Clinical trial NCT00089076: MDX-010 in Treating Patients With Recurrent or Refractory Lymphoma
Official title: Phase I/II Study of Anti-CTLA-4 Monoclonal Antibody (MDX-010) in B-cell Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-08-05
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Biological therapies, such as MDX-010, work in different ways to stimulate the immune system and stop cancer cells from growing. This phase I/II trial is studying the side effects and best dose of MDX-010 and to see how well it works in treating patients with recurrent or refractory B-cell non-Hodgkin's lymphoma.

Detailed description: PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

Eligibility criteria: 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 eligible
* 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 registration
* 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 asthma
* 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

Primary outcomes:
measure: Number of Overall Confirmed Responses(Complete Response or Partial Response)
timeFrame: From registration to month 7
Secondary outcomes:
measure: Time to Progression (Phase 2)
timeFrame: From registration to progression (up to 2 years)
measure: Overall Survival (Phase 2)
timeFrame: From registration to death (up to 2 years)
measure: Duration of Response (Phase 2)
timeFrame: From response to progression (up to 2 years)
measure: Mean Change in % of CD3+CD4+ for Marker HLA-DR+
timeFrame: Before treatment to 1 month after therapy initiation
measure: Mean Change in % of CD3+CD4- for Marker HLA-DR+
timeFrame: Before treatment to 1 month after therapy initiation
measure: Mean Change in % of CD3+CD4+ for Marker CD45RO+
timeFrame: Before treatment to 1 month after therapy initiation
measure: Mean Change in % of CD3+CD4- for the Marker CD45RO+
timeFrame: Before treatment to 1 month after therapy initiation
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Stephen Ansell
role: PRINCIPAL_INVESTIGATOR
References: