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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00471887

Enrollment

Registered

2007-05-10

Start date

2007-01-31

Completion date

2015-03-31

Last updated

2020-10-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma (Skin)

Keywords

stage III melanoma, stage IV melanoma, recurrent melanoma

Brief summary

RATIONALE: Monoclonal antibodies, such as ticilimumab (CP-675,206), can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. PURPOSE: This phase II trial is studying how well ticilimumab (CP-675,206) works in treating patients with stage IIIC or stage IV melanoma.

Detailed description

OBJECTIVES: Primary * Determine the change in melanoma intratumoral infiltrates by cluster of differentiation 8 (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.,biomarkers 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, peripheral blood mononuclear cells (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., cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), and cluster of differentiation 8 (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.

Interventions

BIOLOGICALCP-675,206

Patients will receive intravenous administration of CP-675,206 at a dose of 15mg/kg on Day 1 of an every 90 day cycles. For purposes of treatment visits and scheduling, each cycle is defined as a 90 day period. Patients may receive up to 8 dose (8 cycles) in a 24-month period until progression of disease or intolerable toxicity.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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). * Eastern Cooperative Oncology Group (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 upper limit of normal (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 autoimmune 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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Tumor Infiltration by Cluster of Differentiation 8 (CD8) Positive Cytotoxic T Lymphocytes	pre treatment - post treatment at 24 months	Tumor infiltration of cluster of differentiation 4 and cluster of differentiation 8 (CD4+ and CD8+) cells (intratumoral and peritumoral) was assessed by immunohistochemistry of tumor tissue obtained through biopsy before and after administration of tremelimumab. Up to 10 randomly selected fields per sample were analyzed.

Secondary

Measure	Time frame	Description
Change in Intratumoral Expression of the Proteins HLA-DR, CD45RO, Ki67 and FOXP3 and FOXP3	pre treatment - post treatment at 24 months	HLA-DR is a surface marker of T cell activation after exposure to CTLA4 blocking antibodies. CD45RO is a maker of prior cognate antigen-exposed T cells. Together they mark cells with a surface phenotype of T effector or T effector memory cells. Ki67 is a marker of cell proliferation. The protein FOXP3 is involved in the regulation of the development and function of regulatory T cells, and serves as a marker of this cell type. Intratumoral expression of HLA-DR, CD45RO, Ki67 and FOXP3 was assessed by immunohistochemistry of tumor tissue obtained through biopsy before and after administration of tremelimumab.
Differences in Morphological and Gene Expression Profiling Studies in Peripheral Blood Mononuclear Cells	pre treatment - post treatment at 24 months	T cell receptor (TCR) usage was analyzed in genomic DNA from peripheral blood from patients before and after treatment with tremelimumab. High-throughput deep sequencing of the TCR Vβ CDR3 (Complementarity - determining region 3) region was analyzed to better characterize the expansion and clonality of the T cell repertoire. The frequency of circulating invariant natural killer T cells (iNKT) cell subsets were also characterized by flow cytometry in peripheral blood samples pre- and post-treatment. iNKT cells regulate the balance of Th1/Th2 immune responses.
Changes in the Protein Content in Peripheral Blood With an Increase in Proinflammatory Cytokines and Chemokines	pre treatment - post treatment at 24 months	Th17 cells are CD4+ cells that are potent inducers of tissue inflammation and autoimmunity. The levels of this T cell subset were assessed in peripheral blood from patients before and after administration of tremelimumab. Th17 cells were assessed since the major dose limiting toxicities are inflammatory and autoimmune in nature. In addition, the phosphorylation of signaling molecules downstream of the TCR and cytokine receptors was evaluated in peripheral blood cells from patients before and after treatment with tremelimumab using intracellular flow cytometry. ab#cells = absolute number of cells
Overall Response (Complete or Partial Response) as Measured by RECIST Criteria	pre treatment - post treatment at 24 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression
Overall Safety Profile as Measured by NCI CTCAE v2.0	pre treatment - post treatment at 24 months	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
Treatment: CP-675,206 Monoclonal Antibody See intervention descriptions CP-675,206: Patients will receive intravenous administration of CP-675,206 at a dose of 15mg/kg on Day 1 of an every 90 day cycles. For purposes of treatment visits and scheduling, each cycle is defined as a 90 day period. Patients may receive up to 8 dose (8 cycles) in a 24-month period until progression of disease or intolerable toxicity.	32
Total	32

Arm

Count

Treatment: CP-675,206 Monoclonal Antibody

See intervention descriptions CP-675,206: Patients will receive intravenous administration of CP-675,206 at a dose of 15mg/kg on Day 1 of an every 90 day cycles. For purposes of treatment visits and scheduling, each cycle is defined as a 90 day period. Patients may receive up to 8 dose (8 cycles) in a 24-month period until progression of disease or intolerable toxicity.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	9

Baseline characteristics

Characteristic	Treatment: CP-675,206 Monoclonal Antibody
Age, Continuous	52 years
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants
prior therapies Biological Only	4 participants
prior therapies Chemotherapy Based	13 participants
prior therapies No Prior Therapy	13 participants
prior therapies Other	2 participants
Region of Enrollment United States	32 participants
Sex: Female, Male Female	9 Participants
Sex: Female, Male Male	23 Participants
Stage IIIC	4 participants
Stage M1a	3 participants
Stage M1b	3 participants
Stage M1c	22 participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	13 / 32
other Total, other adverse events	13 / 32
serious Total, serious adverse events	13 / 32

Outcome results

Primary

Change in Tumor Infiltration by Cluster of Differentiation 8 (CD8) Positive Cytotoxic T Lymphocytes

Tumor infiltration of cluster of differentiation 4 and cluster of differentiation 8 (CD4+ and CD8+) cells (intratumoral and peritumoral) was assessed by immunohistochemistry of tumor tissue obtained through biopsy before and after administration of tremelimumab. Up to 10 randomly selected fields per sample were analyzed.