TY - JOUR
T1 - A phase I clinical trial of darinapars in in patients with refractory solid tumors
AU - Tsimberidou, Apostolia Maria
AU - Camacho, Luis H.
AU - Verstovsek, Srdan
AU - Ng, Chaan
AU - Hong, David S.
AU - Uehara, Cynthia K.
AU - Gutierrez, Catalina
AU - Daring, Shawn
AU - Stevens, Jan
AU - Komarnitsky, Philip B.
AU - Schwartz, Brian
AU - Kurzrock, Razelle
PY - 2009/7/15
Y1 - 2009/7/15
N2 - Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limitingt oxicity (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/m2) 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/m2. At 588 mg /m2, 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/m2, one developed similar toxicities. De-escalating the dose to 420 mg/m2 (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m2 (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 increasingd oses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for ≥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/m2 i.v. given daily for 5 days every 4 weeks.
AB - Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limitingt oxicity (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/m2) 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/m2. At 588 mg /m2, 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/m2, one developed similar toxicities. De-escalating the dose to 420 mg/m2 (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m2 (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 increasingd oses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for ≥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/m2 i.v. given daily for 5 days every 4 weeks.
UR - http://www.scopus.com/inward/record.url?scp=68049109550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68049109550&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-2984
DO - 10.1158/1078-0432.CCR-08-2984
M3 - Article
C2 - 19584162
AN - SCOPUS:68049109550
SN - 1078-0432
VL - 15
SP - 4769
EP - 4776
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -