Tremelimumab and CP-870,893 in Patients With Metastatic Melanoma

PRIMARY OBJECTIVES:

I. To assess the safety, dose-limiting toxicities and maximum tolerated doses of tremelimumab
(administered intravenously every 12 weeks) and CP- 870,893 (administered intravenously every
3 weeks).

SECONDARY OBJECTIVES:

I To seek preliminary evidence of anti-tumor efficacy of the combination of tremelimumab and
CP-870,893, including objective response rate at MTD.

II. To determine the immune pharmacodynamic changes associated with the administration of the
combination of tremelimumab and CP-870,893.

OUTLINE: Patients receive tremelimumab IV over 1 hour on day 1 and CD40 agonist monoclonal
antibody CP-870,893 IV over 30 minutes on days 2, 22, 43, and 64. Treatment repeats every 12
weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 4 weeks.

Inclusion

- Patients with metastatic melanoma who have measurable disease

- ECOG PS 0 or 1

- Adequate bone marrow function

- WBC >= 3,000

- Hgb >= 9

- Plt >= 100

- Adequate hepatic function, defined by the following parameters:

- Total bilirubin WNL unless associated with hepatobiliary metastases or Gilbert
syndrome, then total bilirubin =< 2 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
unless associated with hepatic metastases, then ALT and AST =< 5 x ULN

- Signed, written informed consent

Exclusion

- Previous treatment with any other compound that targets CD40 or CTLA4

- Concurrent treatment with any anticancer agent outside of this protocol

- Prior allogeneic bone marrow transplant

- History of brain metastases, even if previously treated

- History of autoimmune disorder, including type 1 diabetes mellitus, pemphigus
vulgaris, systemic mastocytosis, systemic lupus erythromatosis,
dermatomyositis/polymyositis, rheumatoid arthritis, systemic sclerosis, Sjorgen's
syndrome, vasculitis/arteritis, Behcet's syndrome, autoimmune thyroiditis, multiple
sclerosis, or uveitis

- History of chronic inflammatory bowel disease (e.g., Crohn's disease or ulcerative
colitis), celiac disease, or other chronic gastrointestinal conditions associated with
diarrhea, or current acute colitis or enterocolitis of any etiology

- History of diverticulitis (even a single episode) or evidence at baseline, including
evidence limited to CT scan only. Note diverticulosis is not an exclusion criterion
per se.

- History (within the previous year) of stroke or transient ischemic attack, unstable
angina, myocardial infarction, congestive heart failure

- History of deep venous thrombosis or migratory thrombophlebitis (Trousseau)

- Hereditary or acquired coagulopathies (e.g., hemophilia, von Willebrand's disease, or
cancer-associated DIC)

- Prior allergic reactions attributed to other monoclonal antibodies

- Concurrent or planned concurrent treatment with systemic high dose (immunosuppressive)
corticosteroids or treatment with systemic corticosteroids within 4 weeks of baseline

- Treatment on another therapeutic clinical trial within 4 weeks of enrollment in this
trial

- Concurrent or planned concurrent treatment with anticoagulants such as Coumadin or
heparin, except to maintain patency of in-dwelling catheters

- Ongoing or active infection; treatment with systemic antibiotics or antifungals for
ongoing or recurrent infection (topical use of antibiotics or antifungals is allowed)

- Pregnancy or breast-feeding; female patients must be surgically sterile, be
postmenopausal, or must agree to use effective contraception during the period of
therapy and for 12 months following the last dose of either tremelimumab or
CP-870,893; all female patients with reproductive potential must have a negative
pregnancy test prior to enrollment

- Other uncontrolled, concurrent illness that would preclude study participation; or,
psychiatric illness or social challenges that would entail unreasonable risk or
preclude informed consent or compliance with study procedures