A phase I study investigating the combination of orally bioavailable platinum and nanoparticle albumin-bound paclitaxel in advanced solid tumors

Abstract

e13501 Background: The combination of a taxane and a platinum agent is considered a standard chemotherapy regimen for many solid tumors. Adverse effects often limit the administration of these drugs. Satraplatin (S) is an orally bioavailable platinum agent with a similar spectrum of activity to other platinum analogs, but less renal or neurological side effects. The nanoparticle albumin-bound paclitaxel (A) has shown greater efficacy and less toxicity than Cremophor-based paclitaxel as a single agent in the treatment of breast cancer. The primary aim of this study was to determine a safe dose for the combination of S +A and to investigate if there were pharmacokinetic (PK) interactions between S + A in patients (pts) with advanced malignancies. Methods: Cohorts of 3–6 pts were enrolled and treated. Escalating oral doses of S (40–60- 80mg) were administered on days 1–5 in combination with intravenous fixed dose of A (100 mg/m2) on 1, 8, and 15 of a 28 day cycle. Prior to cycle 1 all patients received A day -14. Blood samples for PK studies were drawn with the day -14 and Day 1 treatments. Results: To date 15 pts (2 renal, 3 prostate, 2 bladder, 1 hypopharyngeal, 1 mesothelioma, 1 colorectal, 1 melanoma and 2 leiomyosarcomas) with a median age 51 (range 37 - 78 yrs) have been treated in 3 cohorts. Doses were escalated as follows; Cohort 1 (40 (S)/100(A), n = 4), Cohort 2 (60/100, n = 7), Cohort 3 (80/100, n = 3). 1 patient (testicular cancer) intended for cohort 1 was a screen failure. Two patients in cohort 3 had grade 3\/4 neutropenia (DLT). An additional 4 patients were treated in cohort 2 without DLT and this dose level was determined to be the MTD. Most common severe adverse events were Grade 3 anemia (5%), neutropenia (22%), fatigue (5%) and dehydration (5%). 3 patients had grade 4 neutropenia, 2 in cycle 1 of cohort 3 and 1 in cycle 2 of cohort 2. To date 6 patients had progressive disease, 4 had stable disease (3.8 months), 3 patients (2 with prostate cancer and 1 with hypopharyngeal cancer) had a partial response. Conclusions: The combination of A plus S was well tolerated and the recommended dose for phase 2 studies is paclitaxel 100 mg/m2 weekly for 3 weeks plus satraplatin 60 mg/m2 daily for 5 days every 28 days. PK analyses will be presented. [Table: see text]