A Combination of Ipilimumab and Fotemustine for Treat Unresectable Locally Advanced or Metastatic Melanoma

A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients With Unresectable Locally Advanced or Metastatic Malignant Melanoma

This study is designed to assess the safety and efficacy of a combination of ipilimumab and fotemustine in Patients with Unresectable Locally Advanced or Metastatic Malignant Melanoma.

Immunotherapy, chemotherapy and chemotherapy combinations are currently the most effective accepted systemic treatments for metastatic melanoma. However, significant and prolonged responses are rare.

The trial will determine the additional benefit achieved from adding fotemustine to the anti-CTLA-4 monoclonal antibody,ipilimumab .

It is assumed that the mechanism by which ipilimumab augments the effects of chemotherapy in animal models relies on the ability of the cytotoxic agent to induce apoptosis of tumor cells. These apoptotic cells then can function as potent inducers of an immune response against any non-tolerized antigen that they contain. Thus, the chemotherapy may be creating an in vivo autologous tumor vaccine. Ipilimumab prevents the down regulation of this immune response, allowing for tumor rejection. Animal models evaluating the combination of anti-CTLA4 antibody and chemotherapy have given only a brief acute treatment with chemotherapy - presumably adequate to induce some tumor apoptosis, but inadequate to induce significant prolonged tumor rejection.

Since patients with metastatic melanoma generally require therapy within a relatively short period of time, this protocol will allow for the use of fotemustine. Standard dosing of fotemustine will be used to optimize the chance for tumor control.

Inclusion Criteria:

• Histologic diagnosis of malignant melanoma
• Stage III (unresectable) or Stage IV melanoma
• Maximum 1 line of chemotherapy for advanced disease allowed
• No prior chemotherapy within 4 weeks from treatment start (6 weeks in case of nitrosourea)
• No previous systemic corticosteroid therapy within 10 days
• Prior adjuvant treatment with IFN or other immunotherapy allowed
• Asymptomatic brain metastases allowed
• Measurable disease
• Prior treatment of brain metastases. In case stereotactic radiotherapy (or surgery) was not applicable, whole brain radiotherapy should have been performed
• Life expectancy >= 16 weeks
• ECOG performance status of 0 or 1
• Normal laboratory tests were required
• 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 be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized.

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;
• Previous enrollment in another clinical trial or prior treatment with a CD137 agonist or anti-CTLA-4 and/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.