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Supplementary Materials and Methods; Supplementary Figure 1: Effects of AMG 900 on nuclear morphology and centrosome features are consistent with aurora-B inhibition in MDA-MB-231 cell line; Supplementary Figure 2: Elevated expression of ABC transporter gene ABCB1 and ABCB4 in MDA-MB-231 (F11) PTX-r cell line; Supplementary Figure 3: Cell-cycle profiles of TNBC cell lines treated with paclitaxel or ixabepilone.

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser10, a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F11; parental), MDA-MB-231 (F11) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F11) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F11) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. Mol Cancer Ther; 12(11); 2356–66. ©2013 AACR.

Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (Ktrans), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.Conclusions: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574–84. ©2016 AACR.

Supplemental Table 1 (Patient Incidence of Treatment-Related Adverse Events) and Supplemental Figure 1 (AMG 780 dose cohorts and patient enrollment)

Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors.Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab.Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses.Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents. Clin Cancer Res; 18(12); 3414–27. ©2012 AACR.

PDF file, 93KB, Supplemental Table 1. Study Drug Administration; Supplemental Table 2. Summary of Somatic Mutation Status and Tumor PTEN Expression Versus Best Result Change in Tumor Dimensions.

PDF file, 86KB.

Background Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed i...

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS(G12C). METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

The high-content interrogation of single cells with platforms optimized for the multiparameter characterization of cells in liquid and solid biopsy samples can enable characterization of heterogeneous populations of cells ex vivo. Doing so will advance the diagnosis, prognosis, and treatment of cancer and other diseases. However, it is important to understand the unique issues in resolving heterogeneity and variability at the single cell level before navigating the validation and regulatory requirements in order for these technologies to impact patient care. Since 2013, leading experts representing industry, academia, and government have been brought together as part of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium to foster the potential of high-content data integration for clinical translation.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML. Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3+3 design were used: AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents. This article is protected by copyright. All rights reserved.

BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non–small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C–mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C–mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo-engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r/r ALL setting.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

Clearance of trebananib (AMG 386), a 64-kD antiangiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg i.v. weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight

Purpose Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients and Methods Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Results Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Conclusion Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor. Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation. Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (Ktrans), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease. Conclusions: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574–84. ©2016 AACR.

Purpose Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab. Patients and Methods Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment. Results Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%. Conclusion The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.

Colorectal cancers frequently overexpress the epidermal growth factor receptor. Gefitinib (Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, is synergistic with oxaliplatin in preclinical colon cancer models. The authors conducted a phase I/II trial of gefitinib plus oxaliplatin in patients with previously treated metastatic colorectal cancer. In the phase I portion, 14 patients received oxaliplatin 130 mg/m2 intravenously every 21 days and gefitinib orally daily at 1 of 2 dose levels: 250 mg/day (8 patients), and 500 mg/day (6 patients). There were no objective responses. Three patients (38%) in the 250-mg cohort experienced disease stabilization for a median of 12 weeks, and 1 patient in the 500-mg cohort had stable disease for 18 weeks. Nausea/vomiting and rash were dose limiting. The randomized phase II part of the trial, in which patients were to receive oxaliplatin with or without gefitinib, was canceled due to the inactivity of single-agent gefitinib observed in the phase I portion, and emergent phase III data regarding the minimal activity of single-agent oxaliplatin. The authors conclude that the combination of gefitinib plus oxaliplatin is inactive in advanced colorectal cancer.

Advanced pancreatic cancer is a devastating illness characterized by significant morbidity and a brief median survival. Although standard chemotherapy with gemcitabine achieves only modest improvements in survival and quality of life, classic cytotoxic agents, such as 5-fluorouracil, pemetrexed, irinotecan, exatecan, cisplatin, or oxaliplatin, given alone or in combination with gemcitabine, have not proved superior. Thus, more recent trials have focused on targeting the biologic characteristics of pancreatic cancer. Although phase III trials of farnesyl transferase and matrix metalloproteinase inhibitors have not improved survival, encouraging preliminary results have been observed in phase II studies of inhibitors of the vascular endothelial growth factor and the epidermal growth factor receptor.

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser10, a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F11; parental), MDA-MB-231 (F11) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F11) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F11) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. Mol Cancer Ther; 12(11); 2356–66. ©2013 AACR.

Solutions of the bovine lens protein gamma B (or gamma II) crystallin at neutral pH in the absence of reducing agents, undergo a slow, partial conversion to a new protein species, gamma IIH. This species is an aggregate composed of an intermolecular, disulfide-crosslinked dimer (approximately equal to 32% of total protein by weight) and loosely associated dimers (approximately equal to 66%). gamma IIH has a phase separation temperature (Tph), at least 40 degrees C higher than that of native gamma II crystallin at any given protein concentration. In this paper we demonstrate that pantethine, a derivative of coenzyme A, inhibits the formation of gamma IIH.gamma II crystallin solutions were incubated at pH 7.1 and room temperature with increasing amounts of pantethine. The Tph of the solutions was monitored as a function of incubation time. Corresponding to each Tph measurement, aliquots of each solution were analyzed by cation-exchange HPLC to determine the amount of gamma IIH formed.Incubation of gamma II crystallin with increasing amounts of pantethine lowers Tph and suppresses the formation of gamma IIH. With pantethine to protein mole ratios of 0.66, 1 and 2, the Tph of gamma II crystallin is lowered from 8 degrees C in the native protein, to 2 degrees C, -3 degrees C respectively, at a protein concentration of approximately equal to 200 mg/ml. The amount of gamma IIH accumulated decreases from approximately 25% in the native protein to 10%, 1% and 0% respectively in these pantethine-treated protein solutions. For complete suppression of the rise in Tph and inhibition of gamma IIH formation, a 2:1 mole ratio of pantethine to protein is required.We suggest that pantethine reacts with two cysteine residues of gamma IIH crystallin by forming a mixed disulfide, and effectively suppress protein aggregation and lowers Tph. This is due to the strong polar character of pantethine which reduces the net attractive interactions between the protein molecules.

Purpose: Aurora kinases are associated with acquired resistance to therapy in human cancers. We hypothesized that AURKA amplification is a late event in ovarian cancer (OC) progression and that frequency of amplification might be underestimated if assessed in tumor samples collected at the time of initial diagnosis. To test this hypothesis, we determined AURKA amplification levels in patients with recurrent OC and compared those to AURKA amplification levels in the same patients at the time of diagnosis. Methods: Samples were collected from 33 patients with taxane- and platinum-resistant OC enrolled in a first-in-human (FIH) study that evaluated monotherapy with AMG 900, an orally administered pan-aurora kinase inhibitor (NCT00858377). We performed a targeted analysis of the AURKA locus and surrounding regions using next-generation paired-end sequencing (Illumina HiSeq2500 and 100 bp paired-end reads). By using extremely high sequence coverage (average coverage of > 2,000-fold), we were able to detect and quantify circulating tumor DNA (ctDNA) in plasma and to identify chromosomal alterations characteristic of tumor DNA. Sequencing was performed at Personal Genome Diagnostics (PGDx, Baltimore, MD). In addition, we performed AURKA (20q13) / 20q11 FISH in archival FFPE sections from the same patients. The AURKA (20q13) / 20q11 dual color FISH probe kit was purchased from Kreatech (now Leica Biosystems, Buffalo Grove, IL). Amplification states were defined as follows: amplified: AURKA (20q13) / 20q11 signal > 2.0; borderline: AURKA (20q13) / 20q11 signal < 2.0 and > 1.5; non-amplified: AURKA (20q13) / 20q11 signal < 1.5. FISH analyses were performed at Mosaic Laboratories (Lake Forest, CA). Survival analysis was performed using the Kaplan-Meier method. Results: Plasma samples were available from all patients. Analysis of rearrangements surrounding the AURKA locus in plasma samples identified 11 of the 33 patients as AURKA amplified. Archival FFPE sections were available from 27 of the 33 patients, and 21 of these 27 patients were evaluable by FISH for AURKA amplification. FISH only identified 1 patient as AURKA amplified and 1 additional patient as borderline amplified. Patients with AURKA amplification in plasma had received a median (min, max) of 6 (2,18) prior lines of chemotherapy, while patients without AURKA amplification had received a median (min, max) of 3 (1, 14) lines of prior chemotherapy. AURKA amplification as determined in plasma ctDNA at the time of AMG 900 study entry was an indicator of shorter PFS (median 9.4 vs 19.9 weeks; P = 0.04) and OS (median 9.4 vs 27.6 weeks; P = 0.013). Conclusions: Our results suggest that AURKA amplification is a late event in ovarian cancer progression,and that monitoring AURKA focal amplification in plasma ctDNA allows the non-invasive assessment of acquired resistance to cancer therapy. Citation Format: Gloria Juan, Katherine Paweletz, Abraham Anderson, Erick Gamelin, Gregory Friberg, Robert Loberg, Florian Vogl. Detection of aurora kinase A (AURKA) focal amplification in plasma samples of patients with recurrent ovarian cancer. [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 439.

Purpose: Aurora kinases are associated with high proliferation, poor prognosis, and therapeutic resistance in several human tumor types. AMG 900 is an investigational, oral, highly potent, selective, pan-aurora kinase inhibitor. We evaluated the safety, tolerability, pharmacokinetics, and clinical activity of AMG 900 in pts with advanced solid tumors (NCT00858377). Methods: In the dose escalation phase, eligible pts were ? 18 years old, with advanced solid tumors that were refractory to standard treatment, measurable disease per RECIST, ECOG ? 2, and life expectancy > 3 months. In the dose expansion phase, eligible pts had taxane- and platinum-resistant epithelial ovarian cancer (OC), taxane-resistant triple-negative breast cancer (TNBC), or castration-resistant and taxane- or cisplatin-etoposide-resistant stage IV prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at doses of 1 to 50 mg/day (dose escalation), and at the maximum tolerated dose of 40 mg/day with G-CSF support (dose-expansion). The primary objective was safety. Tumor response was determined per RECIST for all pts and additionally by GCIG CA-125 for pts with OC. Results: Treatment-related AEs were reported by 98 of 105 pts (93.3%). Myelotoxicities were the most common grade ? 3 treatment-related AEs. In the dose escalation (N = 50), 1 pt with OC (30-mg cohort) had a partial response (PR) by RECIST and GCIG. In the dose expansion (N = 55), 3 of 29 pts (10.3%) with OC had a PR by RECIST, and 7 of 29 pts (24.1%) had a PR by GCIG; 72.4% of pts with OC had stable disease (SD), and the disease control rate (PR + SD) was 82.8%. Median (95% CI) duration of response in pts with OC per RECIST was 24.1 (16.1, 34.1) weeks, and median (80% CI) PFS was 31.1 (23.6, 34.1) weeks. See table for additional results. Conclusions: AMG 900 had manageable toxicity with G-CSF support and promising single-agent activity in pts with heavily pretreated taxane- and platinum-resistant OC. Patient demographics, prior therapy, AEs, and best tumor responseDose escalation - advanced solid tumors (N = 50)OC (N = 29)TNBC (N = 14)CRPC (N = 12)Overall (N = 105)Male, n (%)21 (42.0)0 (0.0)0 (0.0)12 (100.0)33 (31.4)Female, n (%)29 (58.0)29 (100.0)14 (100.0)0 (0.0)72 (68.6)White or Caucasian, n (%)35 (70.0)23 (79.3)12 (85.7)11 (91.7)81 (77.1)Age, mean (SD), years56.5 (11.6)61.1 (11.4)54.6 (11.4)67.7 (8.0)58.8 (11.7)Prior lines of anti-cancer therapy, mean (SD)4.9 (3.2)5.3 (4.3)5.8 (3.0)4.5 (2.6)5.1 (3.4)Treatment-related AEs by preferred term (any grade), n (%)Fatigue21 (42.0)15 (51.7)6 (42.9)6 (50.0)48 (45.7)Neutropenia24 (48.0)14 (48.3)4 (28.6)4 (33.3)46 (43.8)Anemia15 (30.0)16 (55.2)6 (42.9)3 (25.0)40 (38.1)Nausea18 (36.0)10 (34.5)5 (35.7)5 (41.7)38 (36.2)Thrombocytopenia15 (30.0)11 (37.9)1 (7.1)2 (16.7)29 (27.6)Diarrhea14 (28.0)10 (34.5)1 (7.1)2 (16.7)27 (25.7)Alopecia13 (26.0)11 (37.9)1 (7.1)1 (8.3)26 (24.8)Decreased appetite11 (22.0)7 (24.1)2 (14.3)4 (33.3)24 (22.9)Vomiting9 (18.0)7 (24.1)5 (35.7)3 (25.0)24 (22.9)Leukopenia19 (38.0)3 (10.3)0 (0.0)1 (8.3)23 (21.9)Best tumor response - RECIST 1.1 criteria (central read), n (%)Complete response0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)Partial response1 (2.0)3 (10.3)0 (0.0)0 (0.0)4 (3.8)Stable disease29 (58.0)21 (72.4)7 (50.0)9 (75.0)66 (62.9)Progressive disease12 (24.0)3 (10.3)4 (28.6)1 (8.3)20 (19.0)Unable to evaluate8 (16.0)2 (6.9)3 (21.4)2 (16.7)15 (14.3) Citation Format: Montasser Shaheen, Ben Markman, Michael Carducci, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar Goodman, Erick Gamelin, Vincent Chow, Gloria Juan, Erik Rasmussen, Gregory R. Friberg, Florian D. Vogl, Jayesh Desai. Phase 1, open-label, first-in-human study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors. [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 CT045.

BACKGROUND: Aurora kinases (AK) A and B play essential roles in multiple stages of mitosis and are frequently overexpressed in a subset of human cancers, including ovarian cancer (OC). AMG 900, a potent and highly selective small molecule inhibitor of AKs, showed promising single-agent activity in heavily pretreated patients with advanced OC in a Phase 1b clinical trial. In this study, we report the preclinical effects of AMG 900 in a panel of well-characterized human cancer cell lines representing clinically-relevant OC subtypes. METHODS: The anti-proliferative effects of AMG 900 were evaluated using a 5-day cell count assay. Cell lines were classified as sensitive to AMG 900 when lethality was > 15% at 10 nM. Molecular markers were profiled including TP53 mutation status, AURKA, CCNE1, MYC copy number, and p53, p21 and cyclin E1 protein by reverse phase protein array. Flow cytometry and imaging methods were used to evaluate the mechanism of action of AMG 900 alone and in combination with chemotherapy. The combination of AMG 900 plus docetaxel was evaluated in an IGROV-1 ovarian endometrioid carcinoma xenograft model. RESULTS: One third of the cell lines (11 of 35) were classified as sensitive to AMG 900 and showed enrichment for TP53 mutations and serous OC subtype. However, 10 of 24 resistant cell lines harbored TP53 mutations, indicating that TP53 mutational status alone was not sufficient for predicting AMG 900 sensitivity. Inhibition of AK activity by AMG 900 in OC cells resulted in aborted cell division leading to polyploidy and cell death (suggestive of aurora-B dominant phenotype). Re-plating of remnant cells after AMG 900 treatment showed an attenuation of cell regrowth, where TP53mut IGROV-1 cells showed minimal regrowth compared to TP53wt OVCAR-5 cells. AMG 900 inhibited proliferation at low nanomolar concentrations in the majority of OC cell lines and enhanced the effects of paclitaxel, carboplatin, and doxorubicin in IGROV-1 cells. In tumor-bearing mice, administration of AMG 900 at 7.5 mg/kg (PO) for two days per week or docetaxel at 10 mg/kg (IP) weekly for four cycles significantly inhibited the growth of IGROV-1 tumor xenografts (P < .0001 vs. vehicle alone). Notably, co-administration of AMG 900 with docetaxel enhanced efficacy and induced a delay in tumor regrowth compared to docetaxel alone. Single-agent-treated mice showed minimal body weight loss (BWL), whereas combination-treated mice showed moderate BWL (average < 10%) that was largely reversible (2 of 12 animals removed due to toxicity). CONCLUSIONS: AMG 900 alone or in combination with chemotherapy such as paclitaxel may be a promising clinical strategy to treat patients with ovarian cancer. Citation Format: Ondrej Kalous, Dylan Conklin, Kanthinh Manivong, William Wayne, Kelly Hanestad, Jude Canon, Robert Loberg, Gregory Friberg, Erick Gamelin, Florian D. Vogl, Gloria Juan, Angela Coxon, Dennis Slamon, Richard Finn, Marc Payton. Preclinical characterization of AMG 900, a pan-aurora kinase inhibitor, alone and in combination with taxanes in ovarian cancer. [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 3008.

Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents. Clin Cancer Res; 18(12); 3414–27. ©2012 AACR.

Conatumumab is a fully human monoclonal agonist antibody against human death receptor 5 (DR5). The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients with advanced solid tumors.This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 and 20 mg/kg were planned. Six patients were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single agent. No conatumumab was administered on day 43 to allow the assessment of terminal PK parameters. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and assessment of PK parameters of conatumumab.Eighteen patients received at least 1 dose of conatumumab. There were no DLTs observed as defined in the protocol. No patients had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics. A best response of stable disease was reported in nine patients. Monocytes were found to express DR5 and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels.Conatumumab administered up to 20 mg/kg once every 2 weeks was well tolerated in Japanese patients with advanced solid tumors. Adverse events and PK in these patients were similar to those in the first in human (FIH) study.

The objectives of this phase II trial were to assess the activity and tolerability of the combination of bevacizumab and erlotinib in patients with recurrent ovarian, primary peritoneal or fallopian tube cancer.This was a single arm, multicenter phase II trial with overall objective response as the primary endpoint. Eligible patients had two or fewer prior chemotherapy regimens for recurrent or refractory disease and no prior anti-VEGF or anti-EGFR agents. Bevacizumab, 15 mg/kg, was administered intravenously every 21 days and erlotinib, 150 mg orally, was given daily.Between July and October 2005, 13 patients were enrolled. There were two major objective responses, one complete response of 16+ month duration and one partial response of 11 month duration, for a response rate of 15% (95% CI 1.9% to 45.4%). Seven patients had a best response of stable disease. The most common grade 3 or 4 toxicities included anemia (n=1), nausea (n=2), vomiting (n=1), hypertension (n=1), and diarrhea (n=2). One patient with an ileostomy was removed from the study secondary to grade 3 diarrhea. Two patients had fatal gastrointestinal perforations.There was no strong suggestion that this combination was superior to single agent bevacizumab, and the rate of gastrointestinal perforation was of concern. The study was therefore stopped. Identification of risk factors for gastrointestinal perforation will be of importance for the use of bevacizumab in the treatment of ovarian cancer.

Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. The median survival of women enrolled in trials for recurrent or metastatic endometrial cancer is only approximately 12 months. Hormonal therapy, most commonly with progestins, benefits a small group of patients. Cytotoxic chemotherapy is indicated as frontline treatment for the majority of women with metastatic or recurrent disease. Anthracyclines, platinum compounds, and taxanes consistently achieve response rates greater than 20% in single-agent trials of chemotherapy-naive patients. Combination chemotherapy typically produces higher response rates, although combination regimens have not always improved survival historically. Doxorubicin plus cisplatin has been accepted as the Gynecologic Oncology Group (GOG) standard regimen based on phase III data. Recently, a COG randomized trial compared doxorubicin plus cisplatin to the triplet of doxorubicin, cisplatin, and paclitaxel, and it was found that the addition of paclitaxel significantly improved response rate, progression-free survival, and overall survival. Moreover, chemotherapy has been reported to improve survival when

Intraperitoneal chemotherapy provides a means by which high concentrations of drugs and long durations of tissue exposure can be attained at the peritoneal surface. It has been studied widely in ovarian cancer, a disease in which intra-abdominal progression remains the major source of morbidity and mortality. Three large randomized trials have shown improved survival in optimally debulked patients who were treated with intraperitoneal chemotherapy as part of a front-line regimen, yet it has not become part of usual therapy. Several factors have contributed to the reluctance to adopt intraperitoneal therapy, including technical issues related to drug delivery and the fact that all of the large randomized trials employed intraperitoneal cisplatin, which has more toxicity than intravenous carboplatin, the current standard of care. Future research is needed for further definition of the clinical benefit of intraperitoneal chemotherapy, modification of existing regimens to minimize side effects, and exploration of intraperitoneal biologic, immunologic, and gene therapy techniques.

Background Trebananib, an investigational peptibody, binds to angiopoietin 1 and 2, thereby blocking their interaction with Tie2. Patients and Methods This open-label phase I study examined trebananib 3 mg/kg or 10 mg/kg intravenous (I.V.) once weekly plus sorafenib 400 mg twice per day or sunitinib 50 mg once per day in advanced RCC. Primary end points were adverse event incidence and pharmacokinetics. Results Thirty-seven patients were enrolled. During trebananib plus sorafenib administration (n = 17), the most common treatment-related adverse events (TRAEs) included rash (n = 12; 71%), diarrhea (n = 12; 71%), hypertension (n = 11; 65%), and fatigue (n = 11; 65%); grade ≥ 3 TRAEs (n = 7; 41%); and 2 patients (12%) had peripheral edema. During trebananib plus sunitinib administration (n = 19), the most common TRAEs included diarrhea (n = 14; 74%), fatigue (n = 13; 68%), hypertension (n = 11; 58%), and decreased appetite (n = 11; 58%); grade ≥ 3 TRAEs (n = 13; 68%); and 8 (42%) patients had peripheral edema. Trebananib did not appear to alter the pharmacokinetics of sorafenib or sunitinib. No patient developed anti-trebananib antibodies. Objective response rates were 29% (trebananib plus sorafenib) and 53% (trebananib plus sunitinib). Conclusion The toxicities of trebananib 3 mg/kg or 10 mg/kg I.V. plus sorafenib or sunitinib in RCC were similar to those of sorafenib or sunitinib monotherapy, with peripheral edema being likely specific to the combinations. Antitumor activity was observed.

2584 Background: Trebananib (AMG 386) is an investigational peptide-Fc fusion protein that inhibits angiogenesis by preventing the interaction between angiopoietin-1/2 and Tie2. In a phase 3 study,...

2542 Background: AMG 780 is a fully human monoclonal antibody binding Ang1/2, thereby inhibiting their interaction with Tie2. This first-in-human study evaluated AMG 780 in advanced solid tumors. M...

Is oral tegafur with leucovorin equivalent to intravenous 5-fluorouracil and leucovorin in colorectal cancer?

Introduction The phosphoinositide 3-kinase p110δ isoform (PI3Kδ) is expressed primarily in hematopoietic cells and is essential in B-cell receptor (BCR) signaling. PI3Kδ is expressed in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). AMG 319 is an investigational, highly selective, small molecule inhibitor of PI3Kδ that blocks B cell proliferation following BCR stimulation both in vitro and in vivo, inhibits basal AKT phosphorylation, and inhibits proliferation in lymphoid tumor cells. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 319. Methods Patients (pts) with relapsed or refractory CLL or NHL were eligible. Key eligibility criteria included ≥ 18 years old, ECOG ≤ 2, and adequate organ function. AMG 319 was administered once per day (QD; except day 2 for PK) until disease progression or unacceptable toxicity. Doses of 25, 50, 100, 200, 300, and 400 mg were administered in sequential cohorts (3 pts per cohort). Dose-limiting toxicities (DLT) were defined during the first 28 days. Response assessments for CLL and NHL were done using IWCLL 2008 and IWG 2007 criteria, respectively. CT scans for CLL pts were done at baseline and week 8. Results 28 pts received AMG 319 (6 at 25 mg; 3 at 50 mg, 100 mg, 200 mg, and 300 mg; and 10 at 400 mg). Demographics: median age 68 years, 71% men, ECOG 0/1 93%. 25 pts had CLL, 3 had NHL, including 2 mantle cell and 1 marginal zone. The median number of prior treatment regimens was 4 (range 1-9) for CLL and 7 (range 5-9) for NHL. Central cytogenetic analysis of CLL pts prior to dosing (n=24) revealed 10 with del 17p (42%), 3 with del 11 and not 17p (13%), 1 with trisomy 12 alone (4%), 9 normal (38%), and 1 del 13q alone (4%). Doses up to 400 mg QD were explored without reaching a maximum tolerated dose. There was 1 DLT: grade 3 hemolytic anemia at 25 mg in a CLL pt after 1 dose, considered as possibly related to AMG 319. AMG 319 was well absorbed and exhibited linear PK with mean plasma half-lives of 3.8 to 6.6 hours across dose cohorts. Dose-dependent coverage of BCR-induced pAKT in CLL samples (ex-vivo IgD stimulated) was observed in all samples with an inducible signal (60%); near complete inhibition for 24 hours was seen at 400 mg. 75% of pts had ≥1 treatment-related adverse event (AE, 25% grade ≥3). Grade ≥3 treatment-related AEs (n>1) were colitis 3 (10%), anemia 3 (10%), leukocytosis 2 (7%), infection 2 (7%), and hemolysis 2 (7%). The colitis cases occurred at 400 mg between days 40 and 60; 2 were successfully re-challenged at a lower dose, while the third was diagnosed with C Diff colitis and discontinued. Grade 3 transaminitis was observed in 1 pt (4%) at 50 mg on day 29, which resolved with holding of drug and did not recur with re-challenge. Subset analysis of lymphocytes revealed no changes in % of T, B, or NK cells. Baseline % of T-regulatory cells (as a function of total CD4) was elevated in CLL pts (14.4% ± 7.6%). Elevated T regulatory cells (>10% of CD4+) tended to normalize during treatment (14/19 pts), suggesting immune restoration. Response data are available for 24 CLL pts (pt with DLT removed after 1 dose) and 3 NHL pts. Lymphocyte counts in CLL were highly variable, with some pts experiencing marked and early lymphocytosis (at all doses) and others showing gradual decline. Consistent nodal regression was observed at all doses by CT and physical exam. Early CT imaging (21 pts) at week 8 revealed lymph node (LN) reduction in all pts, and >50% decrease was seen in 7 pts; all 7 were dosed at 400 mg including 4 with del 17p or del 11q. Two pts at week 8 met IWCLL response criteria for partial response. By physical exam, all 20 evaluable pts had >50% LN reduction as a best response, with 15 (75%) having >90%. Response was present in all cytogenetic subtypes. At the 200-400 mg dose levels, 13/15 CLL pts remain on study after a median follow-up of 30 weeks (range 14-65). 1 pt with mantle cell NHL had 46% shrinkage while on therapy but progressed after 26 weeks; the 2 other NHL pts progressed by the first evaluation. Conclusions AMG 319 exhibited linear absorption and was tolerated at doses up to 400 mg QD. This degree of inhibition provided complete blockade of ex-vivo stimulated pAKT for 24 hours in CLL. Anti-tumor activity was observed early in CLL pts and included high-risk cytogenetic subgroups. While activity was noted at all dose levels, an apparent dose response was observed, with deeper and faster responses in CLL pts at higher doses. Disclosures: Lanasa: Amgen: Consultancy. Glenn:Amgen: Research Funding; Sanofi Aventis: Research Funding. Mato:Amgen: Honoraria. Wong:Amgen: Employment, Equity Ownership. Amore:Amgen: Employment, Equity Ownership. Means:Amgen: Employment, Equity Ownership. Stevens:Amgen: Employment, Equity Ownership. Yan:Amgen: Employment, Equity Ownership. Friberg:Amgen: Employment, Equity Ownership. Goy:Amgen Inc: Research Funding.

Aurora kinases A and B play essential roles in multiple stages of mitosis and are frequently overexpressed in a subset of human cancers, including acute myeloid leukemia (AML) (Ikezoe T et al, 2007). AMG 900, a potent and highly selective small molecule inhibitor of aurora kinases, is currently in Phase 1 clinical testing in adult patients with AML. In this study, we report the preclinical effects of AMG 900 in AML cell lines. We show that AMG 900 inhibits the phosphorylation of Histone H3 on serine-10 (a proximal substrate of aurora-B) leading to aborted cell division, apoptosis and/or polyploidy. We evaluated the activity of AMG 900 and two other well-characterized aurora kinase inhibitors [AZD1152-hQPA (B-selective AKI) and MLN8054 (A-selective AKI)] in a panel of AML cell lines. AMG 900 inhibited proliferation in all 10 cell lines at single-digit nanomolar concentrations. At effective concentrations, AMG 900 and AZD1152-hQPA showed similar cellular phenotypes, indicating that the activity of AMG 900 may occur through inhibition of aurora-B. A subset of cell lines sensitive to AMG 900 and MLN8054 were insensitive to AZD1152-hQPA, suggesting that AMG 900 may be less susceptible to resistance mediated by drug-efflux (Grundy M et al, 2011). Two AMG 900 oral dosing schedules are being evaluated in the ongoing AML clinical trial; patients receive either 4 or 7 consecutive daily doses followed by a drug holiday in 14-day cycles. In this study, we evaluated the in vivo anti-proliferative effects of AMG 900 using the two dose schedules in the skeleton of NOD/SCID IL2γnull mice bearing MOLM-13 (AML) cells expressing luciferase. To assess tumor cell proliferation in vivo, we used 18FLT (radioactive thymidine analog) PET/CT imaging, a technique that has been used to monitor early treatment response in the bone marrow of AML patients (Vanderhoek M et al, 2011). Mice were imaged for luciferase activity and 18FLT uptake before treatment and at multiple time-points during the drug holiday phase within the 14-day cycle. While the two AMG 900 dosing schedules resulted in a similar decrease in tumor burden across study time points (as measured by luciferase activity), they differed in the timing of skeletal 18FLT responses. Mice administered AMG 900 showed an attenuated skeletal 18FLT uptake compared with the vehicle group, followed by an 18FLT flare. This 18FLT flare event is notably higher using the AMG 900 4-day schedule, although the cumulative dose is similar for both schedules. This difference in 18FLT flaring may indicate the schedules differ in the duration and/or level of target inhibition in the skeletal tumor and bone marrow cells. Mice treated with sunitinib (positive control agent) did not show a skeletal 18FLT flare during the drug holiday, suggesting its mode of action is distinct from that of AMG 900. At the end of the study, mouse bone marrow was assessed for tumor burden by flow cytometry. Mice treated with AMG 900 showed a significant decrease in tumor burden compared with the vehicle group. Interestingly, the mice administered AMG 900 7-day schedule showed the most suppression of tumor growth compared with either AMG 900 4-day schedule or sunitinib. Together, our preclinical studies demonstrate that AMG 900 is a potent inhibitor of aurora kinases that robustly suppresses the growth of AML cells in vitro and in vivo. Furthermore, we highlight the utility of in vivo imaging to monitor AMG 900 drug action, which may help to inform future dose scheduling and drug combination studies. Disclosures: Cheung: Amgen Inc: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Wayne:Amgen Inc.: Employment, Equity Ownership. Hanestad:Amgen Inc.: Employment, Equity Ownership. Keegan:Amgen Inc.: Employment, Equity Ownership. Huard:Amgen Inc.: Employment, Equity Ownership. McElroy:Amgen Inc.: Employment, Equity Ownership. Stanton:Amgen Inc.: Employment, Equity Ownership. Bush:Amgen Inc.: Employment, Equity Ownership. Kendall:Amgen Inc.: Employment, Equity Ownership. Radinsky:Amgen Inc.: Employment, Equity Ownership. Abella:Amgen Inc. : Employment, Equity Ownership. Pieslor:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Coxon:Amgen Inc.: Employment, Equity Ownership. Gamelin:Amgen Inc: Employment, Equity Ownership. Payton:Amgen Inc.: Employment, Equity Ownership. Off Label Use: AMG 900 is currently in phase 1 clinical development, there is no approved label.

2071 Background: EGFRvIII is a mutant version of EGF receptor resulting from the genomic deletion of exons 2 through 7 and is expressed only in certain tumors. AMG 595 is an experimental therapeutic specifically targeting EGFRvIII and consists of an EGFRvIII-specific antibody conjugated to the maytansinoid antimicrotubule agent DM-1. Due to its specificity, mechanism of action, and pre-clinical activity, AMG 595 is expected to have clinical effect only in tumors expressing EGFRvIII. Since the reported prevalence of EGFRvIII in glioblastoma multiforme (GBM) is ~30%, prospective selection of patients with EGFRvIII positive tumors was desired for clinical development. An immunohistochemical (IHC) assay developed with Dako using a novel EGFRvIII antibody is currently being employed for patient selection for the AMG 595 phase I study in recurrent GBM (NCT01475006). Methods: An appropriate IHC reagent for human tissue was created using the variable region of a novel EGFRvIII-specific antibody developed using Xenomouse technology. Staining conditions were optimized using Dako pharmDx reagents, the Dako Link 48 Autostainer, and FFPE tissue sections. Confirmatory transcript analyses of adjacent sections were conducted using the NanoString platform. Results: Robust and reproducible staining for EGFRvIII was observed using archived GBM resections. Percentage of stained cells correlated with levels of EGFRvIII transcripts, and tumors without staining did not express EGFRvIII transcripts. Although some tumors exhibited homogenous staining, most were heterogeneous with varying distribution and percentages of stained tumor cells similar to literature reports of IHC analysis utilizing other EGFRvIII-specific antibodies. Tumor samples from patients entering into the AMG 595 Phase 1 study analyzed with this IHC test have displayed the predicted staining prevalence. Conclusions: The developed EGFRvIII IHC assay, approved under an Investigational Device Exemption, is currently being successfully employed to prospectively select patients in an ongoing phase I trial. Use of this well characterized IHC test will enable correlation of clinical outcome and staining characteristics to inform subsequent studies.

3009 Background: Aurora kinases A, B, and, C play essential roles in regulating cell division. Overexpression of aurora A and B in human tumors is associated with high proliferation rates and poor prognosis. AMG 900 is an investigational, orally administered, highly selective inhibitor of aurora A, B, and C that demonstrated activity in drug-resistant cell lines and human tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 900. Methods: Key eligibility criteria: ≥ 18 years old, advanced solid tumors, measurable disease, ECOG ≤ 2, and adequate organ function. AMG 900 was administered orally daily for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation phase, the starting dose was 1 mg and was escalated by 100% in subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation continued in a standard 3+3 design at ≤ 25% if DLT occurred or ≤ 50% if G2 related toxicity occurred. The maximum tolerated dose (MTD) was determined without prophylactic G-CSF support. Results: As of OCT 2011, 19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 mg) had received ≥ 1 dose of AMG 900. Demographics were 58% women, median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 DLTs: G4 neutropenia > 7 days at 24 mg (n=1) and 30 mg (n=1); G4 neutropenia > 7 days + G4 thrombocytopenia at 30 mg (n=1); and febrile neutropenia (FN) at 30 mg (n=1). MTD without G-CSF support was 24 mg. 89% of pts had treatment-related adverse events (AEs). G≥3 treatment-related AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 (11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed no obvious departures from dose-proportionality with a half-life of ~16 h. Tumor-response data were available for 17 pts: stable disease, 13 pts (range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease in CA-125 (SD > 6 months). Conclusions: AMG 900 administered at 24 mg daily for 4D Q2W is the recommended dose for phase 2 trials. Dose escalation is now ongoing to determine the MTD with prophylactic G-CSF.

10001 Background: IGF1 signaling is implicated in the pathobiology of EFT and DSRCT. AMG 479 is a fully human monoclonal antibody antagonist of IGF1R that induced a complete response (CR) in 1 EFT ...

3018 Background: AMG 479, a fully human monoclonal antibody antagonist of IGF1R, showed activity in early clinical trials and additive effects with other therapies in preclinical models. This study examined adverse events (AEs), dose limiting toxicities (DLTs), PK, and WHO tumor response of AMG 479 combined with E, S, panitumumab (P), or gemcitabine (G). P and G results were shown previously (JCO 2008;26 abstr 3583). Methods: Eligible pts had advanced solid tumors, ECOG 0-2, and no hyperglycemia. A sequential 3+3 design was used. Pts received E (150 mg po QD) or S (400 mg po BID) with AMG 479 (6 or 12 mg/kg IV Q2W) until progression. CT scans were done every 8 weeks (wks). Results: A total of 25 pts enrolled and received AMG 479 + E (n = 12) or S (n = 13); median age (range) = 58 (41 to 74); 68% had ≥ 3 prior therapies; 44% were male. Most common emergent AEs are shown (Table). The S arm had no DLTs. There was 1 DLT (grade 4 thrombocytopenia) in the E arm at 12 mg/kg AMG 479. AMG 479 clearance (CL, mL/day...

Background: Conatumumab is an investigational, fully human monoclonal agonist antibody that binds human death receptor-5 (DR5, TR-2), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients (pts) with advanced solid tumors. Method: This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 mg/kg and 20 mg/kg were planned. Six pts were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single-agent. No conatumumab was administered on day 43 to allow assessment of terminal PK parameters. Conatumumab receptor occupancy on monocytes was assessed during the first treatment cycle. Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: Eighteen pts (6 in each dose cohorts) received at least 1 dose of conatumumab; 9 pts were men; median age was 58 years. Tumor types included: colorectal (5), non-small cell lung (4), gastric (2), soft tissue sarcoma (2) and one each of pancreatic cancer, thymoma, mesothelioma, rectal carcinoid and parotid cancer. The grade 3 adverse events included blood creatine phosphokinase increase, pain and increased lipase. One treatment emergent serious adverse event of pain was reported in cohort 2. This serious adverse event was not considered by the investigator to be related to conatumumab. There were no DLTs observed as defined in the protocol. No deaths occurred during treatment or the safety follow-up period. No subjects had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics with a half-life of 12 to16 days. Pharmacokinetic profiles were similar to those in the Caucasian population. Tumor response data were available for all patients. A best response of stable disease (defined as a lack of progression at the first assessment at 8-weeks) was reported in 9 patients and progressive disease in 9 patients. Monocytes were found to express DR5, and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels. Conclusions: Conatumumab administered up to 20 mg/kg once every 2 weeks did not result in dose limiting toxicities in Japanese patients with advanced solid tumors. Adverse events and pharmacokinetics were similar to those in the first in human study conducted in the United States. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C6.

3545 Background: AMG 479 showed anti-tumor activity in a phase 1 (P1) and phase 1b (P1b) trial (Tolcher, J Clin Oncol. 2007;25:3002; Sarantopoulos, J Clin Oncol. 2008;26:3583). We sought to identify predictive markers of response to AMG 479 in these trials by analyzing pharmacodynamic (PD) markers in serum, and expression and mutations of regulators of the IGF-1R pathway in tumors. Methods: Patients (pts) had advanced solid tumors and received AMG 479 (1–20 mg/kg Q2W) in the P1 trial or AMG 479 (6 or 12 mg/kg Q2W) + panitumumab (6 mg/kg Q2W) or gemcitabine (1,000 mg/m2 QW) in the P1b trial. Serum levels of IGF-1 and IGFBP-3 were measured pre dose on Day -1 and post dose at various time points. In the P1 trial, we examined relationships between tumor response (by RECIST) and: 1) levels of IGF-1 and IGFBP-3 (at baseline or PD change from baseline); 2) somatic mutations in key genes (including K-ras, and PTEN) of the IGF-1R pathway (in archival tumors); and 3) expression of PTEN (measured by immunohistochemistry in archival tumors). Results: Serum IGF-1 and IGFBP-3 increased in a concentration-dependent manner between 1 and 12 mg/kg AMG 479, with an apparent plateau between 12 and 20 mg/kg AMG 479. Baseline and PD changes in IGF-1 and IGFBP-3 were not substantially different in pts with a tumor response compared with those without a tumor response. A partial response to AMG 479 was observed in a pt with an activating K-ras mutation. No responses have been observed in tumors that lack expression of PTEN. Conclusions: The PD results suggest near complete biochemical coverage at 12-mg/kg AMG 479. Our hypothesis-generating analyses suggest that: 1) pre and postdose levels of IGF-1 and IGFBP-3 do not predict response to single-agent AMG 479; 2) activating K-ras mutations do not appear to preclude responsiveness to single-agent AMG 479 (in contrast to EGFR inhibitors); 3) expression and mutations of regulators of the PI3K/Akt pathway downstream of IGF-1R activation may be useful in predicting response to AMG 479. [Table: see text]

3583 Background: IGF1R signaling plays a key role in oncogenesis and protects some tumors from anti-cancer agents. AMG 479 is a fully human monoclonal antibody (IgG1) against IGF1R. It has exhibite...

5018 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are commonly over-expressed in OC and correlate with poor prognosis. The anti-VEGF antibody B and the EGFR tyrosine kinase inhibitor E have each demonstrated activity in OC. Dual inhibition with BE may overcome mechanisms of resistance encountered with either agent alone. Methods: We are conducting a 2-stage phase II trial of BE in pts with recurrent OC, primary peritoneal, and FT cancer. Eligible pts had ≤ 2 prior chemo regimens for recurrent or refractory disease; no prior VEGF or EGFR inhibitors; ECOG performance status (PS) 0–2; measurable disease; normal organ function; no proteinuria (1 cm, 3 doses of B (last was 10 and 42 days prior), and small bowel obstructions in the preceding 28 days. Conclusions: The first stage of accrual is complete and further enrollment is on hold pending continued efficacy evaluation. There appeared to be an increased rate of bowel perforation, and identification of potential risk factors for this event would be critical for further development of this combination. Updated results will be presented. Supported by NCI Grant N01-CM-17102. [Table: see text]

3020 Background: Bevacizumab is a monoclonal Ab to the vascular endothelial growth factor (VEGF). VEGF increases vessel permeability by stimulating endothelial nitric oxide and prostaglandin metabolism. Antagonism of this system causes HTN in >30% of pts treated with B 10mg/kg. We conducted a phase II trial of BG in advanced PC pts (Kindler, ASCO 2004). Methods: We hypothesized that early HTN (defined as ≥Gr 2 HTN during the first 56 days of treatment) would be a PD marker for survival. To test this hypothesis, we performed a retrospective analysis of PC pts treated with BG. Blood pressure (BP) was recorded at least every 14 days; HTN was graded by CTC v2.0 (Gr 2: recurrent, persistent, or symptomatic rise in either DBP by >20 mmHg or to >100, or SBP to >150, if previously ≤140/90; Gr 3: requiring new or increased therapy). Pts were excluded from analysis for early removal from study (prior to day 28) or early death (prior to day 56). Kaplan-Meier estimates and Cox proportional hazard (PH) models were use...

4009 Background: Vascular endothelial growth factor (VEGF) and its receptors are overexpressed in PC. In preclinical models, anti-VEGF antibodies suppress PC growth and potentiate the activity of g...