Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study

Abstract

Purpose: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan.

Patients and methods: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model.

Results: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day).

Conclusions: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).

Figure 1.

Time on treatment and overall response. Five partial responses and one complete response were confirmed in the study treatment period; duration of 42 days was required for overall response of stable disease. ^aPatient received radiotherapy in the follow-up period after treatment discontinuation (days 136 to 175). ^bPatient received radiotherapy on study days 526 to 537. ^cPatient received radiotherapy after recording of first partial response. ^dPatient received radiotherapy in the follow-up period after treatment discontinuation. ^ePatient continued treatment with regorafenib plus VI off study. REG, regorafenib; VI, vincristine and irinotecan.

Figure 2.

Best overall response depicted by the percentage of change in target lesion size relative to baseline and by dose level in 18 patients with measurable disease. Of the 21 patients treated, one patient was not evaluated for radiologic response due to early clinical progression, one patient had non-measurable but evaluable disease, and one patient had a different imaging modality post-baseline for determining progression. Conc, concomitant; E, Ewing sarcoma; N, neuroblastoma; R, rhabdomyosarcoma; Seq, sequential; VI, vincristine and irinotecan; W, Wilms tumor.

Figure 3.

BSA-normalized exposure AUC (left) and clearance of regorafenib (right) and pharmacokinetics parameters of regorafenib administered with VI (bottom right table). The closed green circles denote concomitant dosing—lower BSA-normalized clearance in one of the two patients in the concomitant dosing cohort is not likely to be due to a drug–drug interaction, as irinotecan, SN-38, and vincristine do not inhibit CYP3A4. Boxplots show the median (solid line at center of box) and its approximate 95% confidence interval (gray area), the interquartile range (box), 1.5× interquartile range (whiskers), and outliers (closed circles). *An additional two patients received concomitant regorafenib 72 mg/m² (AUC_(0–24)md range, 62.8–114.0 mg•h/L and t½_eff,md range, 50.3–64.3 hours). Box plots for different doses of regorafenib monotherapy (blue boxes) are shown for comparison. AUC_(0–24)md, area under the plasma concentration–time curve over a dosing interval of 24 hours after multiple dosing; BSA, body surface area; CV, coefficient of variation; t½_eff,md, effective half-life after multiple dosing; VI, vincristine and irinotecan.