps. Patients whose cancer is classified as stage IIB, IIC, or III after surgery will continue with standard immunotherapy every six weeks for one year. Patients with stage IB or IIA melanoma will not need additional treatment and will move directly into follow-up care. Regardless of stage, all participants are monitored very closely for five years. This follow-up includes regular physical examinations, blood tests, full-body imaging every four months (PET/CT or whole-body MRI), and optional questionnaires about quality of life and cognitive function. Some patients may also have blood tests that measure tiny amounts of tumor DNA (ctDNA), which might help predict the risk of recurrence.

Inclusion Criteria:

≥ 18 years of age on the day of signing the informed consent.

Histologically confirmed high risk primary cutaneous pT1b-4b melanoma High risk primary melanoma is defined in this study as the following AJCC8 T-stages:

• pT1b-3a, with a poor prognostic score on the Merlin™ test ("Merlin™ high risk");
• pT3b-4b, irrespective of their Merlin™ test result

Amendable to sentinel lymph node biopsy.

No evidence of metastatic dissemination as demonstrated by PET/CT, ultrasound of the draining lymph node basin, and clinical examination.

No prior exposure to systemic treatment for melanoma (adjuvant or curative).

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2 assessed within 7 days prior to the first dose of study treatment.

Adequate baseline organ function as defined by local institutional standards.

Women:

• Female patients must be surgically sterile or be postmenopausal (A postmenopausal state is defined as no menses for 12 months without an alternative medical cause).
• If a female patient is a woman of childbearing potential (WOCBP) they must agree to use highly effective contraception measures during the period of therapy, which should be continued for at least 4 months following the last dose of pembrolizumab as indicated in the SmPC. A list of highly effective contraceptive measures is included in appendix 1 All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment and pregnancy testing should be conducted within 24h prior to the first dose of immune checkpoint inhibitors and thereafter monthly until 4 months following the last dose study treatment.
• Should not be breastfeeding at screening or during study treatment.

Men with a female partner of childbearing potential must agree to use highly effective contraception from 14 days prior to administration of the first dose of study treatment or have either had a prior vasectomy, throughout the treatment period, and for 16 weeks after the last dose of study treatment.

Capable of providing documented informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

Patients with uveal melanoma, mucosal melanoma and melanoma of unknown primary origin.

Active autoimmune disease requiring systemic treatment.

Patients with a history of previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to screening and no additional therapy is required or anticipated to be required during the study period.

Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Exception: subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.

Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.

Active infection at the time of screening (e.g. wound infection).

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatment, or excipients.

History of organ allograft.

Patients who have previously been exposed to checkpoint inhibitors.

Prior transplantation of human cells, tissues and organs (e.g. liver transplant) or candidates for any type of transplantation.

History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Any contra-indication for evaluation by whole body 18F-FDG-PET/CT or MRI.