Faculty Collaboration Database

A phase I clinical trial of darinaparsin in patients with refractory solid tumors. Clin Cancer Res 2009 Jul 15;15(14):4769-76

Date

07/09/2009

Pubmed ID

19584162

DOI

10.1158/1078-0432.CCR-08-2984

Scopus ID

2-s2.0-68049109550 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

PURPOSE: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer.

EXPERIMENTAL DESIGN: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used.

RESULTS: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer.

CONCLUSIONS: The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks.

Author List

Tsimberidou AM, Camacho LH, Verstovsek S, Ng C, Hong DS, Uehara CK, Gutierrez C, Daring S, Stevens J, Komarnitsky PB, Schwartz B, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Area Under Curve
Arsenicals
Ataxia
Dizziness
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Glutathione
Humans
Infusions, Intravenous
Male
Metabolic Clearance Rate
Middle Aged
Nausea
Neoplasms
Nervous System Diseases
Treatment Outcome