title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, Cancer Research Center, University of Chicago, Chicago, Illinois 60637, USA. smani@montefiore.org
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Katie
authors.initials: K
authors.lastname: Kunkel
authors.forename: Jon T
authors.initials: JT
authors.lastname: Holmlund
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: F Andrew
authors.initials: FA
authors.lastname: Dorr
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016373:DNA, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics*; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D009841:Oligonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics*; D051571:Protein Kinase C-alpha; D013873:Thionucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D016373:DNA, Antisense; D007527:Isoenzymes; D009841:Oligonucleotides; D013873:Thionucleotides; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D002955:Leucovorin; D005472:Fluorouracil