RATIONALE: Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. AEG35156 may help docetaxel work better by making tumor cells more sensitive to the drug. PURPOSE: This phase I trial is studying the side effects and best dose of AEG35156 when given together with docetaxel in treating patients with locally advanced, metastatic, or recurrent solid tumors.
OBJECTIVES: Primary * Determine the maximum tolerated dose and define a recommended phase II dose of AEG35156 in combination with docetaxel in patients with locally advanced, metastatic, or recurrent solid tumors. Secondary * Determine the qualitative and quantitative toxicities of AEG35156 in combination with docetaxel given and define the duration and reversibility of those toxicities. * Determine the pharmacokinetic profile of this regimen. * Assess, preliminarily, the antitumor activity of this regimen in these patients. * Assess the pharmacodynamic effects of AEG35156 on X-linked inhibitor of apoptosis levels and apoptosis in peripheral blood mononuclear cells and in tumor tissue of these patients. * Evaluate M30/M65 cytokeratin 18 level (a marker of apoptosis/necrosis of epithelial tumors) in serum of these patients. OUTLINE: This is a multicenter, open-label, dose-escalation study of AEG35156. Patients receive AEG35156 IV over 2 hours on days -1, 0, 1, 8, and 15 during course 1 and on days 1, 8, and 15 of all subsequent courses. Patients also receive docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of AEG35156 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which ≥ 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients receive AEG35156 at the recommended phase II dose (RPTD). Blood is drawn periodically for pharmacokinetic and pharmacodynamic studies. Samples are examined by flow cytometry, immunoenzyme methods, and reverse transcriptase-polymerase chain reaction for biological markers. Tumor tissue (archival and fresh) is collected from patients treated at the RPTD and examined by immunohistochemical methods and biological marker analysis. After completion of study treatment, all patients are followed at 4 weeks. Patients with response or stable disease ongoing are followed every 3 months thereafter until relapse/progression. Patients with protocol-related toxicity also followed q 3 months until resolution to ≤ grade 2. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
Study Type
After a recommended phase II dose (RPTD) of AEG35156 has been determined with docetaxel 75 mg/m2, patients will be accrued to the RPTD-1 plus docetaxel 100 mg/m2, and possibly RPTD plus docetaxel 100 mg/m2, to determine the RPTD of AEG35156 in combination with docetaxel 100 mg/m2 given every three weeks.
After a recommended phase II dose (RPTD) of AEG35156 has been determined with docetaxel 75 mg/m2, patients will be accrued to the RPTD-1 plus docetaxel 100 mg/m2, and possibly RPTD plus docetaxel 100 mg/m2, to determine the RPTD of AEG35156 in combination with docetaxel 100 mg/m2 given every three weeks.
Cycle 1: Pre-dose on Days -2, 1, 8 and 15; repeat every 2-4 days if LFTs \> 5 x ULN1 Cycle 2: Prior to each infusion; repeat every 2-4 days if LFTs \> 5 x ULN1
BCCA - Vancouver Cancer Centre
Vancouver, British Columbia, Canada
Univ. Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
McGill University - Dept. Oncology
Montreal, Quebec, Canada
Maximum tolerated dose of AEG35156 in combination with docetaxel
Doses of AEG35156 escalated as shown in protocol section 4.3 in patient cohorts given a fixed dose of docetaxel. MTD defined as that dose level at which ≥ 2/6 patients experienced DLT (as defined in protocol section 4.6)
Time frame: 2-3 years
Recommended phase II dose
RPTD for AEG35156 defined as one dose lower than MTD
Time frame: 2-3 years
Toxicities
Toxicities evaluated according to NCI CTCAE v3.0
Time frame: Every 3 weeks
Pharmacokinetic profile
Venous blood samples for determination of AEG35156 concentration obtained on all patients during cycle 1 and 2 as per protocol section 17.2
Time frame: Each cycle
Antitumor activity
All patients with measurable disease at baseline evaluated for response using RECIST criteria as described in protocol section 10.0
Time frame: Every 6 weeks
Pharmacodynamic effects of AEG35156 on X-linked inhibitor of apoptosis levels and apoptosis in peripheral blood mononuclear cells and tumor tissue
Venous blood samples collected for PD studies as described in protocol Section 17.0. Fresh tissue biopsies also collected in patients entered at the RPTD.
Time frame: Each cycle
M30/M65 cytokeratin 18 level
Venous blood samples collected for determination of M30/M65 cytokeratin 18 and nucleosomal DNA as described in protocol section 17.0
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INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Data will be summarized by descriptive statistics relevant to each of the proposed pharmacodynamic studies.
Data will be summarized by descriptive statistics relevant to each of the proposed pharmacodynamic studies.
Data will be summarized by descriptive statistics relevant to each of the proposed pharmacodynamic studies.
The plasma concentration/ time data will be analysed using non-compartmental methods. The pharmacokinetic parameters to be determined for AEG35156 include the maximum observed plasma concentration (Cmax), the half-life (T1/2), and mean residence time (MRT).
The plasma concentration/ time data will be analysed using non-compartmental methods. The pharmacokinetic parameters to be determined for AEG35156 include the maximum observed plasma concentration (Cmax), the half-life (T1/2), and mean residence time (MRT).
Time frame: Each cycle