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Background Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. Methods This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. Results Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7–38.6%). Median duration of response was 14.9 months (95% CI, 8.7–26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6–55.8%). Conclusions Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. ClinicalTrials.gov Identifier NCT02361723.

This report summarizes a totality-of-evidence approach supporting recommendation of a 320-mg total daily dose, either as 160-mg twice daily (BID) or 320-mg once daily (QD) for zanubrutinib in patients with mantle cell lymphoma. Data were derived from a phase 2 study in patients receiving 160-mg BID and a phase 1/2 study with similar response rates observed with 160-mg BID or 320-mg QD. Given the limited number of patients in the QD dose group, population pharmacokinetics and exposure-response analyses were employed to bridge the two regimens. The analyses showed that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the two regimens are unlikely to have a meaningful impact on efficacy and safety endpoints. The totality of data, including pharmacokinetic, pharmacodynamic, safety, efficacy, and exposure-response analyses, provided support for the recommended 320-mg total daily dose for the approved indication.

Pamiparib, a selective poly (ADP‐ribose) polymerase 1/2 inhibitor, demonstrated tolerability and antitumor activity in patients with solid tumors at 60 mg orally twice daily. This phase 1 open‐label study (NCT03991494; BGB‐290‐106) investigated the absorption, metabolism, and excretion (AME) of 60 mg [14C]‐pamiparib in 4 patients with solid tumors. The mass balance in excreta, blood, and plasma radioactivity and plasma pamiparib concentration were determined along with metabolite profiles in plasma, urine, and feces. Unchanged pamiparib accounted for the most plasma radioactivity (67.2% ± 10.2%). Pamiparib was rapidly absorbed with a median time to maximum plasma concentration (Cmax) of 2.00 hours (range, 1.00‐3.05 hours). After reaching Cmax, pamiparib declined in a biphasic manner, with a geometric mean terminal half‐life (t1/2) of 28.7 hours. Mean cumulative [14C]‐pamiparib excretion was 84.7% ± 3.5%. Pamiparib was mainly cleared through metabolism, primarily via N‐oxidation and oxidation of the pyrrolidine ring. A dehydrogenated oxidative product (M3) was the most abundant metabolite in biosamples. A mean of 2.11% and 1.11% of [14C]‐pamiparib was excreted as unchanged pamiparib in feces and urine, respectively, indicating near‐complete absorption and low renal clearance of parent drug. Cytochrome P450 (CYP) phenotyping demonstrated CYP2C8 and CYP3A involvement in pamiparib metabolism. These findings provide an understanding of pamiparib AME mechanisms and potential drug‐drug interaction liability.

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Aim This study aims to assess the potential effects of zanubrutinib on the activity of cytochrome P450 (CYP) enzymes and drug transporter proteins using a cocktail probe approach. Methods Patients received single oral doses of probe drugs alone and after at least 8 days of treatment with zanubrutinib 160 mg twice daily in a single-sequence study in 18 healthy male volunteers. Simultaneous doses of 10 mg warfarin (CYP2C9) and 2 mg midazolam (CYP3A) were administered on Day 1 and Day 14, 0.25 mg digoxin (P-glycoprotein [P-gp]) and 10 mg rosuvastatin (breast cancer resistance protein [BCRP]) on Day 3 and Day 16, and 20 mg omeprazole (CYP2C19) on Day 5 and Day 18. Pharmacokinetic (PK) parameters were estimated from samples obtained up to 12 h post dose for zanubrutinib; 24 h for digoxin, omeprazole and midazolam; 48 h for rosuvastatin; and 144 h for warfarin. Results The ratios (%) of geometric least squares means (90% confidence intervals) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of zanubrutinib were 99.80% (97.41-102.2%) for S-warfarin; 52.52% (48.49-56.88%) for midazolam; 111.3% (103.8-119.3%) for digoxin; 89.45% (78.73-101.6%) for rosuvastatin; and 63.52% (57.40-70.30%) for omeprazole. Similar effects were observed for maximum plasma concentrations. Conclusions Zanubrutinib 320 mg total daily dose had minimal or no effect on the activity of CYP2C9, BCRP and P-gp, but decreased the systemic exposure of CYP3A and CYP2C19 substrates (mean reduction

Background Embolic stroke is a common complication of atrial myxoma, whereas multiple cerebral aneurysms associated with atrial myxoma is rare. The pathogenesis of the cerebral vascular disease related to an atrial myxoma is still not well known, and there are no guidelines to guide treatment and anesthesia management in such patients. Case presentation In this report, we present a 38-year-old woman with occasional dizziness and headache diagnosed as multiple cerebral fusiform aneurysms, in whom transthoracic echocardiography revealed a mass attached to the interatrial septum in the left atrium. Myxoma resection was performed in fast track cardiac surgery pathway without neurological complications, and no intervention was carried out on the cerebral aneurysms. She was discharged home 6 days after the procedure for followed-up. Furthermore, we reviewed and analyzed the literature in the PubMed and Google Scholar databases in order to conclude the optimal treatment in such cases. Conclusions Atrial myxoma-related cerebral aneurysms are always multiple and in a fusiform shape in most occasions. Early resection of myxoma and conservative therapy of aneurysm is an optimal treatment. TEE and PbtO2 monitoring play an essential role in anesthesia management. Fast track cardiac anesthesia is safe and effective to early evaluate neurological function. Long term follow-up for “myxomatous aneurysms” is recommended. And outcome of most patients is excellent.

PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAFV600–mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.

This thorough QT (TQT) study evaluated the effect of zanubrutinib on electrocardiogram (ECG) parameters by using concentration‐QTc (C‐QTc) analysis as the primary analysis for this study. Part A of the study determined the safety and tolerability of a single supratherapeutic dose of zanubrutinib (480 mg) in healthy volunteers. Part B was a randomized, blinded, placebo‐controlled and positive‐controlled, four‐way crossover, TQT study of single therapeutic (160 mg) and supratherapeutic (480 mg) doses of zanubrutinib, placebo, and open‐label moxifloxacin 400 mg. Thirty‐two participants received at least 1 dose of zanubrutinib, and 26 participants completed all 4 periods. Zanubrutinib did not have any effect on heart rate or cardiac conduction (pulse rate, QRS interval, or T‐wave morphology) and was generally well‐tolerated. Using C‐QTc analysis, the predicted placebo‐corrected change‐from‐baseline QT interval using Fridericia’s formula (ΔΔQTcF) was −3.4 msec (90% confidence interval: −4.9 to −1.9 msec) at peak concentrations of the 480 mg dose. A QT effect (ΔΔQTcF) exceeding 10 msec could be excluded within the observed concentration range at 160 and 480 mg doses. Assay sensitivity was established by moxifloxacin with 90% lower bound exceeding 5 msec. Implementing a C‐QTc analysis prospectively in this TQT study resulted in a substantially smaller sample size to maintain a similar study power as shown in the traditional time‐point analysis. A single 160‐mg or 480‐mg zanubrutinib dose did not prolong the QTc interval or have any other clinically relevant effects on ECG parameters.

The pharmacokinetics and safety of single-dose zanubrutinib (80 mg) were assessed in subjects with mild, moderate, and severe hepatic impairment (n = 6 each, Child–Pugh class A, B, and C) relative ...

The discovery and development of immuno-oncology (I-O) therapy in recent years represents a milestone in the treatment of cancer. However, treatment challenges persist. Robust and disease-relevant animal models are vital resources for continued preclinical research and development in order to address a range of additional immune checkpoints. Here, we describe a human peripheral blood mononuclear cell (PBMC) - based humanized xenograft model. BGB-A317 (Tislelizumab), an investigational humanized anti-PD-1 antibody in late-stage clinical development, is used as an example to discuss platform set-up, model characterization and drug efficacy evaluations. These humanized mice support the growth of most human tumors tested, thus allowing the assessment of I-O therapies in the context of both human immunity and human cancers. Once established, our model is comparatively time- and cost-effective, and usually yield highly reproducible results. We suggest that the protocol outlined in this article could serve as a general guideline for establishing mouse models reconstituted with human PBMC and tumors for I-O research.

The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX models using gastroscopic biopsies, which are best for evaluating new drugs, are unreported. In our study, a total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo and the mean latency period of xenografts was 65.86 ± 32.84 days (11–160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P = 0.000). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. In summary PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer.

Background: Programmed death receptor-1 (PD-1) is a co-inhibitory immune checkpoint molecule. The engagement of PD-1 by its ligands negatively regulates T cell function and induces immune tolerance in both normal and pathological conditions, especially in cancer. BGB-A317 is a novel humanized IgG4 anti-PD-1 antibody under clinical development. The anti-tumor activity of BGB-A317 was evaluated in mouse models and reported here. Material and methods: NOD/SCID mice transplanted with human peripheral blood monocyte (PBL-SCID models) were employed to examine the anti-tumor activity and pharmacokinetics of BGB-A317. In these models, human PBMCs (4-5×106) from healthy donors were co-injected with human tumor cells (A431, 2.5×106) or primary tumor tissue fragments derived from cancer patients (BCCO-028 and BCLU-054, 3×3×3 mm3) subcutaneously in the right flank of the mice. BCCO-028 is human colon cancer and BCLU-054 is human non-small cell lung cancer (NSCLC). The mice were then treated with BGB-A317 or PBS intra-peritoneally once a week from the day of tumor implantation. The tumor infiltrated lymphocytes and PD-L1 expression were examined by immunohistochemistry staining and flow cytometry. Results: In A431 model, 3 doses of BGB-A317, 1, 3, 10mg/kg, were examined. All three doses of BGB-A317 induced significant tumor growth inhibition (TGI) on day 29 (78%, 89%, and 89%, respectively) (p < 0.001 vs. vehicle treatment). Both AUC0-168h and Cmax of BGB-A317 after single dose (day 1, 1st dose) or at steady state (day 29, 5th dose) increased proportionally from 1 to 10 mg/kg. There was about 2-fold accumulation in drug levels (AUC0-168h and Cmax) at the steady state compared to those after single dose. Increased lymphocyte infiltration and PD-L1 expression were observed in BGB-A317 treated groups. In BCCO-028 model, BGB-A317 at 10 mg/kg QW induced significant tumor growth inhibition, with 83% TGI (p < 0.05 vs. vehicle treatment) on day 36. In BCLU-054 model, BGB-A317 at 10 mg/kg QW induced significant tumor growth inhibition, with 45% of TGI (p < 0.05 vs. vehicle treatment) on day 23. BGB-A317 treatment had no significant impact on animal body weight throughout all of the studies. Conclusions: BGB-A317 demonstrated significant anti-tumor activity in 3 human cancer xenograft PBL-SCID mouse models, including A431 human epidermoid carcinoma, BCCO-028 colon cancer, and BCLU-054 NSCLC models. Citation Format: Xiaomin Song, Zhiyu Tang, Tong Zhang, Mingming Guo, Wenfeng Gong, Yong Liu, Ningning Zhang, Yilu Zhang, Yanjuan Zhang, Jie Ma, Jing Song, Kang Li, Lai Wang. Anti-tumor activity of a novel anti-human PD-1 antibody BGB-A317 in mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5002.

Liver cancer has the third highest mortality rate among all cancers in China and hepatocellular carcinoma (HCC) is the most common type of liver cancer. The mitogen-activated protein kinase (MAPK) signaling pathway is often constitutively active in HCC. The growth of HCC requires the formation of new blood vessels. and VEGF is critical in this process. Sorafenib, a multikinase inhibitor that targets both RAF and VEGF receptor, is to date the only approved drug to treat advanced stages of HCC. Despite sorafenib extended the survival in patients with HCC, its clinical benefits remain modest and drug resistance is common. BGB283 is a second generation RAF inhibitor with unique RAF dimer and VEGFR inhibition activity. Thus, there is good rationale to test BGB-283 in HCC. In this study, we compared the in vitro and in vivo activities of BGB-283 and sorafinib in human HCC cell lines and patient derived HCC xenograft models. In the biochemical assays, BGB-283 demonstrated great potency for BRAF-V600E, BRAF-WT, CRAF(IC50 = 32, 69 and 6.5 nM, respectively) and for VEGFR family enzymes, VEGFR1, VEGFR2 and VEGFR3 (IC50 = 25, 14 and 58 nM, respectively). In the cellular assays, the anti-proliferative effect of BGB-283 and sorafinib was evaluated in several HCC cell lines. A head-to-head comparison of in vivo anti-tumor activities of BGB-283 and sorafinib were also evaluated in human primary HCC xenograft mouse models. The patient derived xenograft (PDX) HCC models were established in house using HCC patient surgical samples. Sorafinib was not active in 2 out of 7 models. Oral administration of BGB-283 resulted in significant tumor growth inhibition in all 7 models and was significantly more efficacious than sorafinib in 4 models and similar in the other 3 models. In conclusion, BGB-283 is a unique RAF dimer inhibitor with VEGFR inhibition activity. BGB-283 has also demonstrated better anti-tumor activity than sorafinib in HCC PDX models, suggesting BGB-283 could be a promising drug candidate for treating HCC patients. Citation Format: Zhiyu Tang, Yong Liu, Beibei Jiang, Yajuan Gao, Wenfeng Gong, Xing Wang, Dan Su, Fenglong Yu, Ye Liu, Min Wei, Lai Wang. BGB-283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1230.

Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in approximately 70% of human malignant melanomas and 5-15% of colorectal cancers (CRC). B-RAFV600E mutation, which gives rise to constitutive MAPK signaling, accounts for at least 90% of oncogenic B-RAF mutations. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating B-RAFV600E metastatic melanoma, their clinical efficacy in B-RAFV600E CRC is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon B-RAF inhibition contributed to the intrinsic resistance of CRC to the first generation B-RAF inhibitors. This report represents the first characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigations. BGB-283 is a potent and selective pan-RAF and EGFR inhibitor with IC50 ranging from 5 to 47 nM on RAF and EGFR kinases. In vitro, BGB-283 potently inhibits B-RAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harbouring B-RAFV600E and EGFR mutation/amplification. In B-RAFV600E CRC cell lines, BGB-283 effectively inhibits the reactivation of EGFR and achieved sustained inhibition of MAPK pathway. In vivo, BGB-283 is highly efficacious in inhibiting tumor growth accompanied by partial and complete tumor regressions in both BRAFV600E mutant cell derived CRC xenograft models, including HT29, Colo205, WiDr, as well as two primary human CRC xenograft models. In particular, BGB-283 shows compelling efficacy and potent inhibition of EGFR/MAPK signaling in WiDr xenograft model where EGFR reactivation occurs upon B-RAF inhibition. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating CRC harboring B-RAFV600E mutation. Citation Format: Zhiyu Tang, Xi Yuan, Rong Du, Shing-Hu Cheung, Guoliang Zhang, Jing Wei, Yuan Zhao, Yingcai Feng, Yi Zhang, Yunguang Du, Xiaoxia Hu, Wenfeng Gong, Yong Liu, Yajuan Gao, Rui Hao, Jiafu Ji, Lianhai Zhang, Shuangxi Li, David Sutton, Min Wei, Changyou Zhou, Lai Wang, Lusong Luo. BGB-283, a novel RAF kinase and EGFR dual inhibitor, displays potent antitumor activity in B-RAF mutated colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4692. doi:10.1158/1538-7445.AM2015-4692

Small cell lung cancer (SCLC) is one of the most aggressive forms of lung cancer with a 5-year survival rate of less than 10%. Despite the initial high response rate to the frontline platinum based chemotherapy, relapse is common and rapid. The clinical activity of PARP inhibitors has shown good correlation with platinum sensitivity in breast and ovarian cancers. Thus, there is good rationale to test PARP inhibitors in SCLC. BGB-290 is a novel PARP-1/2 inhibitor, which is currently under clinical investigation in solid tumors. In this study, we evaluated the in vitro and in vivo activities of BGB-290, and its combination activity with chemotherapies in patient biopsy derived SCLC xenograft models. In the biochemical assays, BGB-290 demonstrated great potency for PARP1/2 (IC50 = 0.83 and 0.11 nM, respectively) and high selectivity over other PARP enzymes. The DNA-trapping activity of BGB-290 was measured in a fluorescence polarization (FP) binding assay. BGB-290 showed potent DNA-trapping activity with IC50 of 13 nM. In the cellular assays, BGB-290 inhibited intracellular PAR formation with an IC50 of 0.24 nM. Tumor cell lines with homologous recombination defects were profoundly sensitive to BGB-290. Oral administration of BGB-290 resulted in time-dependent and dose-dependent inhibition of PARylation in MDA-MB-436 (BRCA1 mutant) breast cancer xenograft, correlating well with the tumor drug concentrations. Compared to olaparib, BGB-290 induced PAR inhibition was more sustained. Consistent with this finding, BGB-290 demonstrated excellent anti-tumor activity in this model, over 10-fold more potent than olaparib. In a panel of 7 SCLC cell lines tested, 3 of them were sensitive to BGB-290. SCLC primary tumor models were established in house using patient biopsy samples obtained from Beijing Cancer Hospital. The anti-tumor activities of BGB-290 as single agent or in combination with etoposide/carboplatin (E/C) were evaluated in 8 SCLC primary tumor models. BGB-290 showed weak single agent activity in these models. Six of the 8 models (75%) were sensitive to E/C treatment, consistent with the clinical response observed in these patients. Addition of BGB-290 as concomitant treatment or maintenance therapy significantly prolonged the response duration in these chemo-sensitive models. In the two chemo-insensitive models, BGB-290 and E/C combo was less effective. Addition of BGB-290 to the chemo regiment was well-tolerated throughout the study. In conclusion, BGB-290 is a potent and selective inhibitor of PARP1/2. It is highly active both in vitro and in vivo in BRCA mutant tumors. BGB-290 has also demonstrated good combination activity with chemotherapeutics in patient biopsy derived SCLC models, supporting further investigation in the clinic. Citation Format: Zhiyu Tang, Ye Liu, Qin Zhen, Bo Ren, Hexiang Wang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Yiyuan Wu, Bing Jiang, Xuebing Sun, Min Wei, Changyou Zhou, Lusong Luo, Zhengxiang Li, Jiangyong Yu, Jun Zhao, Jie Wang, Lai Wang. BGB-290: A highly potent and specific PARP1/2 inhibitor potentiates anti-tumor activity of chemotherapeutics in patient biopsy derived SCLC models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1653. doi:10.1158/1538-7445.AM2015-1653

Temozolomide (TMZ) is a DNA alkylating agent, used for treating several malignancies, including glioblastoma multiforme (GBM) and small cell lung cancer (SCLC) with brain metastasis. PARP inhibition could potentially enhance the cytotoxicity of TMZ by hindering the base excision repair (BER) pathway. BGB-290 is a potent and selective inhibitor of PARP1 and PARP2, which is currently under clinical investigation in solid tumors. BGB-290 has significant brain penetration, making it attractive for combining with TMZ in treating brain tumors or tumors with brain metastasis. In this study, we evaluated the combination effect of BGB-290 and TMZ in cellular assays and in animal models. The in vitro combination effect of BGB-290 and TMZ was evaluated in 7 SCLC and 8 GBM cell lines. BGB-290 demonstrated strong synergism with TMZ in most of those cells lines, lowering EC50 of TMZ by at least 5-fold in 4 out of 7 SCLC cell lines, and 7 out of 8 GBM cell lines. The in vivo combination activity was explored in H209 SCLC xenograft model. TMZ single agent was quite effective in this model. One cycle of treatment resulted in all animals tumor-free. However, resistance occurred quickly during the second cycle. Combination of BGB-290 and TMZ significantly delayed resistance without additional toxicity. Tumors remained sensitive to the combination treatment after multiple cycles. In order to investigate whether BGB-290 could overcome the TMZ resistance, TMZ-resistant (TR) H209 tumors were generated by treating the H209 tumors with multiple cycles of TMZ in vivo. The derived H209-TR lines remained sensitive to the combination of BGB-290 and TMZ both in vitro and in vivo, suggesting BGB-290/TMZ combo might work in the TMZ-resistant settings. Approximately 50% of SCLC patients have brain metastases at the time of postmortem examination. BGB-290 showed significant brain penetration in C57 mice. The drug exposure in brain vs. that in plasma was close to 20% after oral administration of BGB-290. Mice with established intracranial H209 xenografts were used to further investigate the combination activity of BGB-290 and TMZ on SCLC in brain. PARylation in brain/tumor tissues was well inhibited at 4 hours after single oral administration of 3 mg/kg of BGB-290. Addition of BGB-290 significantly prolonged animal survival compared to TMZ single agent in this intracranial model. In conclusion, BGB-290 demonstrated strong synergism with TMZ in cellular assays and in SCLC subcutaneous and intracranial xenograft models. When combined with TMZ, BGB-290 can overcome the induced TMZ resistance. Its favorable brain penetration ability warrants further evaluation of BGB-290 in combination with TMZ in GBMs as well as in SCLCs with brain metastasis. Citation Format: Zhiyu Tang, Bin Jiang, Zhenyan Shi, Wenfeng Gong, Yong Liu, Xing Wang, Yajuan Gao, Fenglong Yu, Changyou Zhou, Lusong Luo, Min Wei, Lai Wang. BGB-290, a novel PARP inhibitor with unique brain penetration ability, demonstrated strong synergism with temozolomide in subcutaneous and intracranial xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2015-1651

This paper proposes a framework for real-time static voltage stability analysis and monitoring of bulk power systems. This framework involves continuous power flow (CPF) studies, weak nodes and weak regions identification, critical cut-set (transmission bottlenecks) selection and visualization of voltage stability regions. It aims to monitor voltage stability of power systems by judging whether the current operation point lies inside a considered static voltage stability region (SVSR) and calculating the voltage stability margin in cut-set power space. The software package based on this framework has been being developed in recent years and has basically taken shape till now. We will introduce the main framework and the functions of this system.

The possibility of a newly synthesized l -arginine derivative, polyaspartoyl- l -arginine (PDR), as a novel anti-thrombotic agent and its mode of action were investigated. The anti-platelet effects of PDR in rats ex vivo, anti-thrombotic effects in three thrombosis models in rats and its effect on some autacoids (nitric oxide [NO], thromboxane [TXA 2 ] and prostacyclin [PGI 2 ]) were studied. PDR (i.g.) significantly inhibited ADP-, collagen- or thrombin-induced rat platelet aggregation. In arteriovenous shunt model and ferric chloride-induced arterial thrombosis model in rats, PDR (i.g.) significantly reduced the thrombus weight. In electrical stimulation-induced arterial thrombosis in rats, PDR (i.v.) dose-dependently prolonged the thrombus occlusion time (OT). PDR increased the concentration of NO in plasma. In contrast with aspirin (ASA), PDR did not influence on the TXA 2 and PGI 2 levels in plasma. In conclusion, PDR is provided with significant inhibitory effect on platelet aggregation and prevention effect on platelet related thrombosis, which is probably attributed to its inhibition on platelet function by l -arginine–NO pathway. The results demonstrate that PDR is a novel, oral and venous effective platelet aggregation inhibitor and has a possibility used as an anti-thrombotic agent.

This paper presents a hyper-plane description approach in a critical cut-set space for visualization of voltage stability region (VSR) of bulk power system. The study on a low dimensional integrated feasible region of voltage stability in critical cut-set space shows that it is the union of hyper-planes vertical to coordinates axes that represent upper and lower limits of the line flows in the critical cut-set, and a hyper-plane which describes critical points in critical cut-set space about voltage stability for a given system configuration with perfect accuracy. Here a critical cut-set separates a geographical region, in which the weak nodes of voltage stability are relatively concentrative and can be identified by an improved voltage stability index L/sub i/, from the residual of the configuration. Examples of visualization of integrated feasible region of the Central-China Power System (1305 buses) are also given to validate the method.