Brentuximab Vedotin, Cyclosporine, and Verapamil in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of the combination of brentuximab vedotin (BV) plus
MDR1 inhibitors cyclosporine (CsA)/verapamil (VRP).

SECONDARY OBJECTIVES:

I. Obtain estimates of overall response rate (ORR), complete response (CR) rate, and response
duration in patients treated with the combination of BV plus CsA/VRP.

II. Estimate overall and progression-free survival in patients treated with the combination
of BV plus CsA/VRP.

III. Characterize pharmacokinetics of plasma MMAE in cycle 1 (for expansion cohort only).

OUTLINE: This is a dose-escalation study of brentuximab vedotin and cyclosporine.

Patients receive cyclosporine orally (PO) twice daily (BID) on days 1-5, verapamil PO four
times daily (QID) on days 1-5, and brentuximab vedotin intravenously (IV) over 30 minutes on
day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

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

Inclusion Criteria:

- All patients and/or their parents or legal guardians must have the ability to
understand and the willingness to sign a written informed consent

- Voluntary written informed consent must be obtained before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the subject at any time without prejudice to future
medical care

- Weight over 40 kg

- Life expectancy of greater than 3 months

- Patients must have histologically documented or cytologically confirmed Hodgkin
lymphoma with CD30 expression

- Patient must have measurable disease > 1.5 cm evidenced by computed tomography (CT) of
the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans

- Patients must be either refractory to or relapsed after at least 1 line of therapy

- Prior brentuximab vedotin is allowed; expansion cohorts are defined as:

- Expansion cohort a): BV naive/sensitive: Patients who have not had prior BV, or
who had achieved at least partial response (PR) to BV and later on developed
relapsed disease while not on active BV therapy

- Expansion cohort b): BV refractory: Patient who had prior exposure to BV, and
either - achieved a best response of stable disease (SD) or progressive disease
(PD) or - achieved a best response of complete response (CR)/PR but developed PD
while on active BV treatment

- Eastern Cooperative Oncology Group (ECOG) performance score of 0-2

- Prior chemotherapy or radiation therapy is allowed if received >= 3 weeks before study
enrollment

- Prior hematopoietic transplantation is allowed (autologous and/or allogeneic)

- Absolute neutrophil count (ANC) >= 1,000/mm^3; filgrastim can be given prior to
enrollment to achieve target ANC >= 1000/uL

- Platelets >= 50,000/mm^3; NOTE: platelet transfusion and packet red blood cell
transfusion can be given prior to enrollment to achieve a target platelet (Plt) >=
50,000/uL and hemoglobin of >= 8.5 g/dL

- Hemoglobin >= 8.5 g/dL

- Total bilirubin within 1.5 x the upper limit of normal institutional limits; patients
with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible

- Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) unless
demonstrated Hodgkin lymphoma involvement of the liver

- Alanine aminotransferase (ALT) =< 3 x ULN unless demonstrated Hodgkin lymphoma
involvement of the liver

- Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula and/or 24 hour
(hr) urine analysis as needed

- If not receiving anticoagulants: international normalization ratio (INR) OR
prothrombin (PT) =< 1.5 x ULN; if on anticoagulant therapy: PT must be within
therapeutic range of intended use of anticoagulants

- If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x
ULN; if on anticoagulant therapy: aPTT must be within therapeutic range of intended
use of anticoagulants

- Female of childbearing potential: negative urine or serum pregnancy test; if the urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
required

- In patients who are to receive VRP, base systolic blood pressure (SBP) > 110;
diastolic blood pressure (DBP) > 60 and baseline heart rate > 60

- Cardiac function (12 lead-electrocardiography [ECG] vs non 12 lead ECG) shows no
underlying arrhythmia or heart blocks (for VRP only)

- Female subjects must be either post-menopausal, surgically sterilized, or willing to
use an acceptable method of birth control (i.e. a hormonal contraceptive,
intra-uterine deice, diaphragm with spermicide, condom with spermicide, or abstinence)
beginning prior to study entry, for the duration of the study, and for six months
following duration of study participation; should a woman become pregnant or suspect
that she is pregnant while participating on the trial, she should inform her treating
physician immediately

- Male subjects must agree to use an acceptable method of contraception beginning prior
to study entry, for the duration of the study, and for six months following duration
of study participation

Exclusion Criteria:

- Patients who are hematopoietic stem cell transplant candidates are excluded

- Vaccinated with live, attenuated vaccines within 4 weeks of enrollment

- Patients may be on steroids prior to initiation of treatment, provided that, by cycle
1 day 1, steroid use is tapered down to less than or equal to 20 mg/day of prednisone

- Patients may not be receiving any other investigational agents, or concurrent
biological therapy, chemotherapy, or radiation therapy

- Active graft versus host disease (GVHD) or on immunosuppressive medication of GVHD

- Recent infection requiring intravenous anti-infective treatment that was completed =<
14 days before enrollment

- Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
Common Terminology Criteria for Adverse Events (CTCAE, version, 4.03), grade 0 or 1,
with the exception of alopecia

- Baseline grade II peripheral neuropathy

- Hypersensitivity to BV or history of allergic reaction attributed to compounds of
similar chemical or biologic composition to BV

- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel, symptomatic
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
obstruction

- Patients should not have any uncontrolled illness including ongoing or active
infection

- Any life-threatening illness, medical condition, or organ system dysfunction that, in
the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk

- Myocardial infarction within 6 months prior to enrollment or New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmia, or electrocardiograph evidence of acute ischemia
or active conduction system abnormalities; prior to study entry, and ECG abnormality
at screening has to be documented by the investigator as not medically relevant

- Significant screening electrocardiogram (ECG) abnormalities including, but not limited
to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd
degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac
pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are
considered not clinically significant as documented via a cardiology evaluation

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

- Patients with active central nervous system (CNS) disease or history of brain
metastases are excluded from study

- Active human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B
virus (HBV); subjects who have an undetectable HIV viral load with CD4 >= 200 and are
on highly active antiretroviral therapy (HAART) medication are allowed; subjects who
are positive for hepatitis B core antibody or hepatitis B surface antigen mush have a
negative polymerase chain reaction (PCR) results before enrollment; those who are PCR
positive will be excluded; patients who have had hepatitis C but have finished
treatment and are PCR negative will be allowed (testing to be done only in patients
suspected of having infections or exposures)

- Pregnant women are excluded from this study; breastfeeding should be discontinued

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)

- Unable to understand the purpose and risks of the study and to provide a signed and
dated informed consent form (ICF) and authorization to use protected health
information (in accordance with national and local subject privacy regulations)