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Phase II trial of karenitecin (BNP1350) in malignant: Clinical and translational study.

7554 Background: To determine the efficacy and safety of the novel camptothecin, karenitecin (BNP1350), in patients with metastatic melanoma and to measure the level of expression of topoisomerase I, IIα and IIβ through directed patient biopsy.


METHODS
Eligible patients had a histopathological diagnosis of metastatic melanoma with up to 3 prior chemotherapy regimens and any prior immunotherapy regimens. Treatment consisted of a 60-minute intravenous infusion of 1 mg/m2 of karenitecin daily for 5 consecutive days with cycles repeated every 3 weeks. Patients were evaluated for progression every 2 cycles and continued on treatment ifthey experienced clinical benefit as evidenced by stable disease or objective response to therapy. Fine needle aspiration biopsies were performed pre-treatment and on Day 3 to determine the topoisomerase expression from patients' tumors.


RESULTS
Forty-three patients were evaluable for tumor response and toxicity. The majority of patients (72%) had stage M1C disease and was previously exposed to chemotherapy (56%). This investigational new drug was well tolerated with limited GI side effects or fatigue. The major dose-limiting toxicity observed was reversible non-cumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were noted, but 33% of the patients had disease stabilization lasting 3 months or longer. Topoisomerase I, IIα and IIβ expression and localization were determined prior to and on Day 3 of chemotherapy in 13 paired tumor samples, and pre- in an additional 7 patients. Topoisomerase I expression was highest, followed by topoisomerase IIβ and topoisomerase IIα.


CONCLUSIONS
Karenitecin was a well-tolerated investigational agent in this Phase 2 study; side effects were generally mild and mostly hematological in this population with largely adverse prognostic factors. Karenitecin has moderate activity in metastatic melanoma. While melanoma metastases express high levels of topoisomerase I, there appears to be no correlation between topoisomerase expression with response in the subset of patients that underwent biopsies. Further studies are planned with this agent. [Table: see text].