MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.
A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade
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]
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