A novel oral tubulin inhibitor: Safety and preliminary efficacy of two Phase I studies with indibulin

B4 Purpose: Indibulin is a novel oral tubulin inhibitor that arrests tumor cell growth at the G2/M phase. Its binding site overlaps with but is distinct from colchicine. It does not bind acetylated (neuronal) tubulin, and the neurotoxicity normally observed with other tubulin binders such as taxanes has not been seen in preclinical studies.
 We are performing two Phase I studies (Phase I, Phase Ib) in the US that administer indibulin capsules to patients diagnosed with solid tumors. The two studies are designed to determine the safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and preliminary metabolic and clinical efficacy of this investigational drug.
 Procedures: In the Phase I study, indibulin is administered continuously for 28 days (4-week cycles) at a starting dose of 400 mg twice daily (BID). In the Phase Ib trial, indibulin is given for either 21 or 28 days (4-week cycles) at a fixed dose of 600 mg BID. Patients remain on study until disease progression or unacceptable toxicity occurs. Efficacy evaluations are regularly performed using either CT/MRI or both CT and PET scans.
 Results: Thirty patients have been treated to date and all are evaluable for safety. Twenty-one (70%) have received at least 2 cycles and are evaluable for efficacy. Baseline ECOG was ≤2. Baseline demographics (median values given, with range in parentheses) are: age=63 years (23-90); number of prior therapies=2 (0-12); and number of cycles administered=2 (0.67 to ≥11; total=79). Twelve patients were older than 65 years. The most common tumor types include sarcoma (13), pancreatic (3), ovarian and lung (2).
 No DLTs have been observed and an MTD has not been reached. Common (>10% of patients) toxicities that are considered possibly study-drug related include mild to moderate fatigue, nausea, diarrhea, and anorexia. Grade 3 neutropenia was reported in 1 patient.
 Disease stabilization for ≥4 months has been reported in 6 patients, of whom 4 (66%) were dosed on the 28-day continuous schedule. Early PET scans (following 2 months of treatment) show a mean reduction in SUV (standard uptake value), with 5 metabolic stabilities, 1 complete metabolic response, and 1 partial metabolic response.
 Conclusions: Indibulin has been well tolerated and demonstrates preliminary evidence of metabolic and clinical activity. Most reported toxicities are mild to moderate, and there has been no drug-related neurotoxicity. Both studies are ongoing and updated data will be presented.