Abstract A89: A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388 (Lipotecan®), administered intravenously to patients with advanced solid tumors.

Introduction: TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients. Results: The enrollment for this study has been concluded and 54 previously-treated patients with advanced or metastatic solid tumors received Lipotecan. The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts (11 dose levels). MTD was reached at 50 mg/m2, following the emergence of two DLTs at 60 mg/m2: one grade 3 febrile neutropenia and one toxicity that precluded treatment within the 14 days specified by the protocol. Other DLTs occurred in other dose levels include hyponatremia (grade 3 and 4; 40 mg/m2) and thrombocytopenia (grade 4; 40 mg/m2). To date, all the subjects except one have completed the study. Lipotecan given at this dosing schedule was well-tolerated and no cumulative toxicity was observed. Non-hematological toxicity was generally mild, including fatigue (41%), nausea (37%), diarrhea (28%), vomiting (14%) and constipation (14%). Anemia was the most frequently reported hematological toxicity (67.0%). Neutropenia (30%), thrombocytopenia (28%), and leukopenia (26%) were also reported. Grade 3 or grade 4 hematological toxicity included neutropenia (28%), anemia (22%), leucopenia (17%), and thrombocytopenia (13%). Other G3/4 non-hematological side effects included hyponatremia (11%), abdominal pain (7%), fatigue (6%), and hypokalaemia (6%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 5 cycles (range of 2–18 cycles), and experienced stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 9 patients (26%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 18 courses and remains on the study. PET-CT scan revealed reduction in his tumor size by 27% at the end of cycle 16. His disease had progressed through prior treatment with cyclophosphamide, cisplatin and doxorubicin. Pharmacokinetics of TLC388 were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 7420 (8151) L/h-m2 for S,R-TLC388 and 4949 (5678) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.76 (1.15) hours for S,R-TLC388 and 0.75 (1.13) hours for S,S-TLC388. Conclusions: Lipotecan administered doses up to 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support Phase 2 disease-specific investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A89.