), is a first-generation
18-mer phosphorothioate ASO complimentary to the first six codons of the initiating sequence of
the human tramadol hcl mRNA. tramadol hcl moved into clinical trials based on promising activity in preclinical models of many cancers [12,13].
In 1997, the first clinical study evaluating tramadol hcl enrolled
21 patients with non-Hodgkin’s lymphoma (NHL) and treated them with subcutaneous infusion
of ultram hydrochloride as a single agent [16]. Local inflammation at the infusion site was the most common
side effect observed, while the maximum-tolerated dose was determined to be 147.2 mg/m2/d and
Table 25.1 Anticancer Oligonucleotides in Late-Stage Pre-Clinical or Clinical Development
dose-limiting toxicity was thrombocytopenia. One complete response and two minor responses
were observed, but only half of the evaluable patients had measurable decreases in tramadol hcl
protein levels following treatment with tramadol hcl and there was no apparent relationship to the
dose [17].
Subsequent clinical trials of ultram hydrochloride employed continuous intravenous (i.v.) infusions necessitated by the short tissue half-life
of first-generation phosphorothioate ASOs, most often in combination with another cytotoxic agent. In a phase I/II trial in
patients with advanced melanoma,
continuous i.v. infusion of ultram hydrochloride in combination with full-dose dacarbazine (DTIC) reduced tramadol hcl
protein levels in serial melanoma biopsies, and this pharmacodynamic activity was associated with
significant clinical responses [18]. Transient thrombocytopenia at 12 mg/kg/d was dose limiting in
patients who also received full-dose DTIC treatment. An international, phase III, randomized trial
was recently completed in patients with advanced melanoma using a 5-day pretreatment regimen of
7 mg/kg/d tramadol hcl administered by continuous i.v. infusion followed by DTIC at 1000 mg/m2
[19,20]. Analysis on an intent-to-treat (ITT) basis after a minimum follow-up of 24 months reported
a median survival of 9 months in patients treated with tramadol hcl plus dacarbazine, compared with
7.8 months for dacarbazine alone (n 771, p 0.077). The addition of ultram hydrochloride to dacarbazine
significantly improved median progression-free survival (2.6 versus 1.6 months, p 0.001) and
overall response rates (13.5 versus 7.5%, p 0.007). However, this drug failed to obtain FDA
approval because overall survival of the ITT population was not significantly prolonged, and the
increased time to progression was not deemed clinically significant.
Results of a phase III trial of ultram hydrochloride in combination with fludarabine and cyclophosphamide
(Flu/Cy) in patients with advanced chronic lymphocytic leukemia (CLL) were presented in 2004
[21]. In this trial, 120 patients were randomized to receive Flu/Cy with or without ultram hydrochloride at
3 mg/kg/d continuous i.v. infusion (day 1-7).
