Determining the recommended phase 2 dose (RP2D) of dose-intense irinotecan combined with IVA chemotherapy (I _R IVA) in newly diagnosed very high risk rhabdomyosarcoma: A phase Ib study within the EpSSG Frontline and Relapsed Rhabdomyosarcoma study (FaR-RMS).

Abstract

10024 Background: Event-free survival for patients in the highest risk groups of rhabdomyosarcoma (RMS) remains poor. The COG ARST0431 study showed that dose-intensified chemotherapy benefits a subset of metastatic RMS patients. This phase Ib trial defined the safety profile, highest tested dose (HTD), and recommended phase 2 dose for dose intense irinotecan on days 8-12 combined with the standard European 3-weekly Ifosfamide, Vincristine, Actinomycin D (IVA) regimen within the European paediatric Soft tissue sarcoma Study Group (E p SSG) Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) study (ClinicalTrials.gov: NCT04625907). Methods: Patients aged >1 to ≤25 years with Very High Risk (VHR) RMS (FOXO1 fusion-positive, node-positive, Subgroup G and metastatic, Subgroup H) were included in designated Phase I centres. Participants received IVA (Ifosfamide 3000 mg/m² on days 1–2; vincristine 1.5 mg/m2 on days 1 and 8 and on day 15 in cycle 1 and 2 only; actinomycin D 1.5 mg/m2 on day 1 with irinotecan on days 8–12. The irinotecan starting dose was 20 mg/m²/day, with dose escalation/de-escalation to a maximum of 50mg/m2/day utilising a rolling six design. The Dose Limiting Toxicity (DLT) period was defined as up to 28 days after the start of cycle 2. All Adverse events (AEs) were assessed against the DLT definition during this time. DLTs included Grade 3 diarrhoea, enterocolitis, ileus or oral mucositis persisting > 3 days; Grade 4 diarrhoea; neutropenia or thrombocytopenia delaying treatment > 7 days; Grade 3/4 toxicities resulting in treatment discontinuation, or any Grade 5 toxicity (death) related to trial treatment. First radiological response assessment was after cycle 3 I R IVA. Results: A total of 22 patients (Subgroup G, 3; Subgroup H, 19) were enrolled across 4 dose levels (20 mg/m2/day (n = 5); 30 mg/m2/day (n = 5); 40 mg/m2/day (n = 6); 50 mg/m2/day (n = 6)). Median age was 13.4 years; interquartile range, 5.2-16.3 years. All patients were evaluable for DLTs. One DLT of Grade 3 enterocolitis was observed at dose level 50 mg/m². The HTD and RP2D of irinotecan in combination with IVA were established as 50 mg/m²/day. The most common Grade 3/4 AEs occurring in > 30% of patients, during the first 3 treatment cycles were: febrile neutropenia 13 (59.1%), neutropenia 13 (59.1%); leukopenia 12 (54.5%); anaemia 10 (45.5%), and lymphopenia 7 (31.8%). The overall Response Rate (Complete or Partial Response) at first assessment was 81.8% (18/22). Conclusions: The RP2D for irinotecan on days 8-12 within I R IVA was identified as 50 mg/m²/day. The intensified I R IVA regimen is under evaluation in randomised questions, in adults and children with paediatric-type RMS, within the FaR-RMS trial in High Risk patients (IVA vs I R IVA) and VHR patients (IVA plus doxorubicin vs I R IVA). Clinical trial information: NCT04625907 .