This partially randomized phase I trial studies the side effects and best dose of ipilimumab
when given together with rituximab in treating patients with B-cell lymphoma that has
returned or has not responded to treatment. Monoclonal antibodies, such as ipilimumab and
rituximab, may interfere with the ability of cancer cells to grow and spread.
PRIMARY OBJECTIVES:
I. To determine a recommended phase II dose for ipilimumab in combination with rituximab.
SECONDARY OBJECTIVES:
I. To obtain preliminary information on the effect of adding ipilimumab to rituximab in
regard to: immune response; clinical anti-tumor response/overall remission rate (ORR)
(complete remission + partial remission); progression free survival (PFS).
OUTLINE: This is a dose-escalation study of ipilimumab followed by a randomized study.
PART I:
INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes once every 3 weeks
for 12 weeks and rituximab IV over 2-6 hours once weekly for 4 weeks.
MAINTENANCE: Patients receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours
once every 12 weeks for up to 1 year.
PART II: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab
IV over 90 minutes once weekly in weeks 1, 4, 7, and 10. Patients then receive ipilimumab IV
over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab
IV over 90 minutes once weekly in weeks 3, 6, 9, and 12. Patients then receive ipilimumab IV
over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 months.
Inclusion Criteria:
- Previously treated, histologically confirmed cluster of differentiation (CD)20+ B cell
lymphoma; bone marrow biopsies as the sole means of diagnosis are not acceptable, but
they may be submitted in conjunction with nodal biopsies or extra nodal biopsies; fine
needle aspirates are not acceptable
- All patients must be informed of the investigative nature of the clinical trial and
give written informed consent in accordance with institutional and federal guidelines
- Able to adhere to the study visit schedule and other protocol requirements
- Karnofsky >= 70%
- Life expectancy expected to be greater than 3 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 50,000/mcL
- Total bilirubin =< 2.0 x institutional upper limit of normal
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal
- Serum creatinine =< 2.0 x upper limit of normal OR calculated creatinine clearance >=
30 ml/min/1.73 M^2 by the modified Cockcroft and Gault formula OR creatinine clearance
>= 30 mL/min obtained from a 24-hour urine collection
- At least one measurable lesion according to international workshop lymphoma response
criteria; there must be measurable lymphadenopathy to follow with serial exam and/or
imaging
- All previous cancer therapy, including radiation, hormonal therapy and surgery, must
have been discontinued at least 4 weeks prior to treatment in this study
- Patients must have evidence of progression of disease during or after last treatment
- Submission of original biopsy for review and verification by participating center
hematopathologist
- Disease free of prior malignancies for >= 3 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
or breast
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier
- Patients with a history of prior treatment with ipilimumab
- Patients with a history of prior treatment with an anti-programmed cell death (PD) 1
antibody, CD137 agonist or other immune activating therapy such as anti-CD 40 antibody
are excluded unless 5 half-lives of the agent (minimum of 8 weeks) have intervened
since the therapy; patients who have received prior vaccine therapy are eligible
- Patients who are receiving any other investigational agents
- Autoimmune disease: patients with a history of inflammatory bowel disease, including
ulcerative colitis and Crohn's disease, are excluded from this study, as are patients
with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic
progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS) or motor
neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and
myasthenia gravis, multiple sclerosis)
- Patients with known immune impairment who may be unable to respond to anti-cytotoxic
T-lymphocyte antigen 4 (CTLA 4) antibody
- Patients with known uncontrolled brain metastases are excluded; however, patients with
stable brain disease (off corticosteroids) at least 2 weeks after completion of
appropriate therapy for their brain metastases are eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to rituximab
- Patients on systemic corticosteroids (except for patients on stable doses of hormone
replacement therapy such as hydrocortisone), or other immunosuppressants (e.g.,
infliximab, mycophenolate mofetil) are excluded
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Patients with chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C
infections are excluded
- Pregnant women are excluded from this study
- HIV-positive patients on combination antiretroviral therapy are ineligible
- Rituximab within six weeks
