MDX-010 in Treating Patients With Recurrent or Refractory Lymphoma

Phase 1

Terminated

Conditions: B-cell Chronic Lymphocytic Leukemia
Cutaneous B-cell Non-Hodgkin Lymphoma
Adult Grade III Lymphomatoid Granulomatosis
Recurrent Grade 1 Follicular Lymphoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Marginal Zone Lymphoma
Small Intestine Lymphoma

Interventions: Biological: ipilimumab
Other: laboratory biomarker analysis

Registration Number: NCT00089076

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 18

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ipilimumab)	ipilimumab	PHASE I: Patients receive 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 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.
Treatment (ipilimumab)	laboratory biomarker analysis	PHASE I: Patients receive 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 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.

Primary Outcome Measures

Name	Time	Method
Number of Overall Confirmed Responses(Complete Response or Partial Response)	From registration to month 7	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (Phase 2)	From registration to death (up to 2 years)	The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Mean Change in % of CD3+CD4- for Marker HLA-DR+	Before treatment to 1 month after therapy initiation	Flow cytometric analysis of T-cell surface markers before and 1 month after initiation therapy
Mean Change in % of CD3+CD4+ for Marker CD45RO+	Before treatment to 1 month after therapy initiation	Flow cytometric analysis of T-cell surface markers before and 1 month after initiation therapy
Duration of Response (Phase 2)	From response to progression (up to 2 years)	Duration of response will be calculated from the documentation of confirmed response until the date of progression in the subset of patients who respond.
Mean Change in % of CD3+CD4- for the Marker CD45RO+	Before treatment to 1 month after therapy initiation	Flow cytometric analysis of T-cell surface markers before and 1 month after initiation therapy
Time to Progression (Phase 2)	From registration to progression (up to 2 years)	The time to progression is defined as the time from registration to the time of progression. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Mean Change in % of CD3+CD4+ for Marker HLA-DR+	Before treatment to 1 month after therapy initiation	Flow cytometric analysis of T-cell surface markers before and 1 month after initiation therapy