A Phase II, Open-Label, Single Arm Clinical Trial to Study the Mechanism of Action of CP-675,206 in Patients With In-Transit and Metastatic Melanoma Amenable to Repeated Outpatient Tumor Biopsies
- Determine the change in melanoma intratumoral infiltrates by CD8 positive cytotoxic T
lymphocytes in patients with stage IIIC or IV melanoma treated with ticilimumab
- 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
- 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
- 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.
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Change in percent tumor infiltration by CD8 positive cytotoxic T lymphocytes
Antoni Ribas, MD
Jonsson Comprehensive Cancer Center
United States: Food and Drug Administration
|Jonsson Comprehensive Cancer Center at UCLA||Los Angeles, California 90095-1781|