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Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m), cisplatin (75 mg/m), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement.

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. ResultsForty-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 mM, 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 (R 2 = 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. ConclusionAt 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.

Context: Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH. Design: Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 g recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16.LBMandappendicularskeletalmusclemass(ASM)weremeasuredbydual-energyx-rayabsorptiometry. Results: One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 2.14 vs. 4.51 1.05, P 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r 0.26, P 0.007; r 0.53, P 0.001) and ASM (r 0.17, P 0.07; r 0.40, P 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r 0.20, P 0.056 and r 0.36, P 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models. Conclusion: Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomar-ker of anabolic response to GH and testosterone. (J Clin Endocrinol Metab 94: 4224-4233, 2009) T he past decade has witnessed substantial pharmaceutical and academic investment in the development of function promoting anabolic therapies that improve physical function and health-related outcomes (1). The leading function promoting anabolic molecules that are under development , androgens, myostatin inhibitors, and GH, are potential promyogenic agents that are expected to improve physical function primarily by increasing skeletal muscle mass. Considering the enormous resources required for conducting large efficacy trials, serum biomar

In screening for drug discovery, chemists often select a large subset of molecules from a very large database (e.g., select 1,000 molecules from 100,000). To generate diverse leads for drug optimization, highly active compounds in several structurally different chemical classes are sought. Molecules can be characterized by numerical descriptors, and the chosen subset should cover the descriptor space or subspaces formed by several descriptors. We propose a method that concentrates on low-dimensional subspaces, a criterion for uniformity of coverage, and a fast exchange algorithm to optimize the criterion. These methods are illustrated by using a National Cancer Institute database.