A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Background Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose‐limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods Eribulin was administered intravenously on days 1 and 8 in 21‐day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2/dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results Twenty‐three patients, ages 3–17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2/dose, respectively. One subject at the 1.4 mg/m2/dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2/dose, 2/5 subjects experienced dose‐limiting (grade 4) neutropenia. Grade 3/4 non‐DLTs included lymphopenia and hypokalemia, while low‐grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half‐life was 39.6 (range 24.2–96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2/dose on days 1 and 8 of a 21‐day cycle.