Trial of Temozolomide in BAP1 Mutated Patients With Advanced or Metastatic Cutaneous Melanoma

Although the therapeutic management of melanoma has undergone a revolution over the past decade with the advent of immune checkpoint inhibitors on the one hand, and BRAF- and MEK-targeted therapies in patients harboring a BRAF V600 mutation on the other hand, half of patients do not achieve a durable response to these strategies. In light of these major advances, chemotherapy has gradually been abandoned, even in patients with limited therapeutic options, because of its very low response rate.

BAP1, or BRCA1-associated protein 1, is involved in DNA repair through homologous recombination and is considered a tumor suppressor gene. It is lost or inactivated in a wide range of tumors, and the presence of germline BAP1 mutations is associated with a tumor predisposition syndrome (BAP1 tumor predisposition syndrome, BAP1-TPDS).

Following the observation by our team of two exceptional responses, both intracranial and extracranial, lasting more than six months, in two young patients with metastatic melanoma harboring a constitutional BAP1 mutation, treated in the third and eighth lines of therapy, respectively, we hypothesize that this mutation may confer increased susceptibility to chemotherapy, as has been reported in pleural mesothelioma. This increased susceptibility could help guide the therapeutic strategy for affected patients, who account for approximately 1% of cutaneous melanomas in the germline setting and 5-17% of cutaneous melanomas when somatic mutations are considered.

As it remains unclear whether this effect is restricted to germline BAP1 mutations, we chose to include both germline and somatic BAP1 mutations in this study. This is particularly relevant because, in routine clinical practice, the germline or somatic nature of a BAP1 mutation is often determined at a later stage. Somatic mutation testing is frequently performed only as part of a molecular biology panel before predictive medicine strategies are considered, guided by molecular tumor boards, in patients with limited therapeutic options.

Validation of this hypothesis could make it possible to identify patients who may benefit from this readily available and inexpensive treatment.

Inclusion criteria

• Adult patient (≥18 years old)
• Patients who have received information about the study and have signed an informed consent form.
• Histopathological confirmation of a diagnosis of stage III (unresectable) or stage IV (metastatic) cutaneous melanoma according to the 8th edition of the AJCC staging system.
• Patient has experienced treatment failure after undergoing at least one line of Immunotherapy with at least one immune checkpoint inhibitor (anti-PD1, anti-PD1+anti-CTLA4, or anti-PD1+anti-LAG3) and one line of targeted therapy combining BRAF and MEK inhibitors, if indicated.
• The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or lower.
• The patient must have at least one measurable lesion defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
• The patient must have a pathogenic BAP1 alteration identified by a molecular biology technique in tumor tissue or in circulating cell-free DNA.
• The inclusion of patients is subject to the following criteria:
• Absolute neutrophil count ≥ 1.5 x 109/L (≥ 1500 per mm3)
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL
• ASAT and/or ALAT ≤ 2.5 x Upper Limit of Normal (ULN); patient with liver metastases ≤ 5 × ULN
• Total bilirubin ≤ 1.5 x ULN
• Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min for patients with creatinine levels > 1.5 x ULN (according to Cockroft-Gault Appendix D) ;
• International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
• Female patients with a negative highly sensitive pregnancy test, or postmenopausal female patients.

Exclusion criteria

• Patients with non-cutaneous melanoma, whether uveal, mucosal, of unknown primary origin or leptomeningeal
• Patients who have received a minimum of one line of chemotherapy for melanoma treatment
• Positive serology results for human immunodeficiency virus (HIV), active hepatitis B or C infection (acute or chronic) or uncontrolled infection
• Concomitant presence or history of another malignancy, except for the following: appropriately treated squamous or basal cell carcinoma of the skin (adequate healing is required prior to study entry); any other solid tumor, curatively treated and without evidence of recurrence for at least 2 years prior to study entry.
• Participation in or ongoing treatment with another investigational agent or use of an investigational device within 28 days prior to study treatment.

NB: Participants who have entered the follow-up phase if an investigational study may participate as long as it has been 4 weeks or an interval of five-half-lives, whichever the shortest is, after the last dose of the previous investigational agent.

• Subjects covered by Articles L1121-5 through L1121-8 of the Public Health Code (minors, adults under guardianship or conservatorship, patients deprived of their liberty, and pregnant or breastfeeding women).
• Any pathology that, in the investigator's opinion, may be a contraindication to the patient's participation in the clinical study, for reasons of safety or compliance with clinical study procedures.
• Patient with hypersensitivity to IMP temozolomide (including hypersensitivity to dacarbazine, severe myelosuppression) or to any of its excipients.