Clinical Review Abstract
Trials in Progress Abstract
Abstracts selected for publication but not presentation at the Annual Meeting
Abstracts granted an exception in accordance with ASCO's Conflict of Interest Policy
Phase I and pharmacokinetic trial of the antitemolerase agent KML001 (KML) and cisplatin (CDDP) in advanced solid tumors.
Cytotoxic and Other Novel Agents
Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
2013 ASCO Annual Meeting
J Clin Oncol 31, 2013 (suppl; abstr 2515)
Author(s): Martin J. Edelman, Josephine Louella Feliciano, Miroslav Styblo, Tao Liu, Rena G. Lapidus, Jesse Saunders, Joga Gobburu; University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD; The University of North Carolina at Chapel Hill, Chapel Hill, NC; University of Maryland School of Pharmacy, Baltimore, MD; University of North Carolina, Durham, NC
Background: Telomerase is overexpressed in most solid tumors and rarely expressed in adult tissues and is therefore a promising target. We have previously demonstrated that KML001 (sodium metaarsenite) displaces hTERT from the nucleus and is cytotoxic (Clin Cancer Res 14:4593-602, 2008). We have also demonstrated that it is synergistic with cisplatin. Methods: Pts with advanced solid tumors, PS 0-1, normal renal and hepatic function were eligible. Treatment was with CDDP 75 mg/m2 day 1 and KML p.o. daily days 1-14 on a 21 day cycle. It was planned that KML doses would be escalated by 2.5 mg beginning at 15 mg/day. A 3+3 design was employed. Blood specimens for arsenic and platinum pk were obtained at hours 0,1,2,3,4,5,6, 24 and day 15 and 22. Tumor blocks were required to assess for telomerase expression. Results: 18 patients (7M,11F) are evaluable for toxicity. Pts were heavily pretreated (median number of prior regimens =3). 16 had prior platinum therapy. The dose limiting toxicity was QTc interval prolongation seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A PR was seen in a patient with heavily pretreated SCLC in cohort 1. 1 other pt with SCLC and 2 with NSCLC also experienced reduction in disease burden. 10/18 pts received >3 cycles of therapy. Other common toxicities observed were nausea, vomiting and cytopenias. Significant, but not dose limiting, neutropenia or thrombocytopenia (> grade 3) was observed in cohorts 1 and 2. Myelosuppression was primarily seen in pts with prior radiotherapy. Non-compartmental analysis for inorganic arsenic (iAs) and the mono (MAs) and dimethylarsenic (DMAs) metabolites was performed (Table). Conclusions: 1. The combination of KML-001 and CDDP is feasible and active. 2. We are currently evaluating CDDP 75 mg/m2 and KML 17.5 mg in an expansion cohorts of advanced SCLC and NSCLC. 3. Studies of telomerase expression are in progress. (R21CA130349-01) Clinical trial information: NCT01110226.
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