Phase II trial of karenitecin in patients with malignant melanoma: clinical and translational study.
OBJECTIVE
A phase II trial of the novel camptothecin karenitecin (BNP1350) was conducted to determine its efficacy and tolerability in patients with metastatic melanoma. Patients were biopsied to determine topoisomerase expression at baseline and response to therapy.


METHODS
Eligible patients had metastatic melanoma with up to three prior chemotherapy and/or any number of immunotherapy regimens. Treatment consisted of an i.v. infusion of 1 mg/m(2) karenitecin daily for 5 days with cycles repeated every 3 weeks. Fine-needle aspiration biopsies were done before treatment and on day 3 to determine topoisomerase expression from patients' tumors.


RESULTS
Forty-three patients were evaluable for response and toxicity. Most patients (72%) had stage M1C disease and were previously exposed to chemotherapy (56%). The investigational agent was well tolerated with limited gastrointestinal side effects or fatigue. The major toxicity seen was reversible noncumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were seen, but 33% of the patients had disease stabilization lasting > or =3 months. Topoisomerase I, IIalpha, and IIbeta expression and localization were determined in a subset of patients. Topoisomerase I expression was highest, followed by topoisomerase IIbeta and topoisomerase IIalpha.


CONCLUSIONS
Karenitecin was a well-tolerated investigational agent in this phase II study; side effects were generally mild and mostly hematologic. Karenitecin has significant activity in metastatic melanoma. Melanoma metastases express high levels of topoisomerase I. We did not observe any compensatory increase in topoisomerase II upon treatment with karenitecin.
Daud
Adil
A
Cutaneous Oncology, Experimental Therapeutics, and Gastrointestinal Oncology Programs, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA. daudai@moffitt.usf.edu
Valkov
Nikola
N
Centeno
Barbara
B
Derderian
Jennifer
J
Sullivan
Patricia
P
Munster
Pamela
P
Urbas
Patricia
P
Deconti
Ronald C
RC
Berghorn
Elmer
E
Liu
Zhenmei
Z
Hausheer
Frederick
F
Sullivan
Daniel
D
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
C406143:cositecan; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin