A phase I clinical trial of darinaparsin in patients with refractory solid tumors.
OBJECTIVE
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.


METHODS
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.
Tsimberidou
Apostolia Maria
AM
Phase I Program, Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Camacho
Luis H
LH
Verstovsek
Srdan
S
Ng
Chaan
C
Hong
David S
DS
Uehara
Cynthia K
CK
Gutierrez
Catalina
C
Daring
Shawn
S
Stevens
Jan
J
Komarnitsky
Philip B
PB
Schwartz
Brian
B
Kurzrock
Razelle
R
D019540:Area Under Curve; D001152:Arsenicals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001259:Ataxia / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009422:Nervous System Diseases / Q000139:chemically induced; D016896:Treatment Outcome
D001152:Arsenicals; C515055:darinaparsin; D005978:Glutathione