Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma
This is a phase 1/2 study of sonidegib, an inhibitor of upstream components of the sonic hedgehog pathway (Hh, PATCH and Smoothened-driven tumors) in patients with relapsed disease (MB and other solid tumors). For the phase 2 component, this agent was tested in children/adults with relapsed MB.
Phase 1: Children with histologically confirmed recurrent MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, or high grade glioma were eligible. Sonidegib was given once daily orally. Recommended phase 2 dose (RP2D) was the highest tolerated dose with at least 6 patients evaluated.
Phase 2: Children and adults with recurrent MB were included for study at the RP2D. Tumor response was assessed every 8 weeks.
Sixty pediatric patients were enrolled (59 on phase 1, 1 on phase 2). Thirty-nine of these patients had MB. For phase 2, 16 adults were enrolled. RP2D was found to be 680 mg/m2/dose. Median treatment exposure was 55 days for pediatric patients and 97 days for adults. Grade 3/4 CPK elevation occurred in 2 pediatric patients and 5 adults, with no evidence of renal dysfunction in the pediatric patients. Three children showed evidence of growth plate closure while on study.
Response was seen in 2/60 pediatrics patients and 3/16 adult patients (2 CRs and 1 PR), all of whom had MB. All 5 responses were within the SHH group. Both pediatric patients with CR stopped treatment after 9 months. Duration of response was 21 months in one of these patients, and the other remains in remission at 49 months. For the adult responders, duration was 1.6 and 8.7 months for the patients in CR and 4.8 for the patient in PR. Stable disease was seen in 11 patients (5 pediatric, 6 adult, all with MB). All other patients had progressive disease.
Not all tissue was evaluated for SHH activation. The tissue that was evaluated could not differentiate between upstream vs downstream activation of the SHH pathway (sonidegib inhibits in the upstream portion of the pathway). The study did not require tissue from the time of recurrence to assess for additional alterations, so archival tissue may not represent changes as a result of radiation or chemotherapy. It is unclear why some patients had stable disease in the absence of SHH pathway activation.
Sonidegib has activity as a targeted agent for some patients with recurrent SHH MB in this phase 1/2 trial. Toxicities observed include CPK elevation without organ impairment and concern for premature growth plate closure in pediatric patients.