7527 Background: R1507 (Hoffman LaRoche) is a selective, fully human, recombinant monoclonal antibody (IgG1 subclass) against IGF-1R. Based on strong pre-clinical evidence supporting co-inhibition of IGF-1R and epidermal growth factor receptors, we conducted a randomized study of R1507 with erlotinib (E). Methods: Advanced NSCLC patients with progression following 1 or 2 prior chemotherapy regimens, ECOG PS 0-2, and measurable disease were eligible. Patients were randomized to receive erlotinib (150 mg PO QD) in combination with either placebo, R1507 at 9mg/kg/week or R1507 at 16 mg/kg/Q 3 weeks, i.v. Treatment cycles were repeated every 3 weeks. The primary endpoint was comparison of the 12-weeks PFS rate. Results: 171 patients were enrolled, with the following characteristics: median age 61 years, female 33%, never-smokers 12%, stage IV 86%, PS 0/1- 88%, squamous histology 25%, adenocarcinoma 51%, and 1 prior regimen 74%. The median number of doses of R1507 was 6 and 3.5 for the weekly and Q3 week arms respectively. Grade 3/4 adverse events were noted in 37%, 44%, and 48% of patients with placebo, weekly, and Q3 week R1507 therapy respectively. The following biomarkers were evaluated in tissue specimens (n=165): Tumor tissue - expression of IGF-1R, and K-ras mutation status; Plasma-free IGF-1 level. In patients with high free IGF-1 levels, the 12-weeks PFS rate was higher with Q3 week schedule of R1507 compared to placebo (46% vs. 18%). The 12-weeks PFS rate in patients with K-ras mutation was 22% with R1507 compared to 0 with placebo. Conclusions: R1507 failed to improve the efficacy of erlotinib in an unselected group of advanced NSCLC patients in the 2nd/3rd line therapy setting. K-ras status and free IGF-1 bioactivity in serum demonstrated predictive potential in an exploratory analysis. Parameter E + Placebo E + R1507 (weekly) E + R1507 (Q 3 wks) N 57 pts 57 pts 57 pts Response rate 8.8% 8.8% 7% 12-weeks PFS rate 39% 37% 44% (NS) Median PFS 1.5 m 1.6 m 2.7 m (P=NS) Median OS 8.1 m 8.1 m 12.1 m (P=0.04) Gr 3/4 skin rash 8% 7% 10% Gr 3/4 fatigue 6% 10% 7% Hyperglycemia (any) 0 3% 9%
Blood on the Tracks was recorded in the month and year in which I was born, September 1974. I mention this for the sake of full disclosure - namely, I don't know what life was like without it. I wasn't in high school or college that year, experiencing my own heartbreak; I didn't rush out to buy the vinyl when it was released in 1975, nor have any expectations at all about Bob Dylan. If anything, I was learning to crawl or maybe getting pieces of bark pulled out of my mouth by my mother. Like the album, I was brand new and open to interpretation. My parents were probably listening to Emerson, Lake, and Palmer, Dan Fogelberg, or if I was lucky, Joni Mitchell. For myself, part of the challenge of listening to Blood on the Tracks is to determine what it means to live concomitant to it. Since I have always lived in a world where the album existed, I have had to figure out ways of appreciating it apart from the noise that has surrounded it since its release. Blood on the Tracks created an emotional dialogue as well as an emotional landscape around music. Whether Dylan intended it or not - and he likely didn't - it became a love album, a salve, for his fans to sing not only to themselves but also back at him; it emboldened fans with a vocabulary. The album expounds on the complexities of love, but it also embodies the contradictory feelings the fans had about Dylan, music, the times they live(d) in, and themselves. Blood on the Tracks is Dylan's civil war; from his secession from the union, to bloody battles, and an eventual but tepid reconciliation, Blood on the Tracks leaves both the artist and the listener scarred. It can be listened to as a series of individual battles, discovered one piece at a time, or one can step back and let the mess of it be revealed as a whole.
It has become increasingly evident that the generation of cell surface proteases including plasmin is fundamental to a wide variety of in vivo biological processes. Cell surface receptors allow for specific controlled proteolysis, provide protection from inhibitors, and enhance catalytic efficiency. Here we describe one such receptor, annexin II, which serves as a coreceptor for tissue plasminogen activator and plasminogen and is found on a wide variety of cell types including endothelial cells, some tumor cells, monocytes and macrophages, and neuronal cells. Evidence indicates that annexin II may be crucial to the efficient generation of cell surface plasmin, endothelial cell formation of new blood vessels, and maintenance of vascular patency. Additionally, it has been shown that annexin II expression in acute promyelocytic leukemia contributes to the bleeding diathesis seen in this disease and that inhibition of annexin II may be an important mechanism in the formation of atherosclerotic plaque. Furthermore, emerging evidence reveals the importance of annexin II on the surface of monocytes and macrophages, where it may contribute to the cells' ability to degrade extracellular matrix proteins and migrate to sites of injury or inflammation.
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 human solid tumors, N inhibits tumor growth. In the dose-escalation (DE) portion of this trial [JCO 31, 2013 (suppl; abstr 2517)] anti-tumor activity (significant decline AFP) was observed in a patient (pt) with HCC, prompting expansion in this indication. Methods: Safety and anti-tumor activity are reported from all pts with HCC treated in the FIH trial in DE and expansion phases combined. In DE, single agent N was administered IV Q2W at 1 of 5 dose levels starting at 1 mg/kg; HCC expansion at 2 doses, 12, and 20 mg/kg Q2W, were studied. Results: 15 pts with HCC were enrolled: [11M/4F; median age 69 (range 24-82); ECOG PS 0=6/1=9; prior sorafenib 60%]. Dose levels were: 1 (n=1), 12 (n=6) and 20 mg/kg (n=8). Median number of doses administered was 8 (range 1-23). No pts experienced protocol defined DLTs. Most common adverse events (AEs) (all/related) were fatigue (8/5), diarrhea (5/0), decreased appetite (4/2), dizziness (4/0), nausea (4/2), abdominal pain (3/1), vomiting (3/1), back pain (3/0) and dyspnea (3/0); 9 grade ≥3 events reported in 7 pts, of which 3 events were assessed as treatment related: abdominal pain, infusion-related reaction, and retinal detachment, each reported in a single pt. One pt treated with 20 mg/kg experienced a non-severe lower GI bleed, assessed as not treatment related. No objective responses were observed. Two pts experienced a ≥ 50% decline in AFP (1 pt >90%). Nine of 15 pts achieved best response of SD (median duration 24 wks); 6 pts achieved SD for ≥ 20 wks. Notably, 5 of 8 pts treated at 20 mg/kg achieved best response of SD; median duration of 40 wks. Conclusions: Single-agent N up to 20mg/kg Q2W was generally tolerated in pts with HCC, with primarily mild and moderate AEs, independent of dose. SD occurred in 60% of pts across doses, with prolonged SD at highest dose. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Expansion in pts with HCC receiving N in addition to sorafenib is ongoing. Clinical trial information: NCT01271972.
2502 Background: Dll4, a Notch receptor ligand, may have a role in tumor angiogenesis and is an emerging anticancer target. REGN421 (R) is a fully human IgG 1 mAb that binds human Dll4 and disrupts Notch-mediated signaling. Methods: Primary objectives of the dose escalation (3+3 design) trial were to determine safety and a recommended phase II dose (RP2D) of R in patients (pts) with advanced cancer. R was given IV at doses of 0.25, 0.5, 1, 2 and 4mg/kg every 3 weeks (Q3W) or 0.75, 1, 1.5, and 3mg/kg every 2 weeks (Q2W). Secondary objectives were PK, immunogenicity, and antitumor activity. Results: 53 pts (M/F=22/31, ECOG 0/1=18/35) were enrolled; 31 pts were treated Q3W at doses of 0.25 - 4 mg/kg; 22 pts were treated Q2W at doses of 0.75 - 3 mg/kg. Two DLTs occurred: Grade 3 (Gr3) nausea (0.5mg/kg Q3W) and Gr3 abdominal pain (1 mg/kg Q2W). A maximum tolerated dose was not reached on either schedule. Grade 3/4 AEs occurred in 29 pts; nausea, abdominal pain, dyspnea, hypoxia, and hypertension (HTN) were reported in ≥ 5%. Most frequent treatment related AEs were fatigue (30%), headache (26%), HTN (26%), and nausea (15%). Six treatment related SAEs (all reversed off treatment) were reported in 4 patients: BNP increase (0.25mg/kg, Gr1), troponin I increase (4mg/kg, Gr3), right ventricular dysfunction (1.5mg/kg, Gr3), left ventricular dysfunction (3mg/kg, Gr3) and 2 events of pulmonary HTN (1.5mg/kg, Gr 3, and 3mg/kg Gr3). Laboratory abnormalities (≥ Gr3) were neutropenia (3) and anemia (2), and elevated ALP (7), ALT (3), bilirubin (3), AST (2), and decreased albumin (1). Anti-tumor activity included 2 PRs (NSCLC BAL-type with a beta-catenin mutation and ovarian cancer [OvCa]), and 16 pts with SD (3 pts had SD > 6 months). Two of 8 pts with OvCa had CA125 responses. R had non-linear target-mediated PK without accumulation. The half-life of R at 3mg/kg Q2W was 7 days. No immunogenicity was observed. Conclusions: REGN421 had an acceptable safety profile, and RP2Ds of 4mg/kg Q3W and 3mg/kg Q2W. Responses and prolonged SD were noted in OvCa pts and other solid tumors. Dose escalation has concluded and disease specific expansion cohorts are ongoing. Clinical trial information: NCT00871559.
7584 Background: R1507 is a monoclonal antibody which specifically inhibits IGF-IR. NO21160 was a randomized, placebo controlled phase II trial of two doses and schedules of R1507 + erlotinib as second/third-line therapy for advanced non-small cell lung cancer. The primary endpoint, comparison of PFS rate at 12 weeks, was not met (HR=0.99 for 16 mg q3W and 1.17 for 9 mg qW) in an unselected patient population. A panel of biomarkers were analyzed in an attempt to identify potential predictive markers and define a subset of the patients who may be more likely to benefit from the investigational drug. Methods: Candidate biomarkers of potential prognostic or predictive significance such as IGF-1R, free IGF1, total IGF, IGFBP-3, pAKT, PTEN, EGFR and Kras, were analyzed in archival tumor tissues collected at diagnosis and in the blood samples collected at the baseline by IHC, ELISA, qRE-PCR and mutation analysis, as appropriate. Correlation between PFS rate at 12 weeks and marker values were investigated. Results: The median IGF1R membrane H–score was 64 (range 0-300). A significantly higher PFS rate was observed in the high (>median) free IGF-1 level patients between the 16 mg/kg regimen and placebo (46% vs. 18%. HR=3.94, CI 95% 1.2-13.6). Somatic mutations of Kras gene, analyzed in 127 available tumor DNA samples, were detected in 6 (15%), 16 (36%) and 11 (26%) patients in placebo, 9 mg/kg and 16 mg/kg arms, respectively. 12.5% and 36.4% of patients with the Kras mutations in the R1507 arms, in comparison with 0% of the 6 Kras mutant patients in the placebo arm, was progression free by week 12. Within either R1507 treatment arm, however, Kras mutant and wild-type patients showed a similar PFS rate (OR=0.88). No significant impact on the treatment was observed when the PFS rates of patient subgroups defined by other biomarkers, including IGF1R level, were compared within each treatment arm and between placebo and treatment arms. Conclusions: Higher free serum IGF-1 level appears to correlate with a higher PFS rate at 12 weeks with 16 mg/kg dose of R1507. Patients with mutant Kras may be more likely to benefit from R1507+ elotinib than elotinib alone.
<p>Supplementary Figure 1 Total Nesvacumab (REGN910) and Total Ang2 vs Time (cycle 1) following IV infusion in Patients. Supplementary Figure 2 Serum levels of ESM1, SDF-1, PLGF-1 and sVCAM-1 following Nesvacumab (REGN910) treatment. Supplementary Figure 3 Correlative analysis of baseline serum Ang2, ESM-1, SDF-1 ,PIGF and cVCAM-1 and treatment duration. Supplementary Figure 4 Correlative analysis of baseline Ang2 in tumor vessels and treatment duration/response. Supplementary Figure 5 Ang2 and VEGF-A protein levels in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 6 Biomarker analysis of archival tumor tissue. Supplementary Figure 7 Microvascular density in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 8 Tumor cell proliferation in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 9 TIE-2 protein levels associated with tumor vessels pre and post treatment with Nesvacumab (REGN910)</p>
