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Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity.Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response.Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

Figure S1. Top: mRNA differential expression of individual proliferation genes (AURKA, CCNB1, MKI67, and MYBL2) and cancer invasion genes (CTSL2 and MMP11) and the bladder cancer marker, UPK3A, in biopsy samples (from patients with bladder cancer at pretreatment and after treatment at 5 mg/kg and 15 mg/kg. Bottom: Composite differential expression score from pretreatment and post-treatment tissues of proliferation, invasion, and bladder cancer markers in cohorts 5 mg/kg and 15 mg/kg.

Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less-than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF-targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. Cancer Res; 72(1); 3–12. ©2012 AACR.

In November, 2008 the AACR held the Seventh Annual Frontiers in Cancer Prevention Research meeting in Washington, DC. At this meeting, a wide range of cutting-edge cancer prevention research was presented. This summary highlights some of the most impactful presentations with a focus on the interaction between inflammation, infections, the immune system, and tumor microenvironment in promoting cancer. Several of these presentations described targeting host-tumor interactions as a means for cancer prevention. As discussed below, this meeting continues to represent all phases of cancer prevention research including epidemiologic studies, behavioral and lifestyle interventions, carcinogenesis research, preclinical studies testing novel preventive interventions, and the results of early- and late-phase cancer prevention trials. Major advances presented at the 2008 meeting included studies showing that immune cells can be either protumorigenic or antitumorigenic, efforts to develop more comprehensive human papillomavirus vaccines to more effectively prevent cervical cancer and other human papillomavirus–related cancers, controversial studies of vitamin D and cancer risk, and studies of single-nucleotide polymorphisms to better assess cancer risk. These and the other presentations at this meeting continue to provide strong support for the concept that cancer will be most effectively controlled by applying modern cancer prevention strategies

Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

TPS2621 Background: MEDI3617 is an investigational monoclonal antibody that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an ongoing phase 1 dose-escalation and dose-expansion study in patients with advanced solid tumors, Karnofsky performance status ≥70, and adequate organ function. Patients were treated with escalating IV doses of MEDI3617 on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are to evaluate the safety profile and determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and clinical activity of MEDI3617. Results: Preliminary data are presented for 21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT occurred: grade 4 neutropenia lasting more than 7 days. The most frequently reported drug-related adverse events (% of patients) were fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and headache (14%), all of which were ≤ grade 2. All monotherapy dose levels have completely enrolled patients without exceeding the maximum tolerated dose. The exposure of MEDI3617 after the first dose showed a more than dose-proportional increase. Suppression of free Ang2 was dose-dependent. Maximum accumulation of total Ang2 was observed at the lowest administered dose. No anti-MEDI3617 neutralizing antibodies were detected. Of the 21 patients, 4 continue on treatment (maximum of 6+ months in a patient with carcinoid tumor of the jejunum) as of the data cut-off date. Of the 17 patients for whom response data are available, 5 had stabilization of disease of 12 weeks or greater. Conclusions: Preliminary safety and activity signals warrant continued evaluation of MEDI3617. This study was funded by MedImmune, LLC.

TPS2618 Background: MEDI-573 is an investigational dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF‑1R and insulin receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid receptors, MEDI-573 may achieve antitumor activity without perturbing glucose homeostasis. Objectives of this phase 1 dose-escalation and expansion study are to evaluate safety and determine the maximum tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI-573 in adult patients with solid tumors. Methods: Patients with advanced solid tumors, Karnofsky status ≥60, and adequate organ function were treated with escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 weeks (30 or 45 mg/kg q3w) using a 3+3 design. Three patients per dose level were evaluated for safety. A biomarker-rich dose-expansion arm tested weekly 5 or 15 mg/kg MEDI‑573 in patients with advanced bladder cancer. Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in ≥10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were ≤ grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45 mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF‑I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI‑573 were detected. Of 43 patients, 8 (19%) had stable disease ≥12 weeks. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development.

e18073 Background: There is increasing interest in assessing progression-free survival (PFS) as a potential surrogate for overall survival (OS) in many tumor types. However, such an assessment has yet to be adequately performed for non-small cell lung cancer (NSCLC). We assessed the relationship between 1st line treatment effects on PFS or OS in advanced NSCLC utilizing published data from clinical trials. Methods: The estimated PFS hazard ratio (HR) and OS HR from 43 randomized trials published between 2000 and 2010 were used to estimate Pearson correlation coefficient and to model the linear relationship between PFS HR and OS HR. Three approaches were considered in fitting the linear model, reflecting different ways of handling the variability of HR estimates used in the model fitting. The analysis was performed on add-on trials and head-to-head trials separately as well as jointly. Results: For add-on trials, the Pearson correlation coefficient r was 0.831 based on the observed HR data weighted by trial size. The R2 was 0.791 for the linear model after Bayesian adjustment of variability in the observed HR data. All showed strong relationship between PFS HR and OS HR for add-on therapies. The relationship is weak for head-to-head therapy (r=0.288 and R2=0.202). The overall relationship, when jointly considering add-on and head-to-head therapies, is moderate (r=0.653 and R2=0.577). Conclusions: Our analysis supports the use of PFS as a reasonable surrogate for OS if an add-on therapy is developed, but not if a head-to-head therapy is developed as 1st line treatment of advanced NSCLC.

271 Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis. Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers. Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer. Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.