Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With Stage II-IV HIV-Associated Hodgkin Lymphoma

PRIMARY OBJECTIVES I. To identify the maximum tolerated dose (MTD) of brentuximab vedotin
when combined with the doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD)
chemotherapy regimen in the treatment of HIV-associated stage II-IV Hodgkin lymphoma. (Phase
I) II. Establish an estimate of the two-year progression-free survival (PFS) for participants
with HIV-associated stage II-IV Hodgkin lymphoma when treated using brentuximab vedotin plus
the AVD chemotherapy regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral
therapy (HAART).

II. To estimate the partial response (PR) rate, complete response (CR) rate, overall survival
(OS), and event free survival (EFS) at 2 and 5 years.

III. To evaluate the effect of AVD and brentuximab vedotin on cluster of differentiation
(CD)4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after
treatment completion for one year.

IV. To investigate the prognostic value of fludeoxyglucose (FDG)-positron emission tomography
(PET)/computed tomography (CT) scans at baseline, after cycle 2, and at treatment completion,
with respect to 2-year progression free survival.

V. To evaluate HAART status at baseline and to correlate this with tumor response to therapy
and OS and PFS.

VI. To characterize the histologic subtypes in HIV-Hodgkin lymphoma (HL) in the highly active
antiretroviral therapy (HAART) era.

VII. To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.

VIII. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at
the completion of therapy, and every 3 months after treatment completion for one year.

IX. To perform pharmacokinetic and immunogenicity studies to determine drug levels during
therapy.

X. To perform micro ribonucleic acid (miRNA) profile analysis on the HIV-HL tumor specimens
and to correlate miRNA expression with OS, PFS, tumor response to therapy, histologic subtype
of HIV-HL, and HIV disease characteristics.

XI. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate the
markers studied with OS, PFS, and tumor response to therapy.

XII. To identify Epstein-Barr virus (EBV)-associated tumor derived deoxyribonucleic acid
(DNA) in the plasma of study participants and to correlate these levels during therapy with
disease response and OS. (Phase II) XIII. To identify cytokines in the plasma of participants
during therapy that can be used as tumor and prognostic markers. (Phase II) XIV. To assess
latent and expressed HIV reservoirs before, during, and post chemotherapy. To understand how
cytotoxic chemotherapeutic agents affect HIV expression.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase
II study.

Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, and
dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes
on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- HIV positive; documentation of HIV-1 infection by means of any one of the following:

- Documentation of HIV diagnosis in the medical record by a licensed health care
provider;

- Documentation of receipt of antiretroviral therapy (ART) by a licensed health
care provider;

- HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA
copies/mL;

- Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay
confirmed by a second licensed HIV assay such as a HIV-1 western blot
confirmation or HIV rapid multispot antibody differentiation assay

- NOTE: A "licensed" assay refers to a United States (US) Food and Drug
Administration (FDA)-approved assay, which is required for all investigational
new drug (IND) studies

- Histologic diagnosis of CD30-positive classical HL as defined by the 2008 World Health
Organization (WHO) Classification of Hematological diseases; nodular lymphocyte
predominant Hodgkin lymphoma is not eligible

- Stage II, III or IV disease as defined by the Ann Arbor Staging System

- Participants must have previously untreated HIV-classical HL (cHL), with the exception
of up to 14 consecutive days of steroids, emergency radiation, or 1 prior cycle of
cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the setting
of lymphoma related liver involvement

- Normal baseline cardiac ejection fraction >= 50%

- Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL, creatinine clearance must
be >= 60 mL/minute

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelets >= 75,000/uL unless related to bone marrow involvement by HIV-cHL

- Total bilirubin must be < 1.5 x the upper limit of normal, unless the elevation of
bilirubin is thought to be secondary to Gilbert's syndrome or combined antiretroviral
therapy (cART); if, however, the elevated bilirubin is felt to be secondary to
antiretroviral therapy, the total bilirubin must be =< 3.5 mg/dL, provided that the
direct bilirubin is normal and the aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) =< 3 x the upper limit of normal; also, if the elevated
bilirubin is thought to be secondary to cHL the same criteria for hyperbilirubinemia
should be applied; however 1 prior cycle of cyclophosphamide is permitted in attempt
to make the participant eligible; patients should not be excluded from study
participation unless dosing cannot be safely established

- Female participants must have a negative pregnancy test within 1 week of enrollment
and all participants must agree to use two reliable methods of contraception
simultaneously if conception is possible during the study and for 6 months after
stopping treatment; should a woman subject become pregnant or suspect she is pregnant
while the subject is participating in this study, she should inform her treating
physician immediately; the participant will then be removed from protocol therapy;
participants who father a child while participating in the study will be permitted to
continue with the protocol; the participant, however, is required to notify the
investigator if he fathers a child

- Ability to understand and the willingness to sign a written informed consent document

- Karnofsky performance status > 30% (given the aggressiveness of this disease and the
often severely debilitated nature of the patients at initial presentation)

- Measurable or non-measurable (evaluable) tumor parameter(s); non-measurable tumor
parameters will be defined as not having bi-dimensional measurements (i.e., gastric or
marrow involvement) but can be followed for response by other diagnostic tests such as
gallium, PET imaging and/or bone marrow biopsy

- Patients already receiving erythropoietin or granulocyte colony stimulating factor
(GCSF) for treatment of HIV-related cytopenia are eligible

- CD4 count >= 50 cells/ul

- Participants are required to be on antiretroviral regimens that are in accordance with
the current International Acquired Immune Deficiency Syndrome (AIDS) Society
guidelines concurrently with chemotherapy; the specific agents are at the discretion
of the investigator and the use of investigational agents currently available on an
expanded access basis is allowed; use of experimental antiretroviral agents or those
containing zidovudine (including Combivir and Trizivir) or ritonavir (includes Norvir
or Kaletra), cobicistat, didanosine (Videx or Videx EC), or similar potent cytochrome
P450 (CYP)3 inhibitors are prohibited; in order to be eligible, participants taking
zidovudine or ritonavir, or cobicistat, didanosine, or other CYP3 inhibitors must
change to a different regimen 7 days prior to therapy initiation; changes to HAART
therapy during the study may be made if medically necessary (toxicity, failure of
regimen, etc.); participants must be on HAART at least 7 days prior to therapy

- Negative for hepatitis B, or if infected with hepatitis B, receiving anti-hepatitis B
therapy; all participants will be required to be screened for hepatitis B; per
Infectious Disease Society of America (IDSA) and Assistance for AIDS Specific Drugs
(AASD) guidelines, those participants that show no immunity, defined by the lack of
hepatitis B surface antigen antibody, and show evidence of chronic infection (i.e.
hepatitis B surface antigen [HBsAg]+, hepatitis B core [HBcore]+, hepatitis B surface
antibody [HBsAB]-) will be required to be on anti-hepatitis B therapy during the study
in order to be eligible; patients will be permitted to enroll in the study provided
normal liver function tests and no evidence of cirrhosis; the exact hepatitis B
therapy will be at the discretion of the infection disease specialist or investigator;
however all patients who present with acute hepatitis B or show normal transaminases
and are hepatitis B virus HBsAg surface protein antigen (HBsAg) positive (+) and
immunoglobulin M (IgM)+ for hepatitis core antigen will not be eligible for trial
enrollment

- Patients diagnosed with hepatitis C who are hepatitis C antibody positive, whether
hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and
have liver function tests

- Brentuximab vedotin is partially metabolized via the CYP3A4 pathway and is cleared
from the cells via the P-glycoprotein pump; therefore, participants must discontinue
use of the following agents within 7 days prior to therapy

- Strong CYP3A4 inhibitors that treat HIV

- Other strong CYP3A inhibitors

- Moderate CYP3A4 inhibitors should be used with caution but are not excluded; if 2
moderate CYP3A4 inhibitors are used concurrently, one must be discontinued at
least 7 days (1 week) prior to the initiation of chemotherapy

- P-glycoprotein inhibitors

- If patients are taking any of these excluded medications, they must be
discontinued at least 7 days (1 week) prior to the initiation of chemotherapy All
concomitant medications must be reviewed by the study chair or co-chair prior to
enrollment by email; because the lists of these agents are constantly changing,
it is important to regularly consult a frequently-updated medical reference for a
list of drugs to avoid or minimize use of

Exclusion Criteria:

- Patients with prior anthracycline therapy will be excluded

- Female participants who are pregnant or breast-feeding; confirmation that the subject
is not pregnant must be established by a negative serum beta (b)-human chorionic
gonadotropin (b-hCG) or urine pregnancy test result obtained during screening;
pregnancy testing is not required for post-menopausal or surgically sterilized women

- Medical illness unrelated to HL, which in the opinion of the study physician will
preclude administration of chemotherapy safely; this includes patients with
uncontrolled infection (including opportunistic), chronic renal failure, myocardial
infarction (MI) within the past 6 months, unstable angina, or cardiac arrhythmias
other than chronic atrial fibrillation, or second malignancy requiring active
treatment

- Prior malignancy within 2 years before enrollment other than curatively treated
cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, anal
intraepithelial neoplasia, or cutaneous Kaposi's sarcoma (KS); participants with prior
malignancies must have completed all therapy at least 2 years before enrollment with
no evidence of disease since therapy completion

- Grade 2 or greater peripheral neuropathy

- Evidence of progressive multifocal leukoencephalopathy (PML) identified on the
pretreatment magnetic resonance imaging (MRI)

- Central nervous system disease

- Patients with history of John Cunningham (JC) virus identified in the cerebrospinal
fluid (CSF) or previous history of PML will be excluded from the study

- Cirrhosis secondary to any cause will be excluded