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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01016730
First received: November 18, 2009
Last updated: November 21, 2014
Last verified: November 2014
  Purpose

This pilot, phase I trial studies the side effects and best dose of bortezomib in treating patients with acquired immune deficiency syndrome (AIDS)-related Kaposi sarcoma that has come back or has not responded to treatment. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
AIDS-Related Kaposi Sarcoma
HIV Infection
Recurrent Kaposi Sarcoma
Drug: Bortezomib
Other: Laboratory Biomarker Analysis
Other: Questionnaire Administration
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    MTD is defined as the highest assigned dose at which < 2 patients (out of 6) experience dose-limiting toxicity. Adverse events will be summarized by type, timing, and severity grade.


Secondary Outcome Measures:
  • Clinical KS response rates based on the Response Evaluation Criteria in Solid Tumors [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Exact binomial 95% confidence intervals will be computed. Descriptive statistics will also be presented for complete and partial response rates.

  • Changes in bortezomib in KSHV copy number in PBMC and plasma [ Time Frame: Baseline to 1 year ] [ 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.

  • Change in lytic gene expression [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    The association between change in lytic gene expression with clinical response of KS tumors will be investigated with exact logistic regression. Hierarchical clustering will be used to explore if gene expression patterns differ according to clinical response.

  • Changes in viral antigen expression in biopsy specimens [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    Spearman's rank correlations will be calculated to examine whether the changes in KSHV viral copy number in PBMC and plasma occur in concert or independently with changes in viral antigen expression in biopsy specimens collected at baseline, day 2 and treatment discontinuation.

  • Changes in levels of tumor survival, proliferation proteins, and NFKappaB gene target mRNA levels [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    Analyzed using the Wilcoxon signed rank test.


Enrollment: 24
Study Start Date: January 2010
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Bortezomib
Given IV
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Questionnaire Administration
Ancillary studies

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01016730

Locations
United States, California
University of California at Los Angeles Health System
Los Angeles, California, United States, 90095
University of California San Diego
San Diego, California, United States, 92103
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Boston Medical Center
Boston, Massachusetts, United States, 02118
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Sponsors and Collaborators
Investigators
Principal Investigator: Erin Reid AIDS Associated Malignancies Clinical Trials Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01016730     History of Changes
Other Study ID Numbers: NCI-2012-03170, NCI-2012-03170, CDR0000659554, AMC-063, AMC-063, U01CA121947
Study First Received: November 18, 2009
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
AIDS-Related Opportunistic Infections
Acquired Immunodeficiency Syndrome
HIV Infections
Sarcoma
Sarcoma, Kaposi
DNA Virus Infections
Herpesviridae Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Infection
Lentivirus Infections
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Neoplasms, Vascular Tissue
Opportunistic Infections
Parasitic Diseases
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Bortezomib
Antineoplastic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014