A Phase 1 Trial of STA-5312, a Microtubule Inhibitor with a Novel Binding Site, in Hematologic and Solid Malignancies.

BACKGROUND: STA-5312, an inhibitor of tubulin polymerization, with a binding site distinct from other agents such as vincristine, colchicine, or paclitaxel, is not a P-gp substrate. STA-5312 shows in vitro and in vivo activity against leukemia and a range of solid tumors and prolonged survival in models of chemotherapy-resistant cancer.

METHODS: A phase 1 trial was initiated in patients with advanced hematologic cancers or solid tumors to determine the safety, toxicity, pharmacokinetics (PK) and maximum tolerated dose (MTD) of STA-5312. Assessment of activity is a secondary objective. STA-5312 is administered iv on days 1, 3 and 5 of a two week cycle. Dose escalation is based on evaluation of toxicity through the first 3 weeks on the study. In the absence of grade (gr) 2 or greater toxicity, 100% escalations are made. If gr 2 or greater toxicity occurs, all future cohorts are expanded to 3 patients, and further escalations limited to 50%. In the event of any dose limiting toxicity (DLT), the cohort is expanded to 6 patients and escalations limited to 33%. The dose below the lowest dose at which 1/3 of 6 or more patients show DLT will be declared the MTD and expanded to at least 12 patients. PK samples were obtained throughout day 1, and trough and peak samples were taken on day 5. Response is assessed by NCI Working Group Response Criteria, International Workshop Response Criteria Recommendations, or RECIST as appropriate.

RESULTS: After an initial cohort of 3 patients at the dose level of 3 mg/m² the dose was successively doubled up to 48 mg/m² with one patient cohorts. At escalation from 48 mg/m², only a 50% dose increase was made, as exposures were approaching those where significant toxicity was seen in animals. A DLT (hospitalization with dehydration and thrush, liver enzyme elevations and prolonged neutropenia) was reported for the first patient at 72 mg/m². Two additional patients were added at a dose of 48 mg/m² and to date no gr 2 toxicities have been reported during the 21 day evaluation. A cohort has been opened at an intermediate dose (60 mg/m²) and enrollment is ongoing to expand it after DLT (dyspnea) was observed in 1 of 3 patients. Other adverse events attributable to STA-5312 include: fatigue, weakness, decreased sensation and hematuria. STA-5312 exhibited relatively linear PK with regard to AUC. Three patients (2 NHL and 1 multiple myeloma) have experienced durable stable disease, with two patients treated for over 8 months.

CONCLUSIONS: STA-5312 was well tolerated through the first five dose levels, with the few adverse events consistent with microtubule disrupting agents. The patients with durable stable disease are encouraging and planning for Phase 2 clinical trials is underway.