PHASE 0 TRIAL OF CERITINIB IN BRAIN METASTASES AND RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical reports suggest ceritinib activity in central nervous system (CNS) malignancies, yet there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in brain metastases and recurrent glioblastoma patients. METHODS Ten patients with brain metastases (n=3) or glioblastoma (n=7) exhibiting high expression of pSTAT5b/pFAK/pIGFR1 were treated with 10 days of oral ceritinib (750 mg daily) prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. RESULTS Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one brain metastasis patient, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor and CSF concentration as compared to all other patients. In all patients, no pharmacodynamic response was detected in sampled tumor tissue. CONCLUSION Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations in brain metastasis and glioblastoma appear insufficient for target modulation. Despite recent reports of clinical response, our findings suggest no role for ceritinib in treating glioblastoma and an unfavorable profile for brain metastases.