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Single-Arm, Dose-Finding Pilot Trial of Single-Agent Bortezomib in Patients With Relapsed/Refractory AIDS-Associated Kaposi Sarcoma With Correlative Assessments of KSHV and HIV

18 Years
Open (Enrolling)
AIDS-related Kaposi Sarcoma, HIV Infection, Recurrent Kaposi Sarcoma

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Trial Information

Single-Arm, Dose-Finding Pilot Trial of Single-Agent Bortezomib in Patients With Relapsed/Refractory AIDS-Associated Kaposi Sarcoma With Correlative Assessments of KSHV and HIV


I. Estimate the MTD of single agent bortezomib in subjects with AIDS-related KS.


I. Evaluate the clinical response of KS tumors to bortezomib. II. Evaluate the impact of
bortezomib on HIV plasma viral loads and peripheral blood mononuclear cells (PBMC) APOBEC3G

III.Determine the impact of bortezomib on 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, VHL, p27, HIF1-alpha) as well as levels of NFkappaB gene target
mRNAs in tumor biopsies.

OUTLINE: This is a multicenter study.

Patients receive bortezomib 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.

Patients undergo blood and tumor tissue sample collection periodically for correlative
biomarker studies, including measurement of KSHV viral loads, gene expression analysis,
measurement of APOBEC3G levels by IHC, and RNA analysis by reverse transcriptase-PCR.

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
PI-based or 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 HAART regimen meets the 12 week criteria

- Serologic documentation of HIV infection at any time prior to study entry, as
evidenced by positive ELISA, positive western blot, or other 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)

- ANC >= 1,000/mm^3; subjects may be receiving growth factor support to meet these

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

- Platelets >= 100,000/mm^3; subjects may be receiving growth factor support to meet
these criteria

- 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

- AST(SGOT) and ALT(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

- ECOG performance status greater than 2

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

- 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 PCR

- Systemic corticosteroid treatment, other than replacement doses

- Female subjects who are pregnant or breast-feeding

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Outcome Time Frame:

Up to 28 days

Safety Issue:


Principal Investigator

Erin Reid

Investigator Role:

Principal Investigator

Investigator Affiliation:

AIDS Associated Malignancies Clinical Trials Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

January 2010

Completion Date:

Related Keywords:

  • AIDS-related Kaposi Sarcoma
  • HIV Infection
  • Recurrent Kaposi Sarcoma
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Sarcoma, Kaposi
  • AIDS-Related Opportunistic Infections
  • Sarcoma



AIDS - Associated Malignancies Clinical Trials Consortium Rockville, Maryland  20850