title: Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer.
abstract: A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2).
authors.affiliation: Department of Medical Oncology Hospital San Martin, Paraná, Entre Rios, Argentina.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cura
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Blanzaco
authors.forename: Cecilia
authors.initials: C
authors.lastname: Brisson
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cura
authors.forename: Rosa
authors.initials: R
authors.lastname: Cabrol
authors.forename: Luis
authors.initials: L
authors.lastname: Larrateguy
authors.forename: Carlos
authors.initials: C
authors.lastname: Mendez
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Sechi
authors.forename: Jorge Solana
authors.initials: JS
authors.lastname: Silveira
authors.forename: Elvira
authors.initials: E
authors.lastname: Theiller
authors.forename: Adolfo R
authors.initials: AR
authors.lastname: de Roodt
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Vidal
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D019540:Area Under Curve; D003402:Creatine Kinase / Q000097:blood / Q000187:drug effects; D003439:Crotoxin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced; D004172:Diplopia / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000139:chemically induced; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D000637:Transaminases / Q000097:blood / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D003439:Crotoxin; D000637:Transaminases; C019741:asparagine-oxo-acid aminotransferase; D000410:Alanine Transaminase; D003402:Creatine Kinase