Bortezomib in Treating Patients With Relapsed or Refractory AIDS-Related Kaposi Sarcoma

PRIMARY OBJECTIVES:

I. Estimate the maximum tolerated dose (MTD) of single agent bortezomib in subjects with
AIDS-related Kaposi sarcoma (KS).

SECONDARY OBJECTIVES:

I. Evaluate the clinical response of KS tumors to bortezomib. II. Evaluate the impact of
bortezomib on human immunodeficiency virus (HIV) plasma viral loads and peripheral blood
mononuclear cells (PBMC) apolipoprotein B messenger ribonucleic acid (mRNA) editing enzyme,
catalytic polypeptide-like 3G (APOBEC3G) levels.

III. Determine the impact of bortezomib on Kaposi's sarcoma-associated herpesvirus (KSHV).

IV. Assess bortezomib effects on KSHV copy number in PBMC and plasma and whether changes in
viral copy number measured in PBMC and plasma are associated with clinical response of KS
tumors.

V. Monitor KSHV gene expression in KS biopsy specimens and PBMC pre- and post-bortezomib and
assess whether changes in viral gene expression (i.e., to a lytic pattern) in tumor biopsy
are associated with clinical response.

VI. Assess whether changes in viral copy number in PBMC and plasma occur in concert with or
independently of changes in viral antigen expression in tumor biopsy specimens.

VII. Assess effects of bortezomib on proteins relevant to KS tumor survival and proliferation
(i.e., P53, von Hippel-Lindau [VHL], p27, hypoxia-inducible factor 1 [HIF1]-alpha) as well as
levels of nuclear factor-kappaB (NFkappaB) gene target mRNAs in tumor biopsies.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib intravenously (IV) on days 1, 8, and 15. Treatment repeats every
28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Adult patients with cutaneous AIDS-related biopsy-proven KS relapsed after or
refractory to at least one other prior systemic therapy

- Patients must have cutaneous KS lesion(s) amenable to biopsy (either one lesion >= 12
mm or 3 >= 4 mm) in addition to at least 5 lesions measurable for assessment; all of
these lesions must not have been previously radiated

- Must have been on stable anti-retroviral therapy for at least 12 weeks with a
principal investigator (PI)-based or non-nucleoside reverse-transcriptase inhibitor
(NNRTI)-based regimen of at least three drugs, with no intention to change the regimen
for the duration of the study; patients who have a high likelihood of better HIV
management with a new antiretroviral regimen should defer enrollment until the changes
are in place and the new highly active antiretroviral therapy (HAART) regimen meets
the 12 week criteria

- Serologic documentation of HIV infection at any time prior to study entry, as
evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive western
blot, or other Food and Drug Administration (FDA)-approved licensed HIV test, or a
detectable blood level of HIV RNA

- Women of child-bearing potential must have a negative pregnancy test within 72 hours
before initiation of study drug dosing; post-menopausal women must be amenorrheic for
at least 12 months to be considered of non-childbearing potential; male and female
subjects of reproductive potential must agree to employ an effective barrier method of
birth control throughout the study and for up to 3 months following discontinuation of
study drug; (Note: a woman of childbearing potential is one who is biologically
capable of becoming pregnant; this includes women who are using contraceptives or
whose sexual partners are either sterile or using contraceptives)

- Absolute neutrophil count (ANC) >= 1,000/mm^3; subjects may be receiving growth factor
support to meet these criteria

- Hemoglobin >= 8.0 gm/dL; subjects may be receiving growth factor support to meet these
criteria

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 mg/dL; if the elevated bilirubin is felt to be secondary to
indinavir or atazanavir therapy, then subjects will be allowed on protocol without any
limit on the total bilirubin if the direct bilirubin is normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal (ULN)

- Serum creatinine =< institutional ULN or creatinine clearance >= 50 mL/min/1.73 m^2
for subjects with creatinine levels above institutional ULN

- Pre-existing grade 3 or 4 peripheral neuropathy

Exclusion Criteria:

- KS that is improving in the 4 weeks prior to enrollment

- Symptomatic visceral KS (oral and lymph node involvement is eligible)

- Symptomatic pulmonary KS; asymptomatic pulmonary KS that is not limiting activities of
daily living is allowable

- Eastern Cooperative Oncology Group (ECOG) performance status greater than 2

- Expected survival < 3 months with standard KS treatments (i.e., radiation, paclitaxel)

- Concurrent active opportunistic infection (OI)

- Herpes zoster (shingles) outbreak within the last 6 months or inability to take herpes
zoster prophylaxis

- Patient is =< 5 years free of another primary malignancy except if the other primary
malignancy is neither currently clinically significant nor requiring active
intervention, or if the other primary malignancy is a localized squamous or basal cell
skin cancer or cervical/anal carcinoma in situ

- Acute treatment for an infection or other serious medical illness within 14 days prior
to study entry

- Patients may not have had anti-neoplastic treatment for Kaposi sarcoma (including
chemotherapy, radiation therapy, biological therapy, or investigational therapy)
within 4 weeks (6 weeks for nitrosourea or mitomycin-C) of study treatment

- Prior treatment with bortezomib or other investigational proteasome inhibitors

- Previous local therapy of any KS indicator lesion within 60 days, unless the lesion
has clearly progressed with enlargement since the local therapy

- Use of any investigational drug or treatment within 4 weeks prior to randomization

- Physical or psychiatric conditions that in the estimation of the investigator place
the patient at high risk of toxicity or non-compliance

- Hypersensitivity to boron

- Subjects with grade III/IV cardiac disease as defined by the New York Heart
Association criteria. (e.g., congestive heart failure, myocardial infarction within 6
months of study)

- Subject has an acute or known chronic liver disease (e.g., chronic active hepatitis,
cirrhosis); subjects with known hepatitis B or C infection may be enrolled if they
have either documentation of no or minimal fibrosis on liver biopsy or undetectable
hepatitis virus on polymerase chain reaction (PCR)

- Systemic corticosteroid treatment, other than replacement doses

- Female subjects who are pregnant or breast-feeding