A Phase I Study of the Novel Dna Topoisomerase-1 Inhibitor, Tlc388, Administered Intravenously to Patients with Advanced Solid Tumors.

e13618 Background: The phase I first-in-human study of TLC388 (Lipotecan) examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles 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 tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2. Results: Fifty four previously treated patients with advanced or metastatic solid tumors were enrolled The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts. MTD was reached at 50 mg/m2. DLTs above that dose were thrombocytopenia and febrile neutropenia. Treatment was well-tolerated and no accumulated toxicity seen. Treatment related G3/4 hematological toxicity include neutropenia (19%), leucopenia (15%), anemia (9%), and thrombocytopenia (7%). G3/4 non-hematological side effects were diarrhea (2%) and hyponatremia (4%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 4.5 cycles (2-12 cycles), and had stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 8 patients (23%), 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 12 courses and remains on the study. PET-CT scan revealed tumor size reduction of 22% at cycle 10. Pharmacokinetics of TLC388 was 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 2174 (2526) L/h-m2 for S,R-TLC388 and 2670 (2988) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.67 (1.15) hours for S,R-TLC388 and 0.64 (1.11) hours for S,S-TLC388. Conclusions: Lipotecan at dose of 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support phase II disease-specific investigations.