PHASE I AND PHARMACOKINETIC TRIAL OF THE ANTITEMOLERASE AGENT KML001 (KML) AND CISPLATIN (CDDP) IN ADVANCED SOLID TUMORS
Martin J. Edelman1, Rena Lapidus1, Josephine Feliciano1, Miroslav Styblo 2, Tao Liu 3, Joga Gobburu 3
1University of Maryland Greenebaum Cancer Center, Baltimore, MD; 2 University of North Carolina, Chapel Hill, NC
3 University of Maryland School of Pharmacy, Center for Translational Medicine
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 synergistic with cisplatin (Clin Cancer Res 14:4593-602, 2008 ).
Methods: Pts with advanced solid tumors that were potentially “platinum sensitive”, PS 0-1, normal renal and hepatic
function were eligible. Treatment was with cisplatin 75 mg/m2 day 1 and KML-001 p.o. daily days 1-14 on a 21 day cycle.
It was planned that KML 001 doses would be escalated by 2.5 mg beginning at 15 mg/day. A standard 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 the primary endpoint of toxicity. Patients were heavily pretreated for a variety
of malignancies (mean number of prior regimens =3). 16 had prior platinum therapy. The dose limiting toxicity was prolongation
of the QTc interval, seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A documented
response was seen in a patient with heavily pretreated SCLC in cohort one. Several other patients had reduction in tumor
burden, not meeting the definition of partial response. In addition to the dose limiting toxicity of QTc prolongation,
the most common toxicities observed were nausea and vomiting and cytopenias. Significant, but not dose limiting,
neutropenia or thrombocytopenia (> grade 3) was observed in cohorts one and two. Myelosuppression was primarily
seen in patients who had undergone prior radiotherapy. Non-compartmental analysis for inorganic arsenic (iA) and the
mono (MA) and dimethylarsenic (DMA) metabolites was performed using Phoenix WinNonlin 6.3 (Pharsight, Mountain View,
CA) and all concentration data was adjusted by corresponding baseline value first (Table).
Conclusions: 1. The combination of KML-001 and cisplatin is feasible and active. 2. We are currently evaluating the
combination of CDDP 75 mg/m2 and KML001 17.5 mg qd x 14 in expansion cohorts of advanced small cell and non-small
cell lung cancer. Supported by R21CA130349
