Brentuximab Vedotin, Bendamustine, and Rituximab in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Complete response (CR) rate and overall response rate (ORR) for patients with relapsed
aggressive high-risk non-Hodgkin lymphoma (NHL) treated with brentuximab vedotin,
bendamustine and rituximab (S-BR).

SECONDARY OBJECTIVES:

I. To estimate 2-year progression-free survival (PFS). II. To evaluate rate of positron
emission tomography (PET)-CR and correlation to 2 year PFS.

III. To evaluate the toxicity of six cycles of S-BR. IV. To evaluate mobilization, stem cell
collection, engraftment in patients that proceed to salvage autologous stem cell transplant
(ASCT).

SCIENTIFIC OBJECTIVES:

I. To evaluate percentage of tumor cells that are positive or negative for cluster of
differentiation (CD)30 by immunohistochemistry (IHC), the subcellular location of CD30
(membrane or cytoplasmic only with absence of membrane expression), intensity of scoring,
and correlating with clinical outcomes.

II. To evaluate gene expression profiling (GEP) by Nanostring Technology and comparing
expression levels of target genes in CD30 membrane positive, CD30 cytoplasmic only positive
or CD30 negative tumor cells.

III. To evaluate correlation between mutations identified through next generation sequencing
(NGS) including ribonucleic acid (RNA) sequencing of the tumor transcriptome, and
correlating to GEP and CD30 IHC, and correlating to clinical outcomes.

IV. To evaluate the levels of soluble CD30 at baseline and in response to treatment.

SCHEDULE:

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1,
bendamustine IV over 30-60 minutes on days 1-2, and rituximab IV on day 2. Treatment repeats
every 21 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- CD30 detectable B lineage relapsed refractory NHL including the following
histologies:

- Aggressive lymphomas: diffuse large B cell lymphoma, primary mediastinal B cell
lymphoma, grey zone lymphomas, high grade B cell lymphomas, and transformed
indolent lymphomas

- Indolent lymphoma: follicular lymphoma, marginal zone lymphoma, small
lymphocytic lymphoma; indolent lymphoma patients eligible for this trial should
have high tumor burden and high risk disease, as defined by:

- The Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria

- Intermediate or high risk by Follicular Lymphoma International Prognostic
Index (FLIPI) score or elevated lactose dehydrogenase (LDH)/ beta-2
microglobulin (B2M)

- Subjects between 18 and 75 years old. Subjects older than 75 years old to be
discussed with PI prior to subject consent; consensus between PI and treating
physician is required.

- Karnofsky performance status (KPS) >= 70%, Eastern Cooperative Oncology Group (ECOG)
=< 2

- At least 1 measurable site of disease according to Revised Response Criteria for
Malignant Lymphoma

- Patients must have received at least one but no more than 4 prior lines of systemic
therapy

- American Heart Association (AHA) class 1 without significant limitation of physical
activity

- Ejection fraction (EF) of at least >= 40% by multigated acquisition (MUGA) or
echocardiography (ECHO)

- Total bilirubin =< 1.5 mg/dl

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) less than 2.5 times
the upper limit of normal without evidence of active infectious hepatitis

- Creatinine clearance >= 40 ml/min

- Platelets > 75,000 cells/ul

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

- Ability to provide informed consent

- Females of childbearing potential must have a negative serum or urine beta-human
chorionic gonadotropin (HCG) pregnancy test at screening; pregnancy testing is not
required for: (a) women who have been post-menopausal for at least 2 years without
menses; or (b) women who are surgically sterile (e.g. by means of hysterectomy, tubal
ligation, etc.)

- Males and females of childbearing potential must be able and willing to use an
effective contraceptive method during treatment and for three months after completing
treatment

Exclusion Criteria:

- Active infections (bacterial, fungal, or viral)

- Evidence of sanctuary site involvement by disease, e.g., central nervous system,
ocular, testicular involvement

- Evidence of second malignancy, abnormal cytogenetics, or morphologic evidence of
myelodysplastic syndromes (MDS)

- Recent chemotherapy within 3 weeks of screening

- Major surgery within 4 weeks of screening

- Diagnosed or treated for malignancy other than NHL for which patient will be treated,
except: malignancy treated with curative intent and with no known active disease
present for >= 3 years before subject registration; adequately treated non-melanoma
skin cancer or lentigo maligna without evidence of disease; adequately treated
carcinoma in situ without evidence of disease

- History of stroke or intracranial hemorrhage within 6 months prior to registration

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists

- Requires treatment with strong cytochrome (CYP3A4/5) inhibitors

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined
by the New York Heart Association Functional Classification

- Known history of human immunodeficiency virus or active hepatitis C virus or active
hepatitis B virus infection or any uncontrolled active systemic infection requiring
intravenous antibiotics

- Women who are pregnant or breastfeeding

- Prior use of brentuximab vedotin

- Prior use of bendamustine for indolent lymphoma allowed if > 2 years, CR to
bendamustine and well tolerated with no residual > grade 1 toxicity; no prior use of
bendamustine for aggressive lymphoma allowed

- Prior allogeneic transplant

- Patients with Child-Pugh B or C hepatic impairment