Perioperative Treatment With Tranexamic Acid in Melanoma (PRIME)

Perioperative Treatment With Tranexamic Acid in Melanoma; Prognostic and Treatment-related Impact of the Plasminogen-plasmin Pathway

Surgery is a key element in the treatment of melanoma, and naturally linked with an inflammatory response and recruitment of innate immune cells. Although surgery has a favorable intent, surgery-induced inflammation, neutrophils in particular, may accelerate growth of local and systemic micrometastases. Thus, improving cancer surgery and modulating the wound microenvironment in ways that benefit the patients is crucial. Repurposing already approved drugs in a cancer setting has gained increasing interest in recent years. Interestingly, tranexamic acid was recently suggested as an anti-cancer drug, capable of reducing tumor growth in experimental animal models and reducing the viability of different melanoma cell lines. As a novel approach, sponsor and investigators will conduct a Randomised Clinical Trial, using perioperative treatment with Tranexamic Acid, aiming to prevent the early relapses for patients with melanoma.

The objective of the proposed clinical trial is to test if perioperative treatment with tranexamic acid (TXA) reduces the early relapses and postoperative complications for patients with melanoma and evaluate perioperative inflammation and the prognostic- and treatment-related impact of the plasminogen-plasmin pathway from human blood- and tissue samples. Primary aim: To test if perioperative treatment with TXA is superior to placebo and reduces the early relapse rates, from 37% to 26%, for patients diagnosed with melanoma undergoing sentinel lymph node biopsy surgery. Secondary aims: Evaluate safety and tolerability: defined as mild (abdominal pain, diarrhea, or nausea) or severe (thromboembolic events) adverse effects. Evaluate postoperative complications: defined as bleeding, seroma formation, and infections within the first three postoperative months. Estimate melanoma-specific survival probabilities and compare the two treatment groups. Explorative: From blood- and tissue samples, baseline and perioperative changes of factors associated with inflammation, fibrinolysis, metabolism, immune cell composition, and activation status will be monitored and factors will be associated with prognostic and treatment-related outcomes.

Participants, care providers, investigators/outcome assessors are all blinded to the intervention. Selected trained personnel who does not treat or assess the participants will be unblinded to prepare the intervention for administration and deliver the intervention to blinded personnel for administration.

A single dose of TXA (15 mg/kg) administered intravenously 30 min (+/-15 min) before skin incision and subsequently, TXA (1000 mg) administered orally 4 and 8 hours post-surgery and TXA (1000 mg) 3 times daily through postoperative day 4.

A single dose of saline matching the volume of the experimental arm treatment regiment (Saline) administered intravenously 30 min (+/-15 min) before skin incision and subsequently, placebo tablets (2 tabs.) administered orally 4 and 8 hours post-surgery and (2 tabs) 3 times daily through postoperative day 4.

Histopathological confirmed relapse, defined as either local, regional (in transit or lymph node) or systemic relapses. Systemic metastases suspected on PET / CT/ MR will be used if a biopsy is not possible. Based on the primary endpoint, we will calculate the relapse risk proportions for each treatment arm as a binary outcome. The date of relapse or completed follow-up is noted and the relapse-free period is defined as the date of wide local excision and sentinel lymph node biopsy until the date of either the first confirmed relapse or the date of completed two-year follow-up without relapse.

Adverse events summarised according to grade: Mild: defined as the patient's report of abdominal pain, diarrhea, or nausea. Severe: thromboembolic events, verified radiologically.

Postoperative complications, summarised according to the type and postoperative timepoint, is defined as binary outcomes: Bleeding: defined as a drained or surgically removed hematoma or suggillation of blood to the skin around the operated area, occurring within the first 10 days post-surgery. Seroma: drained seroma, during the period from end of surgery through 3 months post-surgery. Infection: local wound infection, treated with antibiotics or surgical intervention, during the period from end of surgery through 3 months post-surgery.

Postoperative complications, summarised according to the type and postoperative timepoint, is defined as binary outcomes: Bleeding: defined as a drained or surgically removed hematoma or suggillation of blood to the skin around the operated area, occurring within the first 10 days post-surgery. Seroma: drained seroma, during the period from end of surgery through 3 months post-surgery. Infection: local wound infection, treated with antibiotics or surgical intervention, during the period from end of surgery through 3 months post-surgery. The severity of postoperative complications in need of medical intervention will be graded according to the Good Clinical Practice criteria for serious adverse events.

Time to event estimates: Defined as the period from the date of surgery (wide local excision and sentinel lymph node biopsy) to the date of death from suspected systemic melanoma (histopathologically confirmed relapse or systemic metastases suspected on PET / CT / MR) or the date of completed 2 years follow-up.

Time to event estimates: Defined as the period from the date of surgery (re-excision and sentinel node) to the date of death from all causes or the date of finalised 2 years follow-up.

Time to event estimates: Defined as the period from the date of surgery (re-excision and sentinel node) to the date of histopathologically confirmed relapse (local, regional or systemic), death from all causes or the data or completed 2 years follow-up.

Inclusion Criteria: Patients Diagnosed with invasive cutaneous melanoma (pathological stage/tumor grade ≥T2b), defined as either: Breslow thickness >1.0-2.0 mm with presence of ulceration or Breslow thickness >2.0 mm regardless of ulceration status. Eligible for surgery (wide local excision and sentinel lymph node biopsy). >/=18 years of age and </=80 years of age Signed Informed Consent Form Exclusion Criteria: Patients With a prior history of invasive melanoma Thromboembolic events within the last 3 months Pregnancy Active breastfeeding Known allergy or hypersensitivity to TXA Known and treated epilepsia or previous seizures eGFR 0-50 Current use of tranexamic acid

The study protocol, statistical analysis plan, informed consent will be publically available at Clinical Trials Information System, European Medicines Agency