Phase I and pharmacokinetic study of ABI-007, a Cremophor®-free nanoparticle formulation of paclitaxel, administered once every 3 weeks in Japanese patients with solid tumors. (2007)

B75 Purpose: ABI-007 is a novel Cremophor®-free nanoparticle albumin-bound paclitaxel. The Cremophor®-free formulation allows for a higher dosage of paclitaxel in shorter infusion period without premeditation to prevent hypersensitivity reaction. The primary objective of the study was to determine maximum tolerated dose (MTD) and recommended dose (RD) when administered once every 3 weeks. Efficacy / safety profile and pharmacokinetics (PK) were also assessed as secondary objective.  Patients and Methods: This study was designed to perform standard 3+3 dose escalation on solid tumor patients recruited regardless of pre-treatment history. The examined doses included three levels: Level 1 200 mg/m2, Level 2 260 mg/m2, and Level 3 300mg/m2; The study did not intend to probe further beyond Level 3 because it was MTD found in the overseas PI study. Treatment schedule per course is 30-minutes IV infusion once every 3 weeks. The specified conditions occurring during the first course of treatment were considered dose limiting toxicity (DLT) such as thrombocytopenia (grade 4), thrombocytopenia with blood transfusion (grade 3), neutropenia lasting over 4 days (grade 4), febrile neutropenia, and non-hematologic toxicity (grade 3 or 4). In the absence of DLT until Level 3, investigators and sponsor were to co-decide on potential RD and evaluate additional 3 patients to elucidate RD.  Results: A total of 12 patients were accrued (from August 2006 to June 2007) and all were evaluable for safety, PK and efficacy. Median number of courses delivered was 2.5. No DLT was evident through the dose escalation to the highest Level 3. In the absence of MTD, potential RD was to be re-evaluated. Considering the frequency of grade 1 and 2 peripheral neuropathy induced in Level 2 and Level 3 patients and the situation of the Western patients dosed at the same Level 3, Level 2 was selected as potential RD and subsequent 3 patients showed no DLT. On the other hand, anemia, leukopenia, neutropenia, and lymphopenia were commonly experienced and the latter 3 categories achieved grade 3 or greater in most patients. Common non-hematological toxicities included asthenia, peripheral neuropathy, myalgia, alopecia, rash, and arthralgia. Febrile neutropenia or hypersensitivity reaction did not occur. Two out of 3 patients who were enrolled in Level 3 experienced grade 3 peripheral neuropathy in 3rd or later courses. As for PK analyses, the area under the curve of paclitaxel in Japanese patients increased with increasing the dosage. A comparison with PK reported for Western patients confirmed the similarity across the two ethnic groups. In efficacy assessment by investigator, partial response was observed with 3 lung cancer patients.  Conclusion: As a result of no DLT observed at any level, MTD was not determined. RD was deemed accordingly at 260 mg/m2 in consideration of efficacy observed in Japanese patients, and frequency of peripheral neuropathy reported inside and outside of Japan. This dose is also the RD found in Western studies. Regarding PK profile, similarity between the Japanese and Western population was endorsed. Consistent RD and similar PK profile indicate that the same dose and schedule of ABI-007 can be used in global studies involving different ethnic groups.  (Data cutoff as of July 31, 2007)