Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors

Abstract

10574 Introduction: Activation of Notch signaling occurs in ∼40% of human BCs and high Notch expression is associated with poor outcome. Inhibition of Notch inhibits BC cell proliferation in vitro. Notch signaling requires gamma secretase (GS), which cleaves Notch, releasing the Notch intracellular domain (NICD) to activate transcription of target genes. MK-0752 is a potent GS inhibitor. Methods: In Part 1 of the study, pts with advanced solid tumors were enrolled using an accelerated dose escalation with 1 pt/dose level until the occurrence of ≥Grade 2 toxicity, then 3–6 pts/dose level. MK-0752 was administered by once-daily oral dosing in 28-day cycles. Once a maximum tolerated dose (MTD) was established, an additional 22 pts with advanced BC were to be enrolled in Part 2. Six-point PK plasma profiles were collected over 24 hours on Days 1 and 28 and assayed by LC/MS/MS. PD measurement of plasma Abeta40 peptide (another gamma secretase substrate) was performed pre/post dose on Days 1 and 28. Tumor biopsies on Days 1 and 28 were obtained from a subset of pts to assess changes in Notch activity by immunohistochemical analysis of NICD. Results: In Part 1, two pts were enrolled at 450mg daily, and five pts at 600mg daily. Dose-limiting toxicities (DLTs) were Grade 3 diarrhea, constipation, nausea, and abdominal cramping at 600 mg. In Part 2, an additional 14 pts with BC were enrolled at 450mg daily. In this cohort, Grade 2/3 fatigue requiring dose reduction occurred in 6 pts. Grade 3 diarrhea (1pt), nausea (1 pt) and elevated liver transaminases (2 pt) were also observed. Mean PK parameters (at 450mg, 600 mg) on Day 1 were AUC0–24hr = 1036, 1065μM·hr, Cmax = 72, 61μM, C24hr = 25, 32μM, and tmax = 3, 7 hr. PD measurements of GS inhibition showed a 12–78% (mean 46%) decrease in plasma Abeta40 at 4 hours on Day 1 compared to predose. Conclusion: Continuous dosing of MK-0752 at 450mg daily in pts with BC was associated with significant toxicity, predominantly fatigue, and cannot be considered a MTD. An intermittent dosing schedule is being explored. MK-0752 at all doses inhibited GS, as demonstrated by decreases in plasma Abeta40. Analysis of efficacy and intratumoral Notch inhibition will be reported at the meeting. [Table: see text]

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

“…Based on our recent findings that ex vivo CLL cells have a functional ER stress-triggered caspase cascade initiated by caspase-4 and involving caspase-8 and -3, 24 we first investigated whether GSI I potentiates the activation of these caspases (patients [1][2][3][4][5][6][7][8][9][10][11][12]. Time-course analysis shows that the cleavage of caspase-4 into its active 20-kDa subunit was increased by GSI I, compared with controls, already after 1 hr and continued to be increased until 24 hr ( Fig.…”

“…6 A dysregulated Notch signaling has been associated with the pathogenesis of several malignancies, 7 and GSIs have been shown to inhibit the growth and/ or survival of several tumor cells, 8 including CLL cells. 9 Some GSIs have also been tested in phase I trials for patients with breast cancer 10 and T-cell acute leukemias. 11 However, in these malignancies, minimal clinical responses have been observed, and other studies have also suggested that Notch inhibition is therapeutically effective only when combined with inhibition of other relevant pathogenic pathways.…”

Notch and breast cancer metastasis: Current knowledge, new sights and targeted therapy (Review)

“…Although numerous drugs are in development, significant challenges still exist before a Notch-targeted therapeutic strategy can be clinically applied. For example, patients with BC receiving continuous doses of MK-0752 at 450 mg/daily present with symptoms of toxicity and fatigue (160). Furthermore, gastrointestinal toxicity is also a major side effect in patients treated with GSIs (161).…”

Notch and Breast Cancer Metastasis

“…Though many drugs are in development, enormous challenges remain before a Notchtargeted therapeutic strategy can be clinically applied. BC patients receiving continuous doses of MK-0752 at 450 mg daily present significant symptoms of toxicity and fatigue [95]. Further, gastrointestinal toxicity is also a major side effect in patients being treated with GSIs [96].…”