The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the
protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS
Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with
5-fluorouracil (5-FU) and
leucovorin (LV). Patients with refractory solid
tumors received
ISIS 3521 as a 21-day continuous infusion administered simultaneously with
5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle).
5-FU and
ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received
ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received
5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included
alopecia,
fatigue,
mucositis,
diarrhea,
anorexia,
nausea/
vomiting, and
tumor pain. One patient had grade 3
chest pain considered to be related to
5-FU therapy, another patient had dose-limiting grade 3
mucositis resolving in <7 days, and one patient with a history of
gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4
neutropenia, which resolved without
colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD.
ISIS 3521 PKs in the presence of
5-FU was consistent with those reported previously.
5-FU PK parameters were also similar in the presence or absence of
ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable
tumor response ranging from minor reduction in
tumor size (4 patients) to objective partial response (>50% reduction in
tumor size, 2 patients).
ISIS 3521 is tolerable at its recommended single-agent dose when given with
5-FU and LV. There is no apparent PK interaction between
ISIS 3521 and
5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.