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Introduction: Obesity is associated with a worse breast cancer prognosis, with the most prominent effects seen in hormone responsive postmenopausal patients. It has also been linked to elevated levels of inflammation, including greater cyclooxygenase-2 (COX-2) expression and activity in adipose-infiltrating macrophages. The product of this enzyme, the pro-inflammatory eicosanoid prostaglandin E2 (PGE2), stimulates adipose tissue aromatase expression and subsequent estrogen production, which could promote breast cancer progression. Consequently, we hypothesized that non-steroidal anti-inflammatory drug (NSAID) use decreases estrogen receptor (ER) positive breast cancer recurrence in the obese population via inhibition of PGE2-mediated local aromatase expression. Methods: Four-hundred and forty women treated for invasive, ER positive breast cancer at San Antonio area clinics were retrospectively classified according to NSAID use, body mass index category (Normal Weight (NW): 18.5-24.9 kg/m2; Overweight (OW): 25.0-29.9 kg/m2; Obese (OB): ≥30.0 kg/m2), and disease recurrence. To examine the role of obesity-induced local aromatase expression in the link between NSAID use and disease recurrence, we utilized an in vitro model of obesity in which we exposed macrophages to pooled sera samples from NW or OB postmenopausal breast cancer patients. Adipose stromal cells’ (ASC) aromatase expression was measured following exposure to conditioned media (CM) collected from these sera-exposed macrophages. ER activity and in vitro measures of cancer aggression were assessed in MCF-7 and T47D breast cancer cells cultured in CM from sera-exposed macrophage/ASC co-cultures. Results: Within our patient population, which had an average BMI in the obese range, NSAID users had significantly lower recurrence rates (p = 0.05) and their time to disease progression was delayed by almost 28 months in comparison to nonusers. Our in vitro studies demonstrated that growth in OB macrophage CM significantly enhances ASC aromatase expression in comparison to NW (p Conclusions: Our results indicate that NSAID use can improve the recurrence rate for hormone-responsive breast cancer patients, particularly those with an elevated BMI. The in vitro model suggests that obesity-related enhancement of PGE2-induced local aromatase expression and estrogen production may be a key mechanism mediating this effect. Further studies designed to examine the clinical benefit of NSAID use in the obese breast cancer patient population are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-01.

This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38.Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m(2).Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1-11). Twenty patients (49 %) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m(2) cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m(2) cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51 %), diarrhea (46 %), fatigue (41 %), alopecia (29 %), neutropenia (24 %), and vomiting (22 %). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged, was observed as best response.EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m(2).

This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.

Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use (Sergina et al Nature 2007, Garrett et al SABCS 2009 abstract 63). MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates ligand binding. In preclinical models of HER-2+ gastric, breast, ovarian and lung cancers, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. This first-inhuman phase 1-2 study evaluates the safety and tolerability of MM-111 and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). The safety data obtained during the Phase 1 dose escalation portion of this study provide the basis of this report. Methods: Patients (pts) with histologically confirmed HER-2+ advanced solid tumors progressing or recurring on standard therapy; aged ≥18 years; ECOG PS ≥2 and adequate organ function were eligible for phase I. Pts with stable CNS lesions were also eligible. A Modified Fibonacci schema was used for dose escalation in Phase I. Primary endpoints for Phase 1 were determination of maximum tolerated dose/maximum feasible dose while secondary endpoints included determination of dose-limiting toxicity, adverse events, and pharmacokinetic (PK) and immunogenicity profiles of MM-111. MM-111 was administered intravenously weekly in 4-week cycles. Results: 12 pts (11 ABC and 1 gastric cancer) were treated: median age 59 (range 36-82), median PS 1 (range 0-1), 11♂:1♀, median numberof prior therapies 7 (3-12). A total 19 courses (median 2; range 1-2) of therapy was administered at 4 dose-levels (3 mg/kg, 6mg/kg, 12mg/kg and 20 mg/kg respectively). Common adverse events reported included pain (n=7) fatigue (n=4), dyspepsia (n = 3) and pyrexia (n = 3). There were no treatment interruptions due to adverse events. No dose limiting toxicities were observed and there has been no evidence of cardiotoxicity or immunogenicity to date. PK data indicate dose proportionality at the dose-levels explored and supports weekly dosing. Conclusions: MM-111 is well tolerated at the doses levels studied and the PK profile suggests that weekly dosing is feasible. Enrollment to phase II is anticipated to commence shortly. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-15.

The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer.A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory E (max) model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit.The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.

Purpose Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Patients and Methods Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Results Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. Conclusion At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.

2546Background: XMT-1522 is comprised of 10-15 molecules of the payload AF-HPA, an auristatin-derivative with two-step intra-tumor metabolism intended to optimize therapeutic index, conjugated to a...

To assess the feasibility of administering troxacitabine, an L-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity.Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin.Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m(2), respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months.The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m(2), every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.

Purpose This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma. Patients and Methods This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naïve patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m2 for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS). Results Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile. Conclusion Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population.

The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can be modified, rendering them constitutively active. Because the MAPK pathway is dysregulated in a notable proportion of human malignancies, many of its aberrant and critical components represent strategic targets for therapeutic development against cancer. Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling upstream of the protein (eg, growth factor receptors and mutant Ras) and activating mutations of the protein itself, both of which confer a proliferative advantage. Three isoforms of Raf have been identified, and therapeutics targeting Raf, including small-molecule inhibitors and antisense oligodeoxyribonucleotides (ASON), are undergoing clinical evaluation. The outcomes of these investigations may have far-reaching implications in the management of many types of human cancer. This review outlines the structure and diverse functions of Raf, the rationale for targeting Raf as a therapeutic strategy against cancer, and the present status of various therapeutic approaches including ASONs and small molecules, particularly sorafenib (BAY 43-9006).

Significant advances in the field of molecular biology over the past decade have led to a new era in cancer therapeutics, with an explosion of rationally designed therapeutic strategies directed against selective molecular targets. The complex array of aberrant signal transduction proteins involved in carcinogenesis has been the focus of target-based anticancer agents. Inhibitors of intracellular signal transduction represent a unique approach in that they inhibit critical downstream regulatory proteins, which are vital to the process of cellular communication. Although these agents are in early-phase evaluations, the preliminary data suggest that they are well tolerated and capable of target inhibition in surrogate and tumor tissue. Although the primary therapeutic benefit of these agents is expected to be decreased tumor growth, evidence suggests that objective tumor responses may also be achieved. There are many unresolved questions pertaining to the development of this class of compounds, including selection of optimal dose and schedule, determination of relevant endpoints, methods for target validation, and strategies for combination with cytotoxic agents. However, despite the numerous unresolved issues, the emergence of this class of compounds has resulted in an undeniable impact on the present and future of cancer therapeutics.

4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.

1035 Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.

TPS215 Background: HER2 is expressed above normal levels by many cancers, including a range of gastrointestinal tumors. While HER2 can contribute to tumor growth and survival even when expressed at low levels, antibody-based HER2 targeted therapy has shown efficacy only in breast (trastuzumab [T], pertuzumab [P]) or gastric cancers (T) with the highest levels of HER2 expression or gene amplification. Therefore, there remains significant medical need, particularly for cancers with lower HER2 levels or more heterogeneous patterns of expression. ZW25 is a novel humanized bispecific antibody directed against two distinct epitopes of HER2. The unique structure of ZW25 leads to greater cell decoration and receptor internalization than T, even in the setting of low levels of HER2 expression. In preclinical models, ZW25 has demonstrated greater activity than T in both HER2 high and HER2 low-expressing cancers, including gastric cancer. This first-in-human study will evaluate the safety and preliminary anti-tumor activity of ZW25 in patients with advanced HER2-expressing cancers. Methods: This is a 2-part Phase 1 study utilizing 3+3 dose escalation (Part 1) and expansion cohorts (Part 2) to evaluate the MTD, safety, PK, and anti-tumor activity of ZW25 IV once per week in patients with locally advanced, unresectable and/or metastatic HER2-expressing cancers. Eligibility requirements include any HER2 1+, 2+, or 3+ cancer (Part1) or 2+/FISH negative breast or gastric cancer (Part 2) that has progressed after all approved therapies; ECOG PS ≤ 1; normal left ventricular function; and measurable disease per RECIST 1.1 (Part 2). Assessments include collection of adverse events and laboratory abnormalities, tumor response per RECIST 1.1 and exploratory response biomarkers as well as PET. Recruitment is ongoing at 3 centers in the United States. Clinical trial information: NCT02892123.

MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined.Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m(2) (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A.Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed.The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.

The estrogen receptor (ER or ESR1) drives proliferation and growth of luminal type breast cancers. Endocrine therapies are highly effective in a majority of these cancers types; however, disease progression eventually occurs due to acquired resistance resulting in hormone-independent breast cancer. One mechanism of resistance is acquired mutations at codons 537 and 538 in the ligand binding domain of the receptor which are found in ∼12% of pretreated, ER+ patients. These mutations result in constitutive ER activation and hormone-independent progressive disease. Although ESR1 mutated breast cancers are insensitive to endocrine therapy, novel agents targeting these mutations may be effective; however few preclinical models of ESR1-mutant breast cancer are available for preclinical analysis. To this end we have established two patient derived xenograft (PDX) models harboring mutations at codon 537; ST941 with ESR1Y537S and ST1799 with ESR1Y537C. We have characterized these models using genomic analysis and compared with analysis from paired or serially collected clinical tissue and blood. Dependence on estradiol for model growth and sensitivity to endocrine therapies were also evaluated and compared with a hormone-dependent breast cancer models. The ESR1 mutations were not present in primary clinical tissue while several additional mutations were identified including in TP53 and PIK3CA genes. In vivo the ESR1 mutant models grew in the presence or absence of exogenous estradiol and demonstrated reduced sensitivity to endocrine therapies compared with hormone-dependent breast cancer models. ST941 treated with tamoxifen, letrozole or fulvestrant reported moderate tumor growth inhibition versus control while tumor stasis or regressions were reported in MCF-7 and hormone-dependent PDX breast models. Overall we have established and characterized two models of ESR1 mutant breast cancer which can be utilized for development of targeted therapies. Citation Format: Wick MJ, Helman E, Meade J, Clark MJ, Vaught T, Tolcher AW, Rasco D, Patnaik A, Lang A, Beeram M, Papadopoulos KP. Establishment and characterization of ESR1-mutant breast cancer PDX models. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-04.

BACKGROUND: We conducted a phase 1, multicenter, open-label, dose-escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single-agent trastuzumab emtansine (T-DM1) administered weekly and once every 3 weeks in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here. METHODS: Patients were administered escalating doses of T-DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics. RESULTS: Twenty-eight patients received weekly T-DM1, and the MTD was determined to be 2.4 mg/kg. In general, T-DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade ≥3 AEs were reported in 19 patients (67.9%); treatment-related AEs occurred in 25 (89.3%) patients. Exposure to weekly T-DM1 was dose-proportional at ≥1.2 mg/kg, and accumulation of T-DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6-month clinical benefit rate was 57.1%. CONCLUSION: The results suggest that a weekly dose of T-DM1 2.4 mg/kg has antitumor activity and is well tolerated in patients with HER2-positive metastatic breast cancer. Cancer 2012. © 2012 American Cancer Society.

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways. Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program. Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%. Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.

Purpose: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. Experimental Design: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m2. Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m2 dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean Vss, 2,034 L/m2). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m2. The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

The taxanes are a versatile and important class of drugs that target microtubules. Paclitaxel and docetaxel are some of the most widely used cancer chemofherapeutic agents in clinical oncology. In this chapter, we discuss the most common dose and treatment schedules, clinical efficacy, and the toxicity profiles of these agents in detail.

Background Resistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance. Methods We have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies. Results High levels of Akt activity confer resistance to the aromatase inhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor α activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent. Conclusions Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry. Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m2. Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas. Conclusions: The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m2. The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.

Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability.Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1.Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation.Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.

Purpose: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies. Experimental Design: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation. Results: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m2; further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m2, which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses. Conclusions: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m2 every 3 weeks with vitamin supplementation.

Trametinib is a reversible, selective inhibitor of the MAPKs, MEK1, and MEK2. Trametinib cardiotoxicity is an infrequent, but potentially life-threatening, adverse event (AE); elevated blood pressure (BP), and decreased left ventricular ejection fraction and heart rate have been seen with trametinib. Prolongation of the QT interval due to delayed cardiac repolarization increases the risk of developing a potentially fatal cardiac arrhythmia. Risk of trametinib inducing QT prolongation at supratherapeutic exposure was evaluated. (ClinicalTrials.gov NCT01658553). In this 2-wk study, pts with histologically/cytologically confirmed solid tumors received placebo on Day 1, followed by once-daily trametinib 2mg doses on Days 2-14. On Day 15 all pts received a single 3mg trametinib dose. The regimen was expected to achieve supratherapeutic dosing for QTc measurement on Day 15. ECG was monitored by 12-lead ambulatory continuous 24-hr Holter monitoring pre-study, and on Days 1 and 15. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were also measured. 32/35 pts completed the study. There was no effect of trametinib compared to time-matched placebo on the change from baseline in QTcF (Table), QTcB or QTci. Mean AUC0-24 and Cmax following trametinib 2mg repeat doses were 364ng*hr/mL and 22.9ng/mL, respectively, consistent with those previously reported; the values for 3mg were 454ng*hr/mL and 29.2ng/mL. Median Tmax was approximately 2 hrs for both trametinib doses. There was no relationship between QTcF interval and trametinib plasma concentrations, as supported by statistical analysis and PK/PD modeling. Trametinib had no effect on ambulatory BP. 33/35 pts (94%) reported at least one AE; these were consistent with AEs previously reported. No ECG abnormalities were reported as AEs. This study showed no statistical difference between trametinib and placebo. Trametinib has no significant effect on QT prolongation at the supratherapeutic dose. Trametinib PK parameters were consistent with those previously reported. No new safety signals were seen. Results of Repeated Measures Statistical Analysis of QTcF Change from BaselinePlanned TimeLSmean (msec)Treatment difference (SE) [90% confidence intervals]PlaceboTrametinibTrametinib - Placebo1 hr post-dose2.461.88-0.58 (2.666) [-5.05, 3.88]2 hrs post-dose0.902.651.75 (2.847) [-3.01, 6.51]3 hrs post-dose1.374.803.43 (3.061) [-1.70, 8.55]4 hrs post-dose-0.782.923.70 (2.828) [-1.03, 8.43]6 hrs post-dose-2.71-0.672.04 (2.874) [-2.77, 6.84]8 hrs post-dose-7.47-6.041.44 (2.367) [-2.52, 5.39]10 hrs post-dose-8.66-3.145.53 (2.468) [1.40, 9.65]24 hrs post-dose-2.15-2.83-0.68 (2.704) [-5.20, 3.84]hr(s), hour(s); LS, least squares; msec, milliseconds; SE, standard error Citation Format: Drew Rasco, Amita Patnaik, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Glenda Chambers, Theresa L. Werner, John W. Bauman, Anita Scheuber, Donna Cox, YanYan Zhou, Mohammed Hamid, Daniel Schramek, Peggy Criscitiello, Sunil Sharma. Phase I, placebo-controlled, patient (pt)-blinded study to evaluate the effect of repeat oral dosing of the MEK inhibitor trametinib on cardiac repolarization in pts with solid tumors. [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 CT307. doi:10.1158/1538-7445.AM2015-CT307

522 Background: Abemaciclib, an inhibitor of cyclin dependent kinases CDK4 and CDK6, demonstrated safety and clinical activity as a single agent for hormone receptor positive (HR+) metastatic breas...

647 Background: MM-151 is an oligoclonal anti-EGFR antibody combination designed to provide enhanced targeting of the EGFR network. This work describes the first in human experience of MM-151 alone and in combination with irinotecan. Methods: A standard 3+3 design was used to assess safety and tolerability of MM-151 monotherapy (QW, Q2W, Q3W) and MM-151 (QW) in combination with irinotecan 180mg/m2 (Q2W). A monotherapy expansion cohort has begun in cetuximab-resistant CRC. Results: Results presented are based on preliminary data as of September 2, 2014, for MM-151 monotherapy (n=65; QW/Q2W) and MM-151 in combination with irinotecan (n=10). The most common tumor types were CRC (29 [39%]), NSCLC (9 [12%]), HNSCC (8 [11%]). The monotherapy RP2D has been defined as 10.5 mg/kg QW and dosing continues at 18 mg/kg Q2W. Most adverse events were CTCAE grades 1 and 2. The most common AEs were toxicities related to the EGFR-pathway, including rash (70%), hypomagnesemia (24%), fatigue, dry skin, and diarrhea (21%). IRR was initially observed at high frequencies; however, standardized pre-medication and a modified infusion schedule significantly decreased this frequency. At doses >9 mg/kg QW, trough total antibody levels at steady state were in the expected therapeutic range. Of the CRC patients enrolled, 3 experienced Partial Responses (PRs) per RECIST criteria and a total of 8 (31%) pts had SD for >4 months. Initial biomarker data suggests particular clinical activity in triple-wildtype, EGFR-ligand positive CRC patients. Combination therapy with irinotecan continues with MM-151 at 9 mg/kg QW and 3 PRs have been observed (CRC, HNSCC, melanoma). Initial safety data is consistent with known toxicities of MM-151 and irinotecan. Preliminary results from the monotherapy expansion cohort (10.5 mg/kg QW) in CTX-refractory CRC will also be presented. Conclusions: These results demonstrate that MM-151 monotherapy has an acceptable tolerability profile and objective clinical activity alone and in combination with irinotecan. Results also support further clinical evaluation in triple-wildtype, EGFR-ligand positive CRC and other EGFR dependent cancers. Clinical trial information: NCT01520389.

Purpose: To assess the feasibility of administering erlotinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, in combination with paclitaxel and carboplatin, and to identify pharmacokinetic interactions, evaluate downstream effects of EGFR inhibition on surrogate tissues, and seek preliminary evidence for clinical activity. Experimental Design: Patients with advanced solid malignancies were treated continuously with erlotinib at doses of 100, 125, and 150 mg/d orally along with fixed i.v. doses of paclitaxel 225 mg/m2 and carboplatin AUC 6 mg·min/mL, both on day 1 every 3 weeks. Results: Twenty evaluable patients were treated with 136 courses of erlotinib, paclitaxel, and carboplatin. Myelosuppression, skin rash, and diarrhea were the principal toxicities. Dose limiting diarrhea occurred in 1 of 6 patients at the 100 mg erlotinib dose level, whereas 0 of 9 evaluable patients at the 125 mg erlotinib dose level experienced dose limiting toxicity and 3 of 5 evaluable patients at 150 mg erlotinib experienced dose limiting skin rash and neutropenic sepsis. There was no evidence of pharmacokinetic interactions between paclitaxel and erlotinib; however, total carboplatin exposure trended higher in the presence of erlotinib. No consistent downstream effects on EGFR inhibition were found in skin. Durable objective responses were observed in non–small-cell lung and head and neck cancers. Conclusions: A dose level of erlotinib 125 mg combined with paclitaxel 225 mg/m2 and carboplatin AUC 6 mg·min/mL is recommended for disease-directed studies. This phase I trial was followed by a randomized phase III study in non–small-cell lung cancer using a similar regimen.

Purpose: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination. Patients and methods: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib. Results: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug–drug interactions. Maximum semaximib plasma concentration values were 1.2–3.8 μg/ml in course 1 and 1.1–3.9 μg/ml in course 2. The mean terminal half-life was 1.3 ( ± 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months. Conclusion: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

The mitogen activated protein kinase (MAPK) or Ras/Raf/MAPK kinase (MEK)/ERK signaling cascade is a ubiquitously expressed intracellular signaling pathway that transmits mitogenic stimuli to the nucleus through a series of sequential phosphorylation events and controls such cellular functions as proliferation, differentiation, and apoptosis. Components of this pathway such as ras and raf are oncogenes and as such aberrancy in their encoded proteins results in malignant transformation. The MAPK pathway is dysregulated in approximately 30% of all human tumors and therefore targeting specific components of this pathway that regulate pleiotropic cellular processes using such strategies as isoprenylation inhibitors, antisense oligodeoxyribonucleotides, and inhibitors of the kinase function represent attractive therapeutic options. raf kinase, a downstream effector of ras, has been known to be functionally aberrant in various human tumors. The 3 isoforms of raf have been studied extensively, and agents targeting c-raf are presently undergoing early-phase clinical testing. The outcomes of these trials have wide-ranging clinical implications in the management of cancers. This review addresses the rationale for targeting raf, the diverse cellular functions regulated by c-raf, and the current status of various pharmacological approaches targeting c-raf.

Significant advances in the field of molecular biology over the past decade have led to a new era in cancer therapeutics, with an explosion of rationally designed therapeutic strategies directed against selective molecular targets. The complex array of aberrant signal transduction proteins involved in carcinogenesis has been the focus of target-based anticancer agents. Inhibitors of intracellular signal transduction represent a unique approach in that they inhibit critical downstream regulatory proteins, which are vital to the process of cellular communication. Although these agents are in early-phase evaluations, the preliminary data suggest that they are well tolerated and capable of target inhibition in surrogate and tumor tissue. Although the primary therapeutic benefit of these agents is expected to be decreased tumor growth, evidence suggests that objective tumor responses may also be achieved. There are many unresolved questions pertaining to the development of this class of compounds, including selection of optimal dose and schedule, determination of relevant endpoints, methods for target validation, and strategies for combination with cytotoxic agents. However, despite the numerous unresolved issues, the emergence of this class of compounds has resulted in an undeniable impact on the present and future of cancer therapeutics.

LY2835219 is a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), which act in a protein complex with D-type cyclins to enable G1 to S cell cycle progression. Preclinical models indicate this complex plays a critical role in breast cancer. We conducted a phase I study with expansion cohorts to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types: glioblastoma; melanoma; and cancers of the lung, colon/rectum and breast. In the expansion cohorts, LY2835219 was administered continuously at 150-200mg orally every 12 hours on Days 1-28 of a 28-day cycle. RECIST v1.1 was used to assess tumor response. The most common possibly related treatment-emergent adverse events across the expansion cohorts (n=132) included diarrhea (5% G3/4), nausea (3% G3/4), fatigue (2% G3/4), vomiting (2% G3/4) and neutropenia (11% G3/4). In the metastatic breast cancer (MBC) cohort, 47 patients with a median of 7 prior systemic regimens received therapy with LY2835219. Across all MBC patients, 9 achieved a best overall response of confirmed partial response (PR), 24 achieved stable disease (SD), 11 had progressive disease (PD), and 3 were not evaluable for response. Among the 36 HR+ patients, there were 9 confirmed partial responses for an ORR of 25%. In addition, 20 of these 36 HR+ patients (56%) had SD: 7 patients had SD < 24 weeks and 13 patients (including 2 patients with unconfirmed PR) had SD ≥ 24 weeks. The disease control rate (DCR = CR + PR + SD) was 70% for all patients and 81% for HR+ patients. The median PFS was 5.8 months for all patients and 9.1 months for HR+ patients, with 18 HR+ patients (including the 2 unconfirmed PRs) still on LY2835219 therapy (range: 2.8-15.5 months). In conclusion, LY2835219 demonstrates evidence of durable single-agent activity for women with MBC after multiple prior systemic regimens for metastatic disease, particularly for those women with HR+ tumors, and merits further clinical investigation in MBC. Citation Format: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan W. Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Lily Li, Martin Frenzel, Damien M. Cronier, Edward M. Chan, Keith T. Flaherty, Patrick Y. Wen, Geoffrey I. Shapiro. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT232. doi:10.1158/1538-7445.AM2014-CT232

Aim: MM-151 is an oligoclonal combination of three IgG1, anti-EGFR antibodies designed to bind distinct non-overlapping EGFR epitopes and inhibit ligand-mediated signal amplification. MM-151's molecular composition enables antagonism of clinically relevant EGFR ligand mixtures, EGFR down-regulation and immune effector function (ADCC, CDC). A Phase 1 study was initiated to assess the safety, tolerability, PK, immunogenicity and preliminary clinical activity of MM-151. Methods: 69 patients were enrolled on 3 schedules (QW, Q2W, and Q3W) at escalating doses using standard 3 + 3 design. Response was assessed per RECIST criteria every 8 weeks. Patients continued on study until disease progression or unacceptable toxicity. Results: Results presented are based on preliminary data as of Apr. 25, 2014. 69 patients (median age 63 years; 33 male, 36 female) have been enrolled across 3 dosing schedules. 69 patients were evaluable for safety and 46 evaluable for efficacy. The most common tumor types were CRC (28 [41%]), NSCLC (9 [13%]), SCCHN (5 [7%]), and pancreatic (5 [7%]). An MTD has not been reached and dose escalation continues. Most adverse events were CTCAE grades 1 and 2. Infusion related reaction (IRR) was the most common AE (47 [68.1%]); however, this was managed with premedication and an optimized infusion schedule. The most common non-IRR AEs were comprised of EGFR-pathway toxicities, including rash (54 [78%]), hypomagnesemia (17 [25%]), mucositis (8 [12%]) and diarrhea (15 [22%]). Initial biomarker data in a subset of patients suggest that IRR relates to engagement of the innate immune system, shown in pre- and post - dose cytokine and peripheral blood flow cytometry data. Partial responses were observed in 2 CRC patients and a total of 8 (29% of mCRC) patients had SD for > 4 months (2 of the 8 had SD for 20.1 and 19.8 months). At doses > 9 mg/kg QW, trough total antibody levels at steady state were in expected therapeutic range. Conclusions: Results to date show that MM-151 has an acceptable safety profile and objective clinical activity in CRC. Updated safety, efficacy and preliminary biomarker data will be presented. Disclosure: C. Lieu: Consultant for Sanofi Aventis; L. Power, C. Sloss, J. Kearns, R. Nering, V. Moyo and B. Wolf: employee of Merrimack Pharmaceuticals, stock ownership. All other authors have declared no conflicts of interest.

8026 Background: LY2835219, a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), has shown antitumor activity in human NSCLC xenograft models. Importantly...

2518 Background: MM-151 is a novel oligoclonal anti-EGFR antibody combination designed to overcome key challenges of the EGFR network: ligand redundancy and signal amplification. Preclinical studie...

534 Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to enable cell proliferation. LY2835219, a small molecule inhibitor of CDK4/6, has shown antitumor activity in xeno...

2540 Background: Nesvacumab (N) is an Ang2 selective, human MAb that potently blocks signaling through the Tie2 receptor, inhibiting tumor angiogenesis and growth. In mouse xenograft models of huma...

e13509 Background: Targeted therapy of recurrent/metastatic ovarian and endometrial cancer remains of great interest but has not been established as standard of care. We analyzed a series of patien...

Introduction: Within the tumor microenvironment, CSF1R signaling is thought to play an important role in recruitment and differentiation of tumor-associated macrophages and osteoclasts, promoting disease progression through suppression of anti-tumor immune response, promotion of angiogenesis, tumor cell metastasis and tumor-induced osteolysis. ARRY-382 is a potent, highly selective, oral inhibitor of CSF1R. This Phase 1 dose-escalation study was designed to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ARRY-382 in patients (pts) with advanced or metastatic cancers refractory to standard treatment. Methods: Pts received ARRY-382 orally once daily (QD) in 28-day cycles. Study design included an initial accelerated titration phase, followed by 3+3 dose escalation and an expansion phase. Safety was assessed by adverse events (AEs), ECGs, clinical laboratory tests, physical exams and vital signs. PK parameters were estimated based on serial plasma PK samples. Levels of pERK in pt monocytes stimulated with CSF1 ex vivo, circulating CD14dim/CD16+ nonclassical monocytes (NCM) and CSF1 were evaluated as markers of CSF1R inhibition. Urinary collagen type 1 cross-linked N[[Unable to Display Character: ‑]]telopeptide (NTX) was evaluated as a marker of bone turnover. Results: Twenty-six pts received ARRY-382 at doses ranging from 25 to 500 mg QD. The MTD of ARRY-382 was 400 mg QD. Dose-limiting toxicities were increased creatine kinase (CK), increased AST and pyrexia (1 pt each, all Grade 3). The most common drug-related AEs were fatigue (42%), increased CK (27%), nausea (23%), decreased appetite (15%) and vomiting (12%). Grade 3/4 AEs in >1 pt were increased CK (23%), pneumonia (15%), anemia (8%) and vomiting (8%). Increases in ARRY-382 exposure were approximately dose proportional. At the MTD, a Cmax of 3.06 µg/mL was achieved with a Ctrough > 1 µg/mL after repeated dosing. Doses ≥ 200 mg QD resulted in > 80% mean reduction from Baseline in monocyte pERK, consistent with exposures above the ARRY-382 IC50 value. The PD activity of ARRY-382 was consistent with CSF1R inhibition. Reductions in NCM were observed at doses ≥ 200 mg QD, with a 96% mean decrease from Baseline observed at the MTD. Reductions in urinary NTX were observed at doses ≥ 50 mg QD. Five of 7 pts with elevated urinary NTX at Baseline experienced reductions to within the normal range in the first cycle, including 3 pts with bone metastases. Increases in CSF1 appeared dose-dependent with ∼28-fold maximal increase from Baseline observed at the MTD in the first cycle. No objective responses were observed, although 4 pts (15%) experienced stable disease which lasted > 3 months for 2 pts. Conclusions: ARRY-382 was generally well tolerated in pts with advanced or metastatic cancers. Exposure and PD activity of ARRY[[Unable to Display Character: ‑]]382 indicate that CSF1R was significantly inhibited at tolerated doses. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A252. Citation Format: Johanna C. Bendell, Anthony W. Tolcher, Suzanne F. Jones, Muralidhar Beeram, Jeffrey R. Infante, Paul Larsen, Kevin Rasor, Jennifer E. Garrus, Jinfang Li, P. Louann Cable, Christine Eberhardt, Jennifer Schreiber, Selena Rush, Kenneth W. Wood, Emma Barrett, Amita Patnaik. A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A252.

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.

e22088 Background: Selection of targeted therapeutics for solid tumors depends upon detection of actionable genomic alterations in archival tissue. High-throughput molecular profiling at the community level would allow local pathologists to participate with oncologists in the delivery of personalized cancer medicine. Methods: Between March and December 2012, molecular profiling was performed on FFPE tumor tissue sent to Oncopath (our in-house CAP/CLIA genomic pathology laboratory) from 330 patients with diverse types of metastatic and non-resectable solid tumors. Tumor-targeted DNA was analyzed for genome-wide copy number alterations by array-based comparative hybridization (CGH), and mutation analysis (MA) using multiplex PCR with mass spectrometric genotyping (mass spec), or single gene allele-specific PCR (PCR). Results for 96 actionable genes analyzed by CGH, and MA were correlated with clinically or pre-clinically available targeted therapeutics. Actionable biomarkers for FDA approved therapies (e.g. BRAF V600E/vemurafenib) and prospective biomarkers for Phase I/II trials (e.g. CCND1 gene amplifications and CDKN2A gene deletions/CDK inhibitors) were reported for each patient. Results: Of 330 cases, 216 had at least one and as high as seven actionable biomarkers. The remaining 114 cases had either no tumor specific changes (n=17) or non-actionable oncogenic changes (n=97). The most commonly analyzed tumors were breast, brain, lung, colorectal, pancreatic, head & neck, and ovarian. Rare tumor types with positive biomarkers included an HRAS Q61R positive adenoid cystic carcinoma and a BRAF V600E positive pleomorphic xanthroastrocyoma. Tumor DNA was stored for 100% of patients and all cases were reported synoptically listing actionable biomarkers with therapeutic recommendations. Conclusions: Molecular profiling in a community cancer center facilitates biomarker detection for rational direction of patients to targeted therapeutics. New technologies for detection of actionable biomarkers will continue to be implemented in our center to improve the likelihood of effective treatment for each individual patient’s tumor.

MDM2 is overproduced as a mechanism to impair p53 function in many cancers. By reactivating p53, antagonists of p53-MDM2 interaction could offer a novel approach to treatment of solid tumors and leukemias. RG7112, the first potent and selective small-molecule MDM2 antagonist in clinical testing, is an oral p53 activator and is currently in phase I. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multi-center trial in patients (pts) with advanced solid tumors. In Part I, the impact of high-energy/high-fat meal and formulation (crystalline versus amorphous) was examined in cross-over design. In Part II, schedule optimization (4 schedules of drug adm under fasting condition and 1 cohort with liquid supplementation) was investigated in parallel, dose escalation design. Clinical endpoints were PK/PD and safety/tolerability including platelet reduction (a potential target-mediated hematological toxicity indicator). A total of 76 pts (42F and 34M, mean age 60 yr) participated in the study. In their first-cycle treatment, 36 pts received weekly x3 (26 with food/formulation evaluation), 15 pts daily x5, 6 pts daily x20, and 19 pts daily x3 (3 with food evaluation) doses; daily doses ranged from 500-4500 mg. The most commonly reported AEs (> 20%) were GI-related. Twelve pts have reported 21 SAEs, of which, 4 events in 2 pts (1 pt with G4 thrombocytopenia, anemia, and neutropenia; 1 pt with G3 delirium) were related to study treatment. A high-energy (∼1000 kcal)/high-fat (∼60 g) meal and a reduced energy (∼500 kcal)/fat (∼30 g) liquid supplementation both enhanced overall bioavailability (BA) of tested formulations by 2-fold, with inter-pt variability reduced by half. At steady-state, amorphous formulation also reduced PK variability by half from the crystalline formulation. High-dose consecutive daily dosing for 5 and 3 d yielded highest drug concentrations on the last day of treatment. On the other hand, both weekly and low-dose/long-duration (20-day) schedules yielded lower peak concentrations (note that the per-cycle exposure was comparable to, or higher than, high-dose 5x and 3x daily schedules). Serum profiles of MIC-1, a secreted protein that is strongly induced by activated p53, showed similar patterns to the PK when the clinical pharmacology conditions were varied. The first-cycle platelet profiles indicate that the weekly schedule didn't cause platelet reduction, while the daily schedules showed a trend of dose- and length-dependent platelet reduction with daily x 5 at high doses being the most pronounced (1 pt resulted in G-4 thrombocytopenia). In conclusion, RG7112 is well tolerated with or without food in the therapeutically relevant dose range, food enhanced BA with reduced variability, and high-dose consecutive daily for 3-5 d is superior in yielding sufficiently high PK exposure and PD effects potentially required for cancer treatment efficacy. Citation Format: Amita Patnaik, Anthony Tolcher, Muralidhar Beeram, John Nemunaitis, Glen Weiss, Gwen Nichols, Steven Middleton, Nenad Sarapa, Anna Beryozkina, Jianguo Zhi. Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2013-LB-201