Phase I and pharmacokinetic evaluation of the anti-telomerase agent KML-001 with cisplatin in advanced solid tumors.
OBJECTIVE
KML-001 (sodium metaarsenite) displaces hTERT from the nucleus and is synergistic with cisplatin. This phase I trial tested the tolerability, activity and pharmacology of this combination.


METHODS
Patients with advanced solid tumors that were "platinum sensitive," PS 0-1, normal renal and hepatic function were eligible. Treatment was with cisplatin 75 mg/m2day 1 and KML-001 p.o. daily days 1-14 on a 21-day cycle. A standard 3 + 3 design was employed. Blood specimens for arsenic and platinum pharmacokinetics were obtained at 0, 1, 2, 3, 4, 5, 6, 24 h and days 8, 15 and 22.


RESULTS
Eighteen patients (7 M, 11 F) were evaluable for the primary endpoint of toxicity. Patients were heavily pretreated for a variety of malignancies (mean number of prior regimens = 3). Sixteen 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. In addition to the dose-limiting toxicity of QTc prolongation, the most common toxicities observed were nausea and vomiting and cytopenias. Myelosuppression was primarily seen in patients who had undergone prior radiotherapy.


CONCLUSIONS
The combination of KML-001 and cisplatin was technically feasible and active. However, the occurrence of significant QTc prolongation led to discontinuation of the trial. This prolongation was likely a result of electrolyte abnormalities resulting from cisplatin superimposed on the known risks of arsenicals and QTc prolongation. Combinations with other platinum agents (e.g., carboplatin) should be considered. This is the first fully reported human trial of KML-001.
University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD, 21201, USA. medelman@umm.edu.
Martin J
MJ
Edelman
University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD, 21201, USA.
Rena
R
Lapidus
University of Maryland Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD, 21201, USA.
Josephine
J
Feliciano
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
Miroslav
M
Styblo
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jan H
JH
Beumer
University of Maryland School of Pharmacy, Baltimore, MD, USA.
Tao
T
Liu
University of Maryland School of Pharmacy, Baltimore, MD, USA.
Jogarao
J
Gobbru
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001151:Arsenic / Q000097:blood; D018053:Arsenites / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D023381:Endpoint Determination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000097:blood; D017670:Sodium Compounds / Q000008:administration & dosage; D019098:Telomerase / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018053:Arsenites; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; C017947:sodium arsenite; D010984:Platinum; D019098:Telomerase; D001151:Arsenic; D002945:Cisplatin
Arsenical; KML-001; Phase 1; Telomere