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Brentuximab Vedotin and Rituximab in Treating Patients with Lymphomas Associated with Immunosuppression

Trial Status: Active

This phase I / II trial studies the side effects and best dose of brentuximab vedotin and to see how well it works when given together with rituximab in treating patients with lymphomas associated with suppression of the body's immune system and its ability to fight infections and other diseases. Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving brentuximab vedotin with rituximab may kill more cancer cells.

Inclusion Criteria

  • Patients must have a histologically confirmed CD20+ lymphoproliferative disease that is related to an immunosuppressed state (e.g., post-transplant lymphoproliferative disorder [PTLD], diffuse large B-cell lymphoma [DLBCL] of the elderly, iatrogenic immunodeficiency-associated lymphoproliferative disorder [LPD]) and for which rituximab monotherapy would be considered to be appropriate frontline therapy
  • In cases of lymphoproliferative disease arising in patients who are pharmacologically immunosuppressed, reduction of immunosuppression (RI) must be attempted prior to or in conjunction with enrollment, with the exception of those for whom RI would pose excessive threat of clinically significant graft rejection (as judged by local investigator) * NOTE: Patients who are otherwise immunosuppressed (for reasons such as immune dysregulation related to autoimmune conditions, in the absence of pharmacological immunosuppression) may be eligible if, in the opinion of the treating investigator, the risk of immediate treatment with rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) outweighs the benefit for these patients
  • Patients must have bi-dimensionally measurable disease (at least 1 cm); NOTE: patients with fully resected disease are eligible, and will be evaluable for all toxicity and efficacy endpoints except objective response
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 750/mcL (documented within 28 days of registration)
  • Platelets >= 50,000/mcl (documented within 28 days of registration)
  • Total bilirubin =< 2 X institutional upper limit of normal (ULN) (documented within 28 days of registration)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum pyruvate glutamate transaminase [SPGT]) =< 3 X institutional ULN (documented within 28 days of registration)
  • Creatinine =< 2 X institutional ULN (documented within 28 days of registration)
  • NOTE: patients who do not meet the above criteria because of disease involvement of the organ in question, or because of acute systemic illness due to lymphoma, may enroll with permission of the study principal investigator (PI) and approval from the Data Monitoring Committee; this flexibility be allowed due to the heterogeneity of the patient population, the wide range of complications seen in the initial presentation of EBV-related malignancy, and the frequent difficulty encountered in attempting to clearly document that organ dysfunction is the result of an underlying lymphoproliferative disorder
  • In addition, patients with abnormal renal function may be included if the abnormal function is due to allograft dysfunction resulting from diagnosis of PTLD, or from reduction/cessation of immunosuppression aimed at treatment of PTLD
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  • Patients must be free of any prior malignancies for >= 1 year; NOTE: the exception to this would be currently treated squamous cell and basal cell carcinoma of the skin, carcinoma in situ of the cervix, breast, or bladder, or surgically removed melanoma in situ of the skin (stage 0) with histologically confirmed free margins of excision; in addition, it is well-recognized that patients at highest risk for EBV-related lymphoma (ie, those with chronic immunosuppression) are also at high risk for various malignancies, both invasive and non-invasive; therefore, exceptions may also be granted on a case-by-case basis, at the discretion of the PI with approval from the Data Monitoring Committee, for those patients with good clinical control of active malignancy, if the EBV-related lymphoma is considered to be a more immediate threat to the subject’s health and/or life
  • Patients must have the ability to understand and the willingness to sign a written informed consent; all patients must have signed, witnessed informed consent prior to registration

Exclusion Criteria

  • Patients who have received prior treatment for lymphoma are not eligible * NOTE: Patients may have received corticosteroids for lymphoma for 10 or fewer days at any dose (no washout period required) * NOTE: Patients may have received up to 1 prior dose of rituximab before registration; in this case, patients will only receive 3 doses of rituximab on study
  • Patients who have received chemotherapy (including monoclonal antibodies) or radiotherapy, administered for any condition, within 4 weeks prior to registration are not eligible * NOTE: Patients may have received one dose of rituximab prior to enrollment; in such cases, patients will only continue with 3 doses of rituximab during induction (4 total doses)
  • Patients who have had prior surgical intervention for lymphoma, unless performed for the sake of tissue diagnosis or on an urgent basis for disease-related threat to life, limb, or organ function, are not eligible
  • Patients with incomplete recovery from adverse events due to agents administered more than 4 weeks prior to registration are not eligible
  • Patients must not have ongoing treatment with any other investigational agents =< 14 days prior to registration
  • Patients must not have known central nervous system (CNS) involvement of lymphoma
  • Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to brentuximab vedotin and/or rituximab
  • Patients must not have an 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 must not have known human immunodeficiency virus (HIV) infection
  • Patients must not have known John Cunningham (JC) virus infection and/or progressive multifocal leukoencephalopathy (PML)
  • Patients are not eligible who have clinically active hepatitis B (tested at screening) or known hepatitis A or C infections; * NOTE: Patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection may enroll if other laboratory criteria are met; those with HBV surface antigen positivity may enroll only if maintained on appropriate suppressive antiviral therapy, per treating investigator’s discretion, for the duration of enrollment in the trial
  • Pregnancy or active nursing of an infant is not permitted
  • Patients with a prior history of documented pancreatitis are not eligible
  • Patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) are not eligible; a calculated CrCl is acceptable


Northwestern University
Status: ACTIVE
Contact: Barbara Pro
Phone: 312-695-6180
University of Chicago Comprehensive Cancer Center
Contact: Sonali Mehta Smith
Phone: 773-834-2895


Tufts Medical Center
Status: ACTIVE
Contact: Andreas Kirschmer Klein
Phone: 617-636-2694


I. To evaluate the safety of brentuximab vedotin and rituximab in patients with immunosuppressed lymphoid malignancies, and to determine the recommended phase 2 dose (RP2D) of the combination. (Phase I)

II. To evaluate the efficacy, as measured by response rates, of brentuximab vedotin and rituximab in patients with immunosuppressed lymphoid malignancies. (Phase II)


I. To further evaluate the frequency and severity of toxicity. (Phase II)

II. To further evaluate the clinical efficacy of the combination of brentuximab vedotin and rituximab, as measured by progression free survival (PFS) and overall survival (OS) at one year after the end of treatment. (Phase II)

III. To evaluate the best response to therapy. (Phase II)

IV. To determine the effects of the combination of brentuximab vedotin and rituximab on markers of Epstein-Barr virus (EBV) activation and proliferation. (Phase II)

V. Further evaluate efficacy as measured by time to cytotoxic chemotherapy. (Phase II)

VI. Further evaluate efficacy as measured by observed rates of graft rejection. (Phase II)


I. To determine whether and to what extent CD30 expression predicts for response and outcome.

II. To determine whether and to what extent expression of EBV markers predicts for response and outcome.

III. To determine whether changes in serum levels of EBV correlate with response and subsequent loss of response to therapy.

IV. Collect and store peripheral blood samples for future, unspecified use (phase II patients only).

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.

INDUCTION: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes once weekly for 3 weeks and rituximab IV once weekly for 4 weeks.

CONSOLIDATION (same as induction): Patients achieving stable disease (SD) may receive 1 additional regimen of consolidation therapy. Patients achieving CR or partial remission (PR) after the induction course may receive an additional treatment of consolidation. Following consolidation, patients proceed to maintenance therapy. However, patients achieving CR after induction may receive consolidation as their final planned therapy.

MAINTENANCE THERAPY: Patients receive brentuximab vedotin IV over 30 minutes once every 3 weeks and rituximab IV once every 6 weeks. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Northwestern University

Principal Investigator
Barbara Pro

  • Primary ID NU 12H09
  • Secondary IDs NCI-2012-03090, STU00072695
  • ID NCT01805037