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Trial record 1 of 1 for:    NCT00471887
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Ticilimumab (CP-675,206) in Treating Patients With Stage IIIC or Stage IV Melanoma

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ClinicalTrials.gov Identifier: NCT00471887
Recruitment Status : Completed
First Posted : May 10, 2007
Results First Posted : October 26, 2020
Last Update Posted : October 26, 2020
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE May 8, 2007
First Posted Date  ICMJE May 10, 2007
Results First Submitted Date  ICMJE March 15, 2016
Results First Posted Date  ICMJE October 26, 2020
Last Update Posted Date October 26, 2020
Study Start Date  ICMJE January 2007
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 1, 2020)
Change in Tumor Infiltration by Cluster of Differentiation 8 (CD8) Positive Cytotoxic T Lymphocytes [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 8, 2007)
Change in percent infiltration of tumors by CD8 positive cytotoxic T lymphocytes
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2020)
  • Change in Intratumoral Expression of the Proteins HLA-DR, CD45RO, Ki67 and FOXP3 and FOXP3" [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: pre treatment - post treatment at 24 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2007)
  • Tumor evaluation for other immune cell infiltration and melanoma markers
  • Differences in Morphological and Gene Expression Profiling Studies in Peripheral Blood Mononuclear Cells
  • Changes in the Protein Content in Peripheral Blood With an Increase in Proinflammatory Cytokines and Chemokines
  • Overall response (complete or partial) as measured by RECIST
  • Overall safety profile and tolerability as measured by NCI CTCAE v3.0
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ticilimumab (CP-675,206) in Treating Patients With Stage IIIC or Stage IV Melanoma
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma (Skin)
Intervention  ICMJE Biological: 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.
Study Arms  ICMJE Experimental: Treatment-Single Arm
See intervention descriptions
Intervention: Biological: CP-675,206
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 1, 2020)
32
Original Enrollment  ICMJE
 (submitted: May 8, 2007)
21
Actual Study Completion Date  ICMJE March 2015
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00471887
Other Study ID Numbers  ICMJE 11-0002360
UCLA-0606093-01
PFIZER-UCLA-0606093-01
CDR0000543416 ( Other Identifier: UCLA IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jonsson Comprehensive Cancer Center
Study Sponsor  ICMJE Jonsson Comprehensive Cancer Center
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator: Antoni Ribas, MD Jonsson Comprehensive Cancer Center
Principal Investigator: John A. Glaspy, MD, MPH Jonsson Comprehensive Cancer Center
Principal Investigator: James S. Economou, MD Jonsson Comprehensive Cancer Center
PRS Account Jonsson Comprehensive Cancer Center
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP