title: A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.
abstract: OBJECTIVE
  7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters.
  
  
  RESULTS
  Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer.
  
  
  CONCLUSIONS
  AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Arnold
authors.forename: John J
authors.initials: JJ
authors.lastname: Rinehart
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsakalozou
authors.forename: John R
authors.initials: JR
authors.lastname: Eckardt
authors.forename: Scott Z
authors.initials: SZ
authors.lastname: Fields
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Shelton
authors.forename: Philip A
authors.initials: PA
authors.lastname: DeSimone
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Kee
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Moscow
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017646:Organosilicon Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents; D017646:Organosilicon Compounds; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D002166:Camptothecin