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

This study is currently recruiting participants.
Verified December 2013 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01016730
First received: November 18, 2009
Last updated: April 1, 2014
Last verified: December 2013

November 18, 2009
April 1, 2014
January 2010
September 2014   (final data collection date for primary outcome measure)
  • Maximum tolerated dose (MTD) based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
  • Overall KS response rates based on the Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Exact binomial 95% confidence intervals will be computed.
Maximum tolerated dose of single-agent bortezomib [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01016730 on ClinicalTrials.gov Archive Site
  • Changes in bortezomib in Kaposi's sarcoma associated herpesvirus (KSHV) copy number in peripheral blood mononuclear cells (PBMC) and plasma [ Time Frame: Up to day 29 ] [ Designated as safety issue: No ]
    Analyzed using the Wilcoxon signed rank test. The association between change in KSHV copy number with clinical response of KS tumors will be investigated with exact logistic regression.
  • Association between change in lytic gene expression with clinical response of KS tumors [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Investigated with exact logistic regression. Hierarchical clustering will be used to explore if gene expression patterns differ according to clinical response.
  • Determination whether changes in KSHV viral copy number in PBMC and plasma occur in concert or independently with changes in viral antigen expression in biopsy specimens [ Time Frame: Up to day 29 ] [ Designated as safety issue: No ]
    Spearman's rank correlations will be calculated.
  • Changes in bortezomib in levels of tumor survival and proliferation proteins and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKappaB) gene target messenger ribonucleic acid (mRNA) levels [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Analyzed using the Wilcoxon signed rank test.
  • Clinical response (CR) [ Designated as safety issue: No ]
  • Impact of bortezomib on HIV serum viral loads and peripheral blood mononuclear cell (PBMC) APOBEC3G levels [ Designated as safety issue: No ]
  • Effects of bortezomib on KSHV copy number in PBMC, plasma, and saliva and whether changes in viral copy number are associated with CR [ Designated as safety issue: No ]
  • Pre- and post-treatment KSHV gene expression in tumor biopsy specimens and PBMC and whether changes in viral gene expression are associated with CR [ Designated as safety issue: No ]
  • Association of changes in viral copy number in PBMC, plasma, and saliva with changes in viral antigen expression in tumor biopsy specimens [ Designated as safety issue: No ]
  • Effects of bortezomib on proteins relevant to KS tumor survival and proliferation (i.e., p53, VHL, p27, HIF1-α) as well as levels of NFkappaB gene target mRNAs in tumor biopsy specimens [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Bortezomib in Treating Patients With Relapsed or Refractory AIDS-Related Kaposi Sarcoma
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

This clinical trial is studying the side effects and best dose of bortezomib in treating patients with relapsed or refractory AIDS-related Kaposi sarcoma. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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 levels.

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.

Interventional
Not Provided
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • AIDS-related Kaposi Sarcoma
  • HIV Infection
  • Recurrent Kaposi Sarcoma
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (bortezomib)

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.

Interventions:
  • Drug: bortezomib
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
24
Not Provided
September 2014   (final data collection date for primary outcome measure)

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 criteria
  • 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, 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 PCR
  • Systemic corticosteroid treatment, other than replacement doses
  • Female subjects who are pregnant or breast-feeding
Both
18 Years and older
No
Not Provided
United States
 
NCT01016730
NCI-2012-03170, NCI-2012-03170, CDR0000659554, AMC-063, AMC-063, U01CA121947
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Erin Reid AIDS Associated Malignancies Clinical Trials Consortium
National Cancer Institute (NCI)
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP