Pediatric Cancer Models Research Articles

A pediatric phase I trial and pharmacokinetic study of MLN8237, an oral selective small molecule inhibitor of aurora a kinase: A Children's Oncology Group Phase I Consortium study.

9529 Background: MLN8237, a selective small molecule inhibitor of Aurora A Kinase, has activity in a broad range of in vitro and in vivo preclinical models of pediatric cancer. We performed a phase I trial to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MLN8237 in children with refractory solid tumors. Methods: MLN8237 was administered orally either once daily (part A1) or divided twice daily (part A2) for 7 days, every 21 days. Using the rolling-six design, four dose levels (45, 60, 80, 100 mg/m2/d) were evaluated on the once daily regimen, and subsequently two dose levels (60 and 80 mg/m2/d) on the twice-daily regimen. Pharmacokinetic studies were performed with the initial dose, with trough drug concentrations also being obtained at steady-state. Results: 37 patients were enrolled, 32 were fully evaluable for toxicity [median (range) age 12.5 yrs (4.8 - 21.6)]: 21 on part A1 and 11 on part A2. In part A1, 1/6 pts developed DLT (grade 3 mucositis) at 45 mg/m2 and 1/6 developed DLT (grade 4 mood alteration) at 80 mg/m2. At 100 mg/m2, 3/4 patients developed DLT (neutropenia –thrombocytopenia), thus exceeding the MTD. In part A2, 2/6 patients developed dose limiting myelosuppression at 80 mg/m2; one of whom also experienced grade 3 mucositis. 1/5 patient experienced DLT (grade 3 alkaline phosphatase) at 60 mg/m2. Of note, 5/11 patients experienced hand-foot-skin syndrome (grade 1 - 3) on the bid schedule versus 1/21 (grade 2) on qd schedule. A high degree of inter- patient variability in systemic exposure was observed. Average trough concentrations exceeded 1 μ M, the efficacious concentration in preclinical studies. The mean (±SD) steady state MLN8237 trough concentrations at the 45, 60, 80 and 100 mg/m2/d dose levels were 5.1 ± 5.7, 4.9 ± 6.3, 3.7 ± 3.8, and 5.5 ± 4.9 μ M, respectively. Conclusions: Although the divided dose regimen appears to be well tolerated in adults, children experienced more myelosuppression and hand-foot-skin syndrome with divided versus once daily dosing. Therefore the recommended pediatric phase 2 dose and schedule of MLN8237 is 80 mg/m2/d administered once daily for 7 days. No significant financial relationships to disclose.

In vivo Evaluation of Ixabepilone (BMS247550), A Novel Epothilone B Derivative, against Pediatric Cancer Models

Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types. The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models. Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four), Wilms' tumors (six), osteosarcoma (four), or brain tumors (seven). Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg). At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved > or = 50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms' tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (> or = 50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. Pharmacokinetics following single i.v. administration of ixabepilone at its MTD (10 mg/kg) were biexponential with C(max) of 12.5 micromol/L, elimination half-life of 19.2 hours, and total area under the curve of 5.8 micromol/L-h. The achieved drug exposure of ixabepilone at this efficacious MTD dose level in mice is similar to those achieved in patients given the recommended phase II dose of 40 mg/m2 by either 1- or 3-hour infusion every 3 weeks, a regimen that has shown significant anticancer activity in phase II clinical trials in adult patients. Administered at doses ranging from 66% to 100% of its MTD in mice, the epothilone B derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models. Pharmacokinetic analysis indicates that the systemic ixabepilone exposure achieved in mice at its MTD is similar to that achieved in patients at the recommended phase II dose of 40 mg/m2 administered every 3 weeks. Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this epothilone derivative compared with paclitaxel.

Phase I trial of the epothilone B analog BMS-247550 (ixabepilone) in children with refractory solid tumors

8529 Background: The epothilone B analog ixabepilone is a novel non-taxane microtubule stabilizing agent with in vitro and in vivo activity in adult and pediatric cancer models that are naturally insensitive to paclitaxel or have developed resistance to paclitaxel. In adults, the maximum tolerated dose (MTD) on a daily x 5 days (d) q 21d schedule was 6 mg/m2/d IV over 1 hour. Dose limiting toxicity (DLT) was neutropenia. Methods: Children (median age, 9.5yr; range, 2–18yr), with refractory solid tumors (osteosarcoma n=2, rhabdomyosarcoma n=2, Wilms tumor n=2, hepatoblastoma n=2, other sarcoma n=5, other n=3) were entered on this phase I trial to determine the toxicity profile, DLTs, MTD, and pharmacokinetics (PK) of ixabepilone on the daily x 5 d q 21d schedule. The starting dose level was 3 mg/m2/d (n=3), with escalations to 4.5 (n=4), 6 (n=3), 8 (n=3), and 10 (n=3) mg/m2/d. PK sampling was performed after the first dose, and plasma concentrations were assayed with LC/MS/MS. Dose levels and PK sampling times were identical to the adult daily x 5 d phase I trial. Results: No DLTs (grade ≥3 non-hematologic toxicity, or grade 4 neutropenia for ≥5 days, or grade 4 thrombocytopenia on ≥2 days) were observed at dose levels 1–4 during the first treatment cycle. At dose level 5 (10 mg/m2/d) the MTD was exceeded with dose-limiting neutropenia (n=1) and fatigue (n=1) in 2 patients. The 8 mg/m2 dose level is being expanded to 6 patients. Grade ≥2 non-DLTs during cycle #1 included gr. 3–4 neutropenia (n=7), gr. 2–3 anemia (n=8), gr. 2 fatigue (n=2), and gr. 2 constipation (n=2). Sensory neuropathy (n=4) and thrombocytopenia (n=4) did not exceed gr.1. Five patients had stable disease for 2–13 cycles (median, 5). The mean terminal half-life of ixabepilone (14.8±6h), the volume of distribution at steady state (352 L/m2), and the clearance (489 ml/min/m2) (n=9), were similar to adult values. Conclusions: Ixabepilone is well tolerated in children on the daily x5d schedule at doses exceeding the adult MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb