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Abstract BACKGROUND Recurrent fusions in neurotrophic tropomyosin-receptor kinase genes NTRK 1-3 are found in variety of cancers, including pediatric HGG: DIPG (~4%) and non-brainstem HGG (~10%). For non-brainstem HGG seen in children 3 years of age, approximately 40% harbor NTRK alterations. NTRK fusions provide a promising target for gliomas and to that end, Larotrectinib, a globally approved, highly potent, small molecule inhibitor of TRKA/B/C, has previously been investigated and has shown tolerability and efficacy in children with recurrent solid tumors. Compassionate use in a case of infantile GBM showed proof-of-concept with blood-brain penetrance and efficacy. Further evidence of efficacy in two earlier clinical trials has also been previously demonstrated in children with recurrent TRK-fusion primary intracranial tumors (NCT02637687, NCT02576431). METHODS This international trial conducted through the CONNECT consortium, supported in part by Bayer, investigates larotrectinib monotherapy; its feasibility and tolerability in combination with standard systemic chemotherapy (Baby POG or HIT-SKK) or radiation therapy whereby treatment plan determination is response-based. Objectives include: to assess disease control rate (CR, CCR, PR and SD) after two cycles of larotrectinib monotherapy (28-day cycles); to assess feasibility and to describe toxicities of larotrectinib in combination with standard chemotherapy; to assess objective response rate (CR and PR); to assess OS and PFS as compared to historical data from Baby POG, HIT-SKK and radiotherapy. A phase 0 surgical cohort will be explored whereby patients who are planned to undergo a definitive resection will receive pre-surgery larotrectinib, and target inhibition, intratumoral and plasma pharmacokinetics will be investigated. Radiographic responses will also be quantitated. This trial is currently open to accrual at ten CONNECT sites across North America and Australia and has enrolled five patients to date. Sites in UK, Germany and Netherlands are pending activation. A total of 15 patients are anticipated to be enrolled and evaluable.
Chi et al. (Tue,) studied this question.