Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas

PRIMARY OBJECTIVES:

I. To evaluate the safety of brentuximab vedotin and rituximab in patients with lymphoid
malignancies that are cluster of differentiation (CD) 30 positive (+) and/or Epstein-Barr
virus (EBV)+, 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 lymphoid malignancies that are CD30+ and/or EBV+.
(Phase II)

SECONDARY OBJECTIVES:

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 determine the effects of the combination of brentuximab
vedotin and rituximab on markers of EBV activation and proliferation. (Phase II) IV. Further
evaluate efficacy as measured by time to cytotoxic chemotherapy. (Phase II) V. Further
evaluate efficacy as measured by observed rates of graft rejection. (Phase II)

TERTIARY OBJECTIVES:

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.

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. Patients unable to achieve
complete remission (CR) may receive additional optional consolidation therapy identical to
induction therapy.

MAINTENANCE THERAPY: Patients receive brentuximab vedotin IV 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.

Inclusion Criteria:

- Histologically confirmed CD30+ and/or EBV+ lymphoid malignancy; in addition, there
must be evidence of CD20 expression (at any level)

- In cases of post-transplant lymphoproliferative disorder (PTLD) 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)

- No prior chemotherapy or radiotherapy for PTLD or diffuse large B-cell lymphoma
(DLBCL), with the exception of corticosteroids for 10 or fewer days at any dose (no
washout period required)

- No prior surgical intervention, unless performed for the sake of tissue diagnosis or
on an urgent basis for disease-related threat to life, limb, or organ function

- Bi-dimensionally measurable disease (at least 1 cm)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Absolute neutrophil count >= 750/mcL

- Platelets >= 50,000/mcl

- Total bilirubin =< 2 X institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum pyruvate glutamate transaminase [SPGT])
=< 3 X institutional ULN

- Creatinine =< 2 X institutional ULN

- 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

- 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

- 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:

- Chemotherapy (including monoclonal antibodies) or radiotherapy, administered for any
condition, within 4 weeks prior to entering the study or incomplete recovery from
adverse events due to agents administered more than 4 weeks earlier

- Ongoing treatment with any other investigational agents

- Known central nervous system (CNS) involvement of lymphoma

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to brentuximab vedotin and/or rituximab

- 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

- Known human immunodeficiency virus (HIV) infection

- Known John Cunningham (JC) virus infection and/or progressive multifocal
leukoencephalopathy (PML)

- Clinically active hepatitis A, B, or C infections; NOTE: patients with chronic
hepatitis C (HCV) or hepatitis B (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