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Phase I/II Study of Anti-CTLA-4 Monoclonal Antibody (MDX-010) in B-cell Non-Hodgkin's Lymphoma

Phase 1/Phase 2
18 Years
Not Enrolling
Adult Grade III Lymphomatoid Granulomatosis, B-cell Chronic Lymphocytic Leukemia, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

Phase I/II Study of Anti-CTLA-4 Monoclonal Antibody (MDX-010) in B-cell Non-Hodgkin's Lymphoma


I. To characterize the safety profile of MDX-010 (ipilimumab) monoclonal antibody and
identify a tolerable immunologically active dose level in B cell lymphoma patients.

II. To evaluate the clinical response rate in B cell lymphoma patients treated with MDX-010.


I. To evaluate the phenotype and function of memory T cells before and after treatment with
MDX-010 by:

- Quantitation and phenotypic characterization of peripheral blood and tumor infiltrating
T-cells, including cluster of differentiation (CD)4+CD25+ regulatory T cells.

- Measurement of tumor-specific T cells in peripheral blood lymphocytes.

- Measuring proliferation of memory T cells in response to recall antigens (tetanus
toxoid and keyhole limpet hemocyanin [KLH]).

II. Measurement of anti-tumor antibodies in serum pre- and post-therapy. III. To evaluate
the time to progression. IV. To evaluate the duration of response to treatment with MDX-010.

OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study followed by a
phase II study. Patients are grouped according to prior treatment with a vaccine therapy for
lymphoma (yes vs no).

PHASE I: Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal
antibody (MDX-010) IV over 90 minutes on day 1. Treatment repeats every 28 days for a total
of 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients from each group receive escalating doses of MDX-010 until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive MDX-010 as in phase I at the MTD.

Patients are followed at 1 and 4 months and then every 6 months for up to 2 years.

Inclusion Criteria:

- Histologic proof of recurring or residual follicular B-cell non-Hodgkin's lymphoma
(grade I or II), by Revised European American Lymphoma Classification (REAL) or World
Health Organization (WHO) classifications which has relapsed or persisted after 3 or
fewer conventional therapies, including chemotherapy or monoclonal antibody therapy;
note: all patients with previously treated B-cell lymphomas of any histology with the
exception of small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) are

- Tumor measurable by computed tomography (CT) scans (at least one pathologic node
measuring 2.0 x 2.0 cm, or 2 nodes measuring > 1.5 x 1.5 cm after collection of tumor
for immunologic analyses)

- At least one prior treatment regimen but no more than 3 prior chemotherapy regimens;
patients previously treated with monoclonal antibodies or radiotherapy to a single
site will be eligible; these therapies will be considered prior treatment regimens
but will not be considered as prior chemotherapy; tumor vaccines will not be counted
as prior therapies, as all such agents are investigational

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelets (PLT) >= 75,000/uL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) =< 3 x upper limit or normal (ULN)

- Creatinine =< 1.5 x ULN

- Hemoglobin >= 8 g/dL

- Ability to provide informed consent

- Willingness to return to the Mayo Clinic Rochester or the University of California,
Los Angeles for follow up

- Life expectancy >= 24 weeks

- Willingness to provide all biologic specimens as required by the protocol

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, 3, or 4

- Any uncontrolled infection, hepatitis C virus (HCV)+ (unless HCV ribonucleic acid
[RNA]-negative by polymerase chain reaction [PCR]) or hepatitis B surface antigen
(HBsAg)+, or human immunodeficiency virus (HIV) positive patients or patients with
known immune deficiency states

- Previous MDX-010 therapy regardless of interval since last treatment

- Prior treatment with fludarabine or 2-chlorodeoxyadenosine =< 12 months prior to

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- New York Heart Association classification III or IV or a history of angina pectoris
requiring active treatment

- Clinical evidence of central nervous system involvement by lymphoma

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception (condoms, diaphragm, birth control pills, injections, intrauterine
device [IUD], or abstinence, etc.)

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation)

- Diagnosis of small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL)

- Any requirement for concurrent steroid therapy, including use of inhaled steroids for

- History of autoimmune disease requiring systemic therapy with immunosuppressive
drugs, including but not limited to rheumatoid arthritis, inflammatory bowel disease,
systemic lupus erythematosus, multiple sclerosis, or psoriasis

- Antinuclear antibody (ANA) titer or rheumatoid factor titer > 3x institutional ULN

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Overall Confirmed Responses(Complete Response or Partial Response)

Outcome Description:

Confirmed response is at least a 50% decrease in the sum of the products of the greatest diameters (SPD) of the six largest dominant nodes or nodal masses and no increase in the size of other nodes, liver, or spleen and splenic and hepatic nodules must regress by at least 50% in the SPD and no new sites of disease.

Outcome Time Frame:

From registration to month 7

Safety Issue:


Principal Investigator

Stephen Ansell

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

June 2004

Completion Date:

Related Keywords:

  • Adult Grade III Lymphomatoid Granulomatosis
  • B-cell Chronic Lymphocytic Leukemia
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Intraocular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Refractory Hairy Cell Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell



Mayo Clinic Rochester, Minnesota  55905