PHI-55: (NCI#7427): A phase I study of halichondrin B analog (E7389) in combination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505).

Abstract

2564 Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product Halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. Methods: The goals of this trial were to determine the DLT, the MTD, and PK of E7389 (administered on days 1, 8 and 15 every 28 days) in combination with CDDP (administered on day 1 every 28 days) in patients (pts) with advanced solid tumors. The protocol was amended after dose level 4 (E7389 1.4 mg/m2, CDDP 60 mg/m2) when it was not feasible to administer E7389 on day 15 due to neutropenia; the treatment schedule was changed to E7389 days 1 and 8 and CDDP day 1 every 21 days. Eligibility criteria included normal organ function and < 2 prior chemotherapy regimens. Results: To date, 36 pts have been treated (E7389 0.7-1.4 mg/m2 and CDDP 60-75 mg/m2). Median age 61 years; 19 males; the most common tumor types were lung (8), pancreatic (5), head and neck (6). 36% ECOG 0, 56% ECOG 1, 8% ECOG 2; Median number of cycles was 3 (1 – 8). There were 3 pts with DLT’s on the 28-day cycle: gr 4 febrile neutropenia (1.0/60); gr 3 anorexia/fatigue/hypokalemia (1.2/60); and gr 3 stomatitis/fatigue (1.4/60). There were 3 pts with DLTs treated on the 21-day schedule: gr 3 hypokalemia/hyponatremia (1.4/60); gr 4 mucositis (1.4/60); and gr 3 hypokalemia (1.2/75). With 2 DLTs out of 6 pts at E7389 1.4 mg/m2 and CDDP 60 mg/m2, E7389 was reduced, CDDP was escalated, and the MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2(1 patient out of 6 with a DLT). At the MTD, protocol defined dose modifications or delays were required in 2 of the 6 patients by cycle 2. Notably, all DLTs were observed in patients exposed to at least 2 prior lines of chemotherapy. Two pts had an unconfirmed PR (pancreatic, breast) and 2 had a PR (esophagus, transitional bladder). Conclusions: On a 21 day schedule,E7389 in combination with CDDP appears well tolerated and showed preliminary activity. The MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2. Clinical trial information: 00400829.