Brentuximab Vedotin With or Without Nivolumab in Treating Patients With Relapsed or Refractory CD30+ Lymphoma

PRIMARY OBJECTIVES:

I. To estimate the response rate following weekly brentuximab vedotin (1.2 mg/kg 3 of 4 weeks
for up to four 28-day cycles) in patients with lack of response (< partial response [PR]) or
progression following brentuximab vedotin and demonstrating persistent expression of CD30.
(Arm A)

II. To evaluate the response rate of combination brentuximab vedotin and nivolumab in
patients with lack of response (< PR) or progression within 6 months following brentuximab
vedotin. (Arm B)

SECONDARY OBJECTIVES:

I. To monitor clinical outcome following the study treatment regimen.

II. To estimate the frequency of CD30 loss in patients following resistance to brentuximab
vedotin.

III. To describe the pattern of CD30 expression (membranous, cytoplasmic, Golgi) in
comparison to the pre-brentuximab vedotin expression.

IV. To semi-quantitatively estimate and compare the surface density of CD30 pre and post
brentuximab vedotin as measured by flow cytometry.

V. To correlate response with CD30 density as measured by flow cytometry.

VI. To evaluate the tolerability of the weekly regimen in patients previously exposed to
brentuximab vedotin.

VII. To explore the tolerability of brentuximab vedotin and nivolumab in patients previously
exposed to brentuximab vedotin in a 21-day cycle.

OUTLINE:

ARM A (CLOSED TO ACCRUAL): Patients receive brentuximab vedotin intravenously (IV) over 30
minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

ARM B: Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30-60
minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3-5 weeks, every 3 months
for 1 year, and then every 6 months for 4 years.

Inclusion Criteria:

- Relapsed or refractory CD30+ lymphoma that has either achieved < PR to brentuximab
vedotin (minimum of 2 cycles), progressed while receiving brentuximab vedotin, or
progressed within 6 months of the last dose of brentuximab vedotin

- Documented expression of CD30 on tumor cells

- Absolute neutrophil count (ANC) > 1,000/uL

- Platelets > 50,000/uL

- Serum creatinine < 1.5 mg/dL OR creatinine clearance > 60 mL/min

- Bilirubin < 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN

- Measurable disease by computed tomography (CT) or similar (e.g. magnetic resonance
imaging [MRI]) criteria (> 1.5 cm)

- Resolution of all non-hematologic brentuximab vedotin-related adverse events (AEs) to
< grade 2

- All patients must be informed of the investigational nature of this study and have
given written consent in accordance with institutional and federal guidelines

- Patients must be anticipated to complete at least 2 cycles of chemotherapy on study

- Expected survival if untreated of > 90 days

Exclusion Criteria:

- Prior transplant within 100 days

- Radioimmunotherapy within 12 weeks

- Known human immunodeficiency virus (HIV) or hepatitis B positivity or prior
progressive multifocal leukoencephalopathy (PML)

- Active infection or other medical condition which would preclude treatment in the
opinion of the principal investigator; this would include a corrected diffusing
capacity of the lungs for carbon monoxide (DLCO) of < 60% predicted or symptomatic
interstitial lung disease

- Eastern Cooperative Oncology Group (ECOG) performance status > 2

- Known active central nervous system (CNS) involvement

- Peripheral neuropathy > grade 1 if due to brentuximab vedotin or any peripheral
neuropathy > grade 2

- Intolerance to brentuximab vedotin

- Concurrent use of other anti-cancer agents or experimental treatments

- No current or prior autoimmune disease with the exception of vitiligo and autoimmune
alopecia (Arm B only)

- Pregnancy or breastfeeding; (females of childbearing potential must have a negative
serum or urine beta human chorionic gonadotropin [beta-hCG] pregnancy test result
within 7 days prior to the first dose of brentuximab vedotin; females with false
positive results and documented verification that the patient is not pregnant are
eligible for participation; females of non-childbearing potential are those who are
postmenopausal greater than 1 year or who have had a bilateral tubal ligation or
hysterectomy; females of childbearing potential and males who have partners of
childbearing potential must agree to use 2 effective contraceptive methods during the
study and for 6 months following the last dose of brentuximab vedotin or 8 months
following the last dose of nivolumab, whichever is later)