A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias

Abstract

6585 Background: Functional screening of T-ALL cell lines for sensitivity to NOTCH inhibitors has led to the discovery of frequent NOTCH1 gain-of-function mutations in the majority of human T-ALL. Gamma secretase catalyzes the cleavage of the Notch receptor within the transmembrane domain thereby releasing the Notch intracellular domain, which translocates to the nucleus to activate transcription of target genes. Gamma secretase inhibitors can induce G0/G1 arrest, decrease cell viability, and cause apoptosis of T-ALL cell lines carrying Notch activating mutations. MK-0752 is a potent gamma secretase inhibitor in clinical development (IC50 ∼50 nM). Methods: Patients with relapsed T-ALL and other leukemias were enrolled using an accelerated dose escalation scheme with 1 patient/dose level until ≥ grade 2 toxicity, followed by 3–6 patients/level. MK-0752 was administered by once-daily oral dosing in 28 day cycles. DLT was grade 3 or 4 non-hematologic toxicity during cycle 1. Plasma pharmacokinetic (PK) profiles and Abeta40 peptide levels were measured. Results: Six adult and two pediatric patients with leukemia (seven with T-ALL and one with AML) received MK-0752 dosed at 150, 225, and 300 mg/m2. Treatment duration ranged from 2 days to 56 days before patients discontinued for disease progression or drug-related toxicity. Dose-limiting toxicity (DLT) was Grade 3/4 diarrhea at 300 mg/m2. Four of the seven T-ALL patients had Notch activating mutations. One patient with T-ALL and a Notch activating mutation treated with 150 mg/m2 (300 mg) daily achieved a 45% reduction in a mediastinal mass at the end of 28 days as best response, but subsequently progressed by 56 days. Mean PK parameters at 150, 225, and 300 mg/m2 on Day 1 were AUC0–24hr = 723, 754, 1592 μM·hr, Cmax = 55, 40, 121 μM, C24hr = 18, 28, 59 μM, and tmax = 1, 8, 9 hr. Measurements of gamma secretase inhibition showed a 24–69% decrease in plasma Abeta40 peptide levels on Day 14 compared to predose. Conclusions: MK-0752 was well-tolerated in a limited number of patients below 300 mg/m2, and further enrollment is underway to establish the MTD. Plasma concentrations of MK-0752 at all doses were sufficient to inhibit gamma secretase. Leukemia samples will be assessed for Notch inhibition. [Table: see text]

Initial testing (stage 1) of the notch inhibitor PF‐03084014, by the pediatric preclinical testing program

“…Results for PF-03084014 show similarities to those reported for RO4929097 [22]. For the T-cell ALL xenografts, the PPTP results for PF-03084014 with no induction of remission were consistent with those for RO4929097, as well as with clinical results for the GSI MK-0752 [23].…”

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

“…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. [12][13][14] It has been recently shown that GSI I (Z-Leu-Leu-Nle-CHO), a tripeptide aldehyde inhibiting chymotryptic and aspartyl protease activity, chemically similar to the proteasome inhibitor MG132 (Z-Leu-Leu-Leu-CHO), 15 induces apoptosis in breast 16,17 and glioblastoma tumor cells, 18 and in precursor-B acute lymphoblastic leukemia (ALL) cells 19 by inhibiting both c-secretase and proteasome activity or only proteasome activity.…”

Molecular‐genetic insights in paediatric T‐cell acute lymphoblastic leukaemia

“…GSIs induce growth arrest in some T-ALL cell lines and cause prolonged cell cycle arrest and apoptosis in primary T-ALL cells (Weng et al, 2004;Lewis et al, 2007). Unfortunately, a clinical trial using GSI-based therapies in T-ALL has thus far been unsuccessful due to limited toxicity on leukaemic blasts in vivo and the emergence of serious side effects, such as severe gastrointestinal toxicity (Milano et al, 2004;van Es et al, 2005;DeAngelo, 2006).…”