Craig Fancourt

Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors.

Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML)

OBJECTIVE Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML. METHODS MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID). RESULTS 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7μM·h,Cmax 1.5μM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L. CONCLUSIONS The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.

Segmentation of arterial vessel wall motion to sub-pixel resolution using M-mode ultrasound

We describe a method for segmenting arterial vessel wall motion to sub-pixel resolution, using the returns from M-mode ultrasound. The technique involves measuring the spatial offset between all pairs of scans from their cross-correlation, converting the spatial offsets to relative wall motion through a global optimization, and finally translating from relative to absolute wall motion by interpolation over the M-mode image. The resulting detailed wall distension waveform has the potential to enhance existing vascular biomarkers, such as strain and compliance, as well as enable new ones.

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

The goal of this investigation was to examine clinical translation of glucose responsiveness of MK‐2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK‐2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK‐2640 was ~25‐fold reduced relative to regular human insulin. In a randomized, 2‐period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose‐responsiveness of i.v. administered MK‐2640, we were unable to demonstrate a glucose‐dependent change in MK‐2640 clearance, although a significant glucose‐dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose‐responsive insulin analog.

High-Resolution Arterial Pressure-Area Loops in Rats

The artery wall is compliant and stretches in response to the traveling pressure pulse generated by the contracting heart. The dynamics of this motion are known to convey important information about the health of the artery and cardio-vascular system. For example, compliance, a measure of artery flexibility, decreases due to aging, as well as disease states such as hypertension and atherosclerosis. It also exhibits acute and chronic changes under pharmacological interventions.Copyright

Registration and Matching of Perspective Surface Normal Maps

We present a method for the registration and matching of perspective surface normal maps. Registration of two maps consists of optimally aligning their normals through a 2-D warping in the image plane in conjunction with a 3-D rotation of the normals. Once aligned, the average dot-product then serves as a match metric for automatic target recognition (ATR). We conduct an ATR experiment using synthesized views of 25 commercial vehicles, and obtain perfect recognition results when the test azimuth is within [-6deg,+10deg] of the reference pose, even when the normals are corrupted by up to 20deg uniform random noise. The results suggest that needle maps are a rich yet compact representation of an object, which may be useful for exploiting information from stereo images, shape from shading algorithms, or sensors which obtain the normals from polarization information.