A phase I study of the combination of TZT-1027 (soblidotin) and gemcitabine administered on day 1 and 8 every three weeks to patients with advanced or metastatic solid tumors

Background: TZT-1027 is a dolastatin 10 analog interfering with microtubule assembly, with increased antitumor activity when combined with gemcitabine in animal models. Patients and Methods: Eligible patients with refractory solid tumors received gemcitabine followed by TZT-1027 on Days 1 and 8 every 21 days, with pharmacokinetic sampling during the first 24 hours. Results: Fourteen patients received at least one course of study drug (10 at TZT-1027 dose 1.6 mg/m2 and 4 at 2.0 mg/m2). There were 36% male, median age 59 years, median PS 0, median number of prior treatments 2. Reasons for withdrawal included: progression of disease (n=12) and adverse events (n=2). A total of 66 courses were administered. Of 12 instances of dose delay, 8 were due to neutropenia. Grade 3/4 adverse events included neutropenia (50%), thrombocytopenia (14%), fatigue (14%), and anorexia (7%). Cmax and AUCinf were 181 mcg/L (CV% 38.2) and 537 ng.h/mL (n=10 in cohort 1), and peaked at 1.05 hours after the end of TZT-1027 infusion, with a biphasic elimination. T1/2 was 5.12 h, clearance 3.9 L/h/m2, and VSS 16.5 L/m2. Conclusions: The recommended phase II dose is 1.6 mg/m2 of TZT and 800 mg/m2 of gemcitabine. Pharmacokinetics are consistent between studies.C. F. Verschraegen, H. Raftopoulos, K. Feit, R. De Jager, S. Joon Lee & C. Sweene