AEG35156 and Docetaxel in Treating Patients With Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and define the recommended phase II dose of AEG35156 in combination with docetaxel in patients with solid tumors.

Secondary

• Determine the qualitative and quantitative toxicities of AEG35156 and docetaxel and define duration and reversibility of those toxicities.
• Determine the pharmacokinetic profile of this regimen.
• Assess, preliminarily, the antitumor activity of this regimen in patients with measurable disease.
• Assess the pharmacodynamic effects of AEG35156 administration on X-linked inhibitor of apoptosis protein (XIAP) levels and apoptosis in peripheral blood mononuclear cells and, in selected patients, in tumor tissue.
• Evaluate M30/M65 cytokeratin 18 level, a marker of apoptosis/necrosis of epithelial tumors, in these patients.

OUTLINE: This is a multicenter, open-label, dose-escalation study of AEG35156.

Patients receive AEG35156 IV continuously on days -2 and -1. Patients then receive AEG35156 IV continuously over 24 hours on days 1, 8, and 15. Beginning with course 2, patients also receive docetaxel IV over 1 hour on day 1. Treatment repeats every 3 weeks 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.

Blood is collected at baseline and periodically during study treatment for pharmacokinetic and pharmacodynamic assessment.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor

• Locally advanced, metastatic, or recurrent disease that is refractory to standard curative therapy or for which no curative therapy exists
• Clinically and/or radiographically documented disease
• Docetaxel single-agent therapy must be a reasonable treatment option
• No newly diagnosed CNS metastases

• Previously treated, intracranial disease that has been stable for ≥ 6 months allowed

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin normal
• Creatinine normal
• AST and ALT ≤ 1.5 times upper limit of normal
• PT or INR normal
• PTT normal
• No known bleeding disorder
• No preexisting peripheral neuropathy ≥ grade 2
• No prior serious allergic reaction to taxanes (e.g., paclitaxel or docetaxel)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other serious illness or medical condition that would be aggravated by treatment or preclude study requirements, including any of the following:

• Serious uncontrolled infection
• Significant cardiac dysfunction
• Significant neurological disorder

PRIOR CONCURRENT THERAPY:

• No more than 2 prior chemotherapy regimens for metastatic or recurrent disease
• No more than 1 prior adjuvant chemotherapy regimen
• No more than 1 prior taxane-containing regimen
• At least 4 weeks since prior chemotherapy and recovered
• At least 4 weeks since prior external-beam radiotherapy provided < 30% of marrow-bearing areas are irradiated*
• At least 4 weeks since prior investigational agents or new anticancer therapy
• At least 2 weeks since prior hormonal therapy or immunotherapy
• At least 2 weeks since prior surgery and recovered
• No prior nephrectomy
• No concurrent anticoagulant therapy in therapeutic doses

• Nontherapeutic dose anticoagulant therapy (e.g., 1 mg warfarin once daily) allowed
• No other concurrent experimental drugs or anticancer therapy
• No other concurrent cytotoxic therapy or radiotherapy

• Small-volume, nonmyelosuppressive palliative radiotherapy allowed NOTE: *Exceptions are made for prior low-dose non-myelosuppressive radiotherapy