Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study

Abstract

Purpose Amplification and high-levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. Methods MK-0752 was administered once weekly at 1,000 mg/m2 and 1,400 mg/m2 using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. Results Ten eligible patients were enrolled (median age 8.8 years; range 3.1–19.2) with diagnoses of brain stem glioma (n=3), ependymoma (n=2), anaplastic astrocytoma (n=1), choroid plexus carcinoma (n=2), medulloblastoma (n=1), and primitive neuroectodermal tumor (n=1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the 6 evaluable patients enrolled at 1,000 mg/m2/dose. No DLTs were experienced by 3 patients treated at 1,400 mg/m2/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1–10). Two patients continued on therapy for at least 6 months. The median (range) Cmax of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1,000 mg/m2/week and 1,400 mg/m2/week, respectively. NOTCH expression was decreased in 6 of 7 patients for whom tissue was available at 24 hours post-MK-0752. Conclusion MK-0752 is well-tolerated and exhibits target inhibition at 1,000 mg/m2/week and 1,400 mg/m2/week in children with recurrent CNS malignancies.

Targeting cancer stem cell pathways for cancer therapy

“…576 MK-0752 is well tolerated and shows targeted inhibition in recurrent pediatric central nervous system tumors. 577 In addition, combining MK-0752 with cisplatin treatment for ovarian cancer, 578,579 docetaxel treatment for locally advanced or metastatic breast cancer, 569 and gemcitabine treatment for ductal adenocarcinoma of the pancreas 580 has shown good efficacy. However, the clinical effect was minimal in patients with advanced solid tumors, 576,581 including metastatic pancreatic cancer.…”

Therapeutic implications of cancer epithelial-mesenchymal transition (EMT)

“…A c-secretase inhibitor, RO4929097 (RG-4733), went through clinical trial phase II for metastatic pancreatic adenocarcinoma (De Jesus-Acosta et al 2014), metastatic melanoma (Lee et al 2015), recurrent ovarian cancer (Diaz-Padilla et al 2015), and metastatic colorectal cancer (Strosberg et al 2012) with minimal efficiency as a single agent. Another c-secretase inhibitor, MK-0752, was in phase I for advance solid tumors with clinical benefits and tolerability (Krop et al 2012;Hoffman et al 2015).…”

Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases

“…GSIs were tested either as single agents or in combination with standard cancer chemotherapy regimen. From these early clinical studies, tolerability and toxicity have been acceptable, in both single or combined therapies, 151,152 with side-effects (mainly gastrointestinal disorders) comparable, but not worse, than standard chemotherapeutics. The main side-effects encountered were gastrointestinal disorders.…”