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
PRIMARY ENDPOINT: Estimate the maximum tolerated dose (MTD) of single agent bortezomib in subjects with AIDS-related Kaposi's sarcoma (KS). SECONDARY ENDPOINTS: Evaluate the clinical response of KS tumors to bortezomib. Evaluate the impact of bortezomib on HIV serum viral loads and peripheral blood mononuclear cells (PBMC) APOBEC3G. Determine the impact of bortezomib on KSHV. a)Assess bortezomib effects on KSHV copy number in PBMC, plasma and saliva and whether changes in viral copy number measured in PBMC, plasma, or saliva are associated with clinical response of KS tumors. b)Monitor KSHV gene expression in KS biopsy specimens and PBMC pre- and post-bortezomib and assess whether changes in viral gene expression (i.e., increases in lytic gene expression) in tumor biopsies are associated with clinical response. c)Assess whether changes in viral copy number in PBMC, plasma and saliva occur in concert with, or independently of changes in viral antigen expression in tumor biopsy specimens. 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.
Inclusion Criteria - Adult patients age greater than 18 with cutaneous AIDS-related biopsy-proven KS relapsed after or refractory to liposomal anthracycline. Subjects with disease relapsed after or refractory to other agents in addition to liposomal anthracycline are eligible as well. - Patients must have cutaneous KS lesion(s) amenable to biopsy (either one lesion greater than 12 mm or 3 greater than 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.) - Subjects must have adequate organ and marrow function as defined below: o ANC greater than 1,000/mm3* o Hemoglobin greater than 8.0 gm/dL* o Platelets greater than 100,000/mm3 o Total bilirubin less than 1.5 mg/dL** o AST(SGOT) and ALT(SGPT) less than 2.5 X institutional upper limit of normal (ULN) o Serum creatinine less than institutional ULN or o Creatinine clearance greater than 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN *Subjects may be receiving growth factor support to meet these criteria ** If the elevated bilirubin is felt to be secondary to indinivir or atazanavir therapy, then subjects will be allowed on protocol without any limit on the total bilirubin if the direct bilirubin is normal. Exclusion Criteria - KS that is improving in the 4 weeks prior to enrollment.- Symptomatic visceral KS (oral and lymph node involvement is eligible) - CXR or Chest CT findings suggestive of pulmonary KS will preclude enrollment on this study unless bronchoscopy does not confirm KS - Pre-existing grade 3 or 4 peripheral neuropathy - ECOG performance status ? 2. - Expected survival less than 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 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.
REGIMEN: Subjects will be entered sequentially on to four pre-specified dose levels of bortezomib (0.75 mg/m2, 1 mg/m2, 1.3 mg/m2, 1.6 mg/m2), given on Days 1, 8, and 15 of a 28-day cycle based on the toxicities observed in prior subjects. DURATION: Patients who tolerate bortezomib may continue for a total of 8 cycles. Those with stable disease or lack of acceleration in progression of their disease after cycle 2 may be eligible for dose escalation after cycle 2. Protocol treatment will be discontinued if the subject develops accelerated tumor progression, a KSHV-related inflammatory syndrome, unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation at any time during the study.
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