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Melanoma (Skin)Phase 2NCT00471887

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

A Phase 2 study testing CP-675,206 in people with Melanoma (Skin), run by Jonsson Comprehensive Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma (Skin)
What is being tested?
CP-675,206
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
1 siteUnited States
Study dates
Jan 2007to Mar 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 19Show fewer
  • 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.

Who cannot join

  • 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
Show all 9Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Jonsson Comprehensive Cancer Center at UCLA

    Los Angeles, California, 90095-1781

Other trials in United States

About this study

Official title: 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

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.

Read the 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.

Conditions
Melanoma (Skin)
Being tested
CP-675,206
Keywords
stage III melanoma, stage IV melanoma, recurrent melanoma
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CP-675,206Biological

    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 groups in NCT00471887
Study groupRoleWhat they receive
Treatment-Single ArmExperimentalSee intervention descriptions
Receives: Biological: CP-675,206

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: pre treatment - post treatment at 24 months

Secondary outcomes (5)

  1. Change in Intratumoral Expression of the Proteins HLA-DR, CD45RO, Ki67 and FOXP3 and FOXP3"

    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.

    Measured: pre treatment - post treatment at 24 months

  2. Differences in Morphological and Gene Expression Profiling Studies in Peripheral Blood Mononuclear Cells

    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.

    Measured: pre treatment - post treatment at 24 months

  3. Changes in the Protein Content in Peripheral Blood With an Increase in Proinflammatory Cytokines and Chemokines

    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

    Measured: pre treatment - post treatment at 24 months

  4. Overall Response (Complete or Partial Response) as Measured by RECIST Criteria

    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

    Measured: pre treatment - post treatment at 24 months

  5. Overall Safety Profile as Measured by NCI CTCAE v2.0

    Measured: pre treatment - post treatment at 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 May 2007 (estimated)
  2. Study startJan 2007
  3. Primary completionJul 2011
  4. Study completionMar 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00471887
Sponsor's protocol ID
11-0002360
Other IDs
UCLA-0606093-01, PFIZER-UCLA-0606093-01, CDR0000543416
Status last verified
Jan 2016
First submitted
8 May 2007
Last updated
26 Oct 2020
Data monitoring committee
Yes

Publications

  • von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B, Ribas A. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med. 2009 May 20;7:35. doi: 10.1186/1479-5876-7-35.

    PubMed 19457253

  • Huang RR, Jalil J, Economou JS, Chmielowski B, Koya RC, Mok S, Sazegar H, Seja E, Villanueva A, Gomez-Navarro J, Glaspy JA, Cochran AJ, Ribas A. CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res. 2011 Jun 15;17(12):4101-9. doi: 10.1158/1078-0432.CCR-11-0407. Epub 2011 May 10.

    PubMed 21558401

  • Comin-Anduix B, Sazegar H, Chodon T, Matsunaga D, Jalil J, von Euw E, Escuin-Ordinas H, Balderas R, Chmielowski B, Gomez-Navarro J, Koya RC, Ribas A. Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma. PLoS One. 2010 Sep 15;5(9):e12711. doi: 10.1371/journal.pone.0012711.

    PubMed 20856802

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing CP-675,206 in people with Melanoma (Skin), run by Jonsson Comprehensive Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Tumor Infiltration by Cluster of Differentiation 8 (CD8) Positive Cytotoxic T Lymphocytes (time frame: pre treatment - post treatment at 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00471887, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2020.

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