Ticilimumab (CP-675,206) in Treating Patients With Stage IIIC or Stage IV Melanoma

OBJECTIVES:

Primary

- Determine the change in melanoma intratumoral infiltrates by CD8 positive cytotoxic T
lymphocytes in patients with stage IIIC or IV melanoma treated with ticilimumab
(CP-675,206).

Secondary

- Determine the effects of this drug on intratumoral immune effector cells and tumor cells
in these patients.

- Determine the effects of this drug on circulating immune effector cells in these
patients.

- Determine the gene expression profile of immune effector cells and tumor cells in
regressing and nonregressing tumors in these patients.

- Bank plasma from peripheral blood obtained from patients with regressing and
nonregressing tumors for future exploratory analysis of proteomic profile.

- Assess additional evidence of antitumor activity of this drug, as measured by best
on-study response rate, in these patients.

- Characterize the safety profile and tolerability of this drug in these patients.

- Obtain pharmacokinetic data to be used in a future meta-analysis of this drug's
pharmacokinetics.

- Determine whether the CTLA4 genotype influences the safety, immune response, and/or
efficacy of this drug in these patients.

- Determine the relationships between clinical response (i.e., efficacy or toxicity) and
tumor and/or blood ex vivo analysis in patients treated with this drug.

OUTLINE: This is an open-label, randomized study.

Patients receive ticilimumab (CP-675,206) IV over 2 hours on day 1. Treatment repeats every
90 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during study for correlative pharmacokinetic
(PK), pharmacogenetic, and pharmacogenomic analyses. Blood specimens are obtained for PK
measurement at baseline and periodically during study treatment for analysis by enzyme-linked
immunosorbent assay. Blood specimens are also evaluated by pharmacogenetic assessment of
polymorphisms in CTLA4. Patients also undergo leukapheresis at baseline and at least once
between days 30-60 for biomarker analysis of immune cell activation (i.e., CD45RO, CD45RA,
HLA-DR, CCR5, CCR7, CD62L, CD69); Treg phenotype (i.e., CD4/CD25/GITR/intracellular FoxP3);
and Treg function. In HLA-A2.1 positive patients, PBMC are analyzed for antigen-specific
immune reactivity by MART-1, gp100, and tyrosine MHC tetramer using enzyme-linked
immunosorbent spot assay. Plasma obtained during leukapheresis is assessed for levels of
circulating cytokines and chemokines. Some plasma is stored for future proteomic profile
analysis.

Patients also undergo excisional or punch biopsy at baseline and between days 30-60 during
course 1. Tumor tissue samples embedded in paraffin are analyzed by hematoxylin-eosin and
immunohistochemical staining for several biomarkers, including biomarkers of immune cell
response (i.e., CD3, CD4, and CD8) and biomarkers of melanoma (i.e., S-100, MART-1, and/or
HMB45). Frozen tumor tissue samples are analyzed by gene chips and gene arrays for gene
expression profile and by quantitative real-time polymerase chain reaction for FoxP3. Minced
tumor tissue samples are analyzed by flow cytometry in nonadherent cells for HLA-DR (if
tumor-infiltrating lymphocytes are available) and by Braf sequencing in adherent cells (if
melanoma cells are available).

After completion of study therapy, patients are followed every 6 months.

PROJECTED ACCRUAL: A total of 21 patients will be accrued for this study.

Inclusion Criteria:

- Histologically confirmed melanoma that is surgically incurable and either:

- Stage IIIc melanoma including locally relapsed, satellite, in-transit lesions or
bulky draining lymph node metastasis.

- Stage IV melanoma (M1a, M1b, M1c) with accessible lesions for biopsy.

- At least 2 lesions amenable for outpatient biopsies

- No restriction based on prior treatments

- Disease progression after the last dose of prior therapy

- A minimum of one measurable lesion defined as:

- Meeting the criteria for measurable disease according to Response Evaluation
Criteria in Solid Tumors

- Skin lesion(s) selected as non-completely biopsied target lesions that can be
accurately measured and recorded by color photography with a ruler to document
the size of the target lesion(s).

- ECOG performance status 0 or 1

- Adequate bone marrow and hepatic function determined within 30 days prior to
enrollment, defined as:

- Absolute neutrophil count > 1.0 x 10^9 cells/L

- Platelets > 90 x 10^9 /L

- Hemoglobin > 9 g/L

- Aspartate and alanine aminotransferases < 2.5 x ULN (< 5 x ULN, if documented
liver metastases are present)

- Total bilirubin < 2 x ULN (except patients with documented Gilbert's syndrome)

- Must be willing and able to provide writing informed consent.

- Must be willing and able to accept at least two tumor biopsies.

- Must be willing and able to accept at least two leukapheresis procedures.

Exclusion Criteria:

- Received treatment for cancer, including immunotherapy, within one month prior to
dosing.

- Previous participation in Pfizer study A3671009: A Phase 3, Open Label, Randomized
Comparative Study of CP-675,206 and Either Dacarbazine or Temozolomide in Patients
with Advanced Melanoma

- Eligible for enrollment to Pfizer A3671008: A Phase 2, Open Label, Single Arm Study to
Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of CP-675,206 in
Patients with Advanced Refractory and/or Relapsed Melanoma

- History of significant evidence of risk for chronic inflammatory or autoimmue disease.
Patents will be eligible if prior autoimmune disease of the hypophysis was treated
locally or have resulted in fibrotic damage requiring thyroid hormone replacement.
Vitiligo will not be a basis for exclusion.

- History of inflammatory bowel disease, celiac disease, or other chronic
gastrointestinal conditions associated with diarrhea or bleeding, or current acute
colitis or any origin

- Potential requirement for systemic corticosteroids or concurrent immunosuppressive
drugs based on prior history or received systemic steroids within the last 4 weeks
prior to enrollment

- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this protocol

- Clinically active brain metastases. Radiological documentation of absence of brain
metastases at screening is required for all patients

- Pregnancy or breast-feeding.