Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors.

Abstract

PURPOSE:

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.

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Ian Krop, Tim Demuth, Tina Guthrie, Patrick Y Wen, Warren P Mason, Prakash Chinnaiyan, Nicholas Butowski, Morris D Groves, Santosh Kesari, Steven J Freedman, Samuel Blackman, James Watters, Andrey Loboda, Alexei Podtelezhnikov, Jared Lunceford, Cong Chen, Maxine Giannotti, Jeremy Hing, Robert Beckman, Patricia Lorusso
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 19 Pg. 2307-13 (Jul 01 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22547604 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
• Benzene Derivatives
• Propionates
• Sulfones
• Amyloid Precursor Protein Secretases

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Benzene Derivatives
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism, pathology)
• Propionates (adverse effects, pharmacokinetics, pharmacology)
• Sulfones (adverse effects, pharmacokinetics, pharmacology)
• Treatment Outcome