Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer

Clin Cancer Res. 2002 Apr;8(4):1042-8.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Area Under Curve
  • DNA, Antisense / adverse effects
  • DNA, Antisense / pharmacokinetics*
  • DNA, Antisense / therapeutic use
  • Diarrhea / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Fatigue / chemically induced
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / pharmacokinetics
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics*
  • Leucovorin / administration & dosage
  • Leucovorin / adverse effects
  • Leucovorin / pharmacokinetics
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neutropenia / chemically induced
  • Oligonucleotides / adverse effects
  • Oligonucleotides / pharmacokinetics
  • Oligonucleotides / therapeutic use
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics*
  • Protein Kinase C-alpha
  • Thionucleotides / adverse effects
  • Thionucleotides / pharmacokinetics
  • Thionucleotides / therapeutic use
  • Thrombocytopenia / chemically induced
  • Treatment Outcome
  • Vomiting / chemically induced


  • DNA, Antisense
  • Isoenzymes
  • Oligonucleotides
  • Thionucleotides
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Leucovorin
  • Fluorouracil