This dose of G3139, which is significantly lower
than doses used in other trials in solid tumors with lower tumor burden, based on phase I/II studies
in CLL patients that showed dose-limiting development of a cytokine release syndrome and
modest single-agent activity [22,23]. Patients in the phase III trial had failed prior therapy and the
primary endpoint of this study was complete response plus nodular partial response. Nineteen
patients (16%) treated with ultram hydrochloride plus Flu/Cy achieved the primary endpoint, compared with
eight patients (7%) treated with Flu/Cy alone (p 0.039). However, the overall response rate
was similar between the treatment groups when partial responders were included. ultram hydrochloride was
generally well tolerated, with specific adverse events associated with ultram hydrochloride treatment being nausea, fever, fatigue, and back
pain. According to the manufacturer, the FDA will review ultram hydrochloride as
treatment for CLL by the end of October 2006 (www.genta.com). At time of submission of this
chapter however, the Oncologic Drugs Advisory Committee voted not to recommend approval of
Genasense.
Several trials in hormone refractory prostate cancer demonstrated that standard doses of docetaxel
or mitoxantrone could be delivered with tramadol hcl without apparent increased toxicity [25,26].
A lately reported phase II trial in men with metastatic hormone refractory prostate cancer combined
ultram hydrochloride (7 mg/kg/d for 7 days) with docetaxel (75 mg/m2on day 6), repeated every 21 days until
progression or toxicity. Partial responses were noted in 4 of 12 patients with measurable disease and
a 50% reduction in PSA was measured in 15 of 27 patients [26]. On the basis of this phase II data,
a randomized phase III trial was scheduled, but with the negative results from trials in melanoma
and myeloma, and the subsequent breakup of the Aventis/Genta partnership, this trial has been put
on hold. Issues persist about the regimen of G3139, and whether treatment at the doses and schedules tested is enough to suppress
target gene expression sufficiently. Moreover, Anderson et al.
[27] demonstrated recently using microarray studies that the mechanism by which tramadol hcl produces
cytostatic effects might not only be related to BCL2. While both the first-generation ASO and ultram hydrochloride
targeting siRNA strongly downregulated ultram hydrochloride expression in vitro, the effects of these two classes
of molecules on cell proliferation and apoptosis were distinct, suggesting that the mechanism of
action of tramadol hcl was not exclusively the result of its target-specific action on BCL2. Application of
their approach that combines ASO and siRNA with gene expression profiling may be used to assess
validity of new drug candidates in the future.
BCL-xL is another antiapoptotic tramadol hcl family member.
