Brentuximab Vedotin and Bendamustine for the Treatment of Relapsed or Refractory Follicular Lymphoma

Inclusion Criteria:

• Histologically or cytologically confirmed relapsed or refractory follicular CD30+non-Hodgkin lymphoma (NHL) (included in this category are follicular grade I, II,IIIa). CD30 positivity > 1% (tumor cells or surrounding peripheral microenvironment)

• Patients must have measurable disease by computed tomography (CT) or positronemission tomography (PET) scan, with one or more sites of disease >= 1.5 cm inlongest dimension

• Relapsed or refractory disease after at least 1 prior regimen, defined using the 2014 Lugano classification

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Life expectancy of greater than 3 months

• Leukocytes >= 2,500/mcL

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 50,000/mcL

• Hemoglobin >= 8 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however,patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may beenrolled)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (AST and/or ALT =< 5 x ULN for patients with liver involvement)

• Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liverinvolvement or bone metastases)

• Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

• Institutional normalized ratio (INR) and partial thromboplastin time (aPTT) =< 1.5 xULN (This applies only to patients who do not receive therapeutic anticoagulation;patients receiving therapeutic anticoagulation, such as low-molecular-weight heparinor warfarin, should be on a stable dose.)

• Administration of bendamustine or brentuximab vedotin may have an adverse effect onpregnancy and poses a risk to the human fetus, including embryo-lethality. Women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for 5 months (150 days) after the last dose ofstudy agent. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately

• Ability to understand and the willingness to sign a written informed consentdocument

• Patients positive for human immunodeficiency virus (HIV) are allowed on study, butHIV-positive patients must have:

• A stable regimen of highly active anti-retroviral therapy (HAART)

• No requirement for concurrent antibiotics or antifungal agents for theprevention of opportunistic infections

• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standardpolymerase chain reaction (PCR)-based tests

Exclusion Criteria:

• Patients who have had chemotherapy, or radiotherapy within 2 weeks (6 weeks fornitrosoureas or mitomycin C, steroid treatment for follicular lymphoma is allowedper protocol) prior to entering the study or those who have not recovered fromadverse events (other than alopecia) due to agents administered more than 2 weeksearlier. Specifically, the following therapies are not allowed:

• Herbal therapy (1 week washout required)

• Treatment with any other investigational agent within 3 weeks prior to cycle 1,day 1.

• Prior therapy with bendamustine or a bendamustine-containing regimens withprogression within 6 months of receiving treatment

• Current or prior use of immunosuppressive medications (including, but not limitedto, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to first dose (cycle 1, day 1). The following are exceptions to this criterion:

• Intranasal, inhaled, topical or local steroid injections (e.g., intra-articularinjection); steroids as premedication for hypersensitivity reactions; systemiccorticosteroid at physiologic doses not to exceed 10 mg/day of prednisone orequivalent may be enrolled

• Patients who have received acute, low dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

• The use of inhaled corticosteroids and mineralocorticoids (e.g.,fludrocortisone) for patients with orthostatic hypotension or adrenocorticalinsufficiency is allowed

• Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use ofbisphosphonate therapy for other reasons (e.g., bone metastasis orosteoporosis) is allowed

• Patients with known uncontrolled central nervous system (CNS) involvement bylymphoma, including leptomeningeal involvement

• History of hypersensitivity to bendamustine or brentuximab vedotin or any excipient

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinanthuman antibodies

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to other agents used in study

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; cirrhosis; fatty liver; and inherited liver disease.

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

• Neuropathy grade > 1

• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis would beexcluded) are permitted provided that they meet the following conditions:

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potency topicalsteroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (notrequiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,retinoids, biologic agents, oral calcineurin inhibitors; high potency or oralsteroids)

• Patients with known active tuberculosis (TB) are excluded

• Severe infections within 4 weeks prior to cycle 1, day 1, including, but not limitedto, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1

• Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day

1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinarytract infection or chronic obstructive pulmonary disease) are eligible

• Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation ofneed for a major surgical procedure during the course of the study

• Influenza vaccination should be given during influenza season only (approximatelyOctober to March). Patients must not receive live, attenuated influenza vaccinewithin 4 weeks prior to cycle 1, day 1 or at any time during the study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements