A Study of Fotemustine(FTM) Vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis

This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis.

Metastatic melanoma is an aggressive tumor associated with very poor prognosis. Brain metastases develop in nearly half of MM pts and in 30 to 40% of these subjects, the brain is the first site of relapse. The limited activity of available agents, along with relative resistance to radiotherapy and poor CNS penetration of most chemotherapeutic agents, make this one of the most daunting problems in oncology. There is no optimal systemic or local therapy for melanoma metastatic to the brain. Though MM pts with brain metastases have been excluded from most phase II-III trials with ipilimumab, initial evidences suggest that the anti-CTLA-4 monoclonal antibody ipilimumab might be active as single-agent also in this clinical setting. Preliminary results from the NIBIT-M1 phase II trial suggest for the safety and efficacy of the combination of fotemustine plus ipilimumab in MM pts with or w/o brain metastases.Recent data from a phase I study in MM pts w/o brain metastases have shown that concurrent administration of ipilimumab (3 mg/kg) plus the anti-PD1 mAb nivolumab (1 mg/kg) induced objective responses in 53% of pts, with a tumor reduction of ≥80% in 41% of pts, with an 82% 1-year OS, and with an acceptable safety profile.Based on the long-term follow-up of the NIBIT-M1 study, and on the activity of the concurrent administration of ipilimumab and nivolumabthe NIBIT-M2 study will explore the efficacy of the combination of ipilimumab and fotemustine or ipilimumab and nivolumab versus fotemustine alone in pts with melanoma metastatic to the brain.

Eligibility Criteria:
Inclusion Criteria:

* Willing and able to give written informed consent.
* Histologic diagnosis of malignant melanoma;
* Stage IV melanoma;
* No prior therapy for advanced (unresectable Stage III or Stage IV) disease;
* No previous systemic corticosteroid therapy within 7 days;
* Prior adjuvant treatment with IFN or other immunotherapy allowed with exception of anti-CTLA-4;
* Presence of asymptomatic brain metastases: patients must have measurable metastases in the brain, defined as lesions that can be accurately measured in 2 dimensions as ≥ 0.5 cm (maximum 2 cm) in the brain MRI with contrast;
* Pts who have been previously treated with brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT) and/or surgery, must have developed new measurable brain lesions;
* Life expectancy ≥ 12 weeks;
* ECOG performance status of 0 or 1 (see Appendix 2);
* Normal laboratory tests were required.
* Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard.
* Negative screening tests for HIV, Hepatitis B, and Hepatitis C.
* Men and women, of and over 18 years old.Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug

Exclusion Criteria:

* Any malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix;
* Primary ocular or mucosal melanoma.

Medical History and Concurrent Diseases:

* Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
* Autoimmune disease
* Any underlying medical condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.

Prohibited Treatments and/or Therapies:

* Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy ; other investigational anti-cancer therapies; or chronic use of systemic corticosteroids
* Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
* Prior treatment with anti-CTLA-4 and/or , anti-PD1/PD-L1 or fotemustine.

Sex and Reproductive Status:

* WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study;
* Women who are pregnant or breastfeeding;
* Women with a positive pregnancy test on enrollment or prior to investigational product administration;
* Sexually active fertile men not using effective birth control if their partners are WOCBP.

Other Exclusion Criteria:

* Prisoners or subjects who are involuntarily incarcerated;
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.