Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors

• Published in: Journal of clinical oncology Vol. 30; no. 19; pp. 2307 - 2313
• Main Authors: Krop, Ian, Demuth, Tim, Guthrie, Tina, Wen, Patrick Y., Mason, Warren P., Chinnaiyan, Prakash, Butowski, Nicholas, Groves, Morris D., Kesari, Santosh, Freedman, Steven J., Blackman, Samuel, Watters, James, Loboda, Andrey, Podtelezhnikov, Alexei, Lunceford, Jared, Chen, Cong, Giannotti, Maxine, Hing, Jeremy, Beckman, Robert, LoRusso, Patricia
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01.07.2012
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Benzene Derivatives; Biological and medical sciences; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Propionates - adverse effects; Propionates - pharmacokinetics; Propionates - pharmacology; Sulfones - adverse effects; Sulfones - pharmacokinetics; Sulfones - pharmacology; Treatment Outcome; Tumors; Human; Solid tumor; Pharmacodynamics; Notch receptor; Cancerology; Treatment; Phase I trial; Adult; Advanced stage; Inhibitor; Malignant tumor; Cancer
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.2011.39.1540

Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752. MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition. Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas. MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.