Phase I study of YM155, a first-in-class survivin suppressant, in patients with advanced solid tumors in Japan

Abstract

3536 Background: YM155 is a small molecule expected to induce apoptosis in tumor tissue by suppressing survivin. In the US, a phase I study was conducted with a 168-hr continuous infusion every 3 wks. In Japan, we conducted a similar phase I study to evaluate toxicity profile of YM155 compared with the results of the US study. Methods: The objectives were to determine the MTD, characterize the pharmacokinetics (PK) and observe anti-tumor activity. A standard 3+3 dose escalation scheme was utilized. Results: 34 pts (M/F: 24/10, median age 60, range 26 - 81) were enrolled into 6 dose cohorts [1.8 mg/m2/day (N=3), 3.6 (6), 4.8 (6), 6.0 (8), 8.0 (6), and 10.6 (5)]. 2/5 pts experienced dose-limiting toxicities (DLT) during cycle (C) 1 at 10.6 mg/m2/day (blood creatinine increased (2), lymphocyte count decreased (1)), thus the MTD was 8.0 mg/m2/day. Both pts experienced a DLT (56 yo female, 57 yo male), reached to NCI-CTC grade 2 blood creatinine level at the end of infusion. One of them developed to grade 3 blood creatinine level on day10. They recovered to grade 1 or below in 2 wks without plasma dialysis, so that they continued YM155 infusion decreased to 8.0 mg/m2/day. Renal parameters of them changed in a regular manner, as urine microalbumin increased from day 3 to 7, protein urine from day 6 to 8, and blood creatinine from day 8 to 10. As the other DLT during C1, 1/6 pt experienced AST increased at 6.0 mg/m2/day.. The most frequent AEs were: fatigue (39%), urine microalbumin present (39%), pyrexia (33%), and anemia / haemoglobin decreased (30%). At the MTD, the median YM155 clearance was 39 L/hr with a median steady state concentration of 13 ng/mL and a median terminal half-life of 20 hours. 9/33 pts showed stable disease (SD) and minor tumor shrinkage was observed in 5 of them. One pt (thyroid carcinoma) is ongoing (40 wks) and has had disappearance of pleural effusion. Another patient (malignant fibrous histiocytoma) showed tumor regression in abdominal cavity confirmed by CT scan. Conclusions: YM155, the first survivin suppressant, was well tolerated and the MTD was 8.0 mg/m2/day x 168-hr in Japan. The contribution of YM155 to the treatment of advanced solid tumors should be evaluated in further trials. No significant financial relationships to disclose.