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Recent clinical trial results suggest that anti-angiogenic therapy may be effective against recurrent malignant glioma. Though these treatments prolong progression-free survival, the extent to which they prolong overall survival is unknown. We pooled data from 34 patients treated at a single institution on phase II clinical trials of bevacizumab and cediranib, and we compared these data to 18 patients treated on clinical trials of cytotoxic chemotherapies. In univariate and multivariate analyses, treatment group was a significant predictor of progression-free but not overall survival. Median progression-free survival was 8 vs. 22 weeks in patients treated with cytotoxic as compared to anti-angiogenic therapy (P = 0.01). Median overall survival was nearly identical in the two groups (39 vs. 37 weeks). The results of this exploratory analysis suggest that anti-angiogenic therapy may fail to prolong overall survival in patients with recurrent malignant glioma. If this conclusion proves correct, progression-free survival may be an inappropriate endpoint for phase II trials of anti-angiogenic therapies.

3075 Background: AGEN1884 is a fully human IgG1 monoclonal antibody targeting the co-inhibitory protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade has been shown to augment T cell activation and proliferation, resulting in immune infiltration of the tumor and subsequent regression. Objectives: Assess the safety, maximum tolerated dose (MTD), and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN1884 in patients (pts) with advanced and refractory malignancies using a “3+3” trial design. Methods: Eleven pts have been enrolled and treated to date. AGEN1884 was administered intravenously q3w for 4 doses and then q12w. Three (0.1, 0.3 and 1 mg/kg) of six (3, 6 and 10 mg/kg) planned dose levels have been completed. Results: Five pts were accrued at 0.1 mg/kg dose level (2 were not DLT evaluable) and three pts each at doses of 0.3 mg/kg and 1 mg/kg. Median age was 56 years (range 26–70), ECOG 0–2, with a median of 4 (range 1–8) prior therapies. No DLT events have been observed thus far. Data from 5 pts were available for PK evaluation. Half-life of AGEN1884 post first dose was 8.8 and 9.6 days for 0.3 mg/kg and 0.1 mg/kg dose levels, respectively, as measured by ELISA. As of Jan 31, 2017, pts across cohorts were followed for a median of 6 weeks (range 0-28). Six pts (54.5%) have come off study due to disease progression, while 5 (45.5 %) remain on study. One confirmed partial response (80% reduction) by RECIST criteria was seen at 0.1 mg/kg in a patient with angiosarcoma. Conclusions: AGEN1884 is safe at 0.1 and 0.3 mg/kg dose levels. Dose escalation is ongoing and updated safety and PK data will be presented. Clinical trial information: NCT02694822.

Adenosine A2A receptor (A2AR) agonists reduce invariant natural killer T (iNKT) cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A2AR agonist regadenoson in adults with SCD. The target dose was 1.44 μg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-κB (phospho-NF-κB p65), interferon-γ (IFN-γ), and A2AR. Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-κB p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-γ expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-κB p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P = .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 μg/kg/h during pVOC decreases activation of iNKT cells without toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01085201.

A humanized murine sickle cell–disease (SCD) model (NY1DD) has been used to study ischemia/reperfusion injury (IRI) in sickle cell anemia, and iNKT cells (a very small subset of murine and human T cells) have been found to instigate such injury in this model. Furthermore, levels of activated iNKT cells are generally elevated in the circulation of patients with SCD. Because activated iNKT cells are rich in adenosine A2A receptors which, when agonized, down-regulate the inflammatory cytokine expression that characterizes the cells, we have conducted a phase 1 trial of a constant infusion of low-dose regadenoson (an adenosine analogue with high A2A receptor specificity) to determine its safety and the capacity of a safe dose to down-regulate circulating iNKT cells in patients with SCD. We have found two dose rates that are both safe and effective and now plan a controlled Phase 2B clinical trial to determine whether our highest dose, administered as a 48-hour constant infusion, will induce faster remission in both painful vaso-occlusive crisis (pVOC) and acute chest syndrome (ACS).

Oral iron replacement is the standard therapy in iron-deficiency anemia (IDA). However, 59% of patients have gastrointestinal toxicity. With impaired iron uptake from the gastrointestinal tract (in anemia of chronic disease (ACD) or after bariatric surgery), suboptimal responsiveness to exogenous erythropoietin (in chronic renal failure), in patients with cancer receiving chemotherapy, or when oral iron is poorly tolerated, IV iron therapy is the preferred mode of repletion. Although effective in increasing hemoglobin, the relative safety of the available IV iron preparations is not well documented. We examined the comparative safety of IV iron formulations used at hospitals associated with our institution. Among 619 unique patients who received IV iron over a 2-year period, we found 32 adverse events (AEs), ranging from urticaria to chest pain. There were no serious AEs or anaphylactic-type reactions. In a multivariate model, there was no difference in AE rates between low-molecular-weight iron dextran (LMWD) and ferric gluconate; however, iron sucrose had significantly higher odds ratio of AEs (OR = 5.7; 95% CI = 1.6–21.3). Our data suggest that AE rates with IV iron are acceptable. More widespread use of LMWD, in particular, which can be given safely as a total dose infusion (TDI), should be considered.

Abstract 849FN2 Adenosine 2A receptor (A2AR) agonists decrease pulmonary inflammation and injury in a murine model of sickle cell disease (SCD) by interrupting invariant NKT (iNKT) cell activation that occurs as a result of vaso-occlusion (Clin Immunol 2011). iNKT cells represent a subpopulation of T lymphocytes that rapidly generates pro-inflammatory cytokines upon activation and thereby may play a role in sustaining or propagating vaso-occlusion in human SCD. To evaluate the effects of A2AR activation in human SCD, we are conducting a dose-seeking and safety study of the FDA-approved, highly selective A2AR agonist regadenoson in patients with SCD ≥ 14 years of age. This is a multi-center, phase I clinical trial of infusional regadenoson that utilizes a 3+3 design and is comprised of four stages to determine maximum tolerated dose and safety during a 12 hour infusion in adults at baseline (defined as absence of increased pain, ED or hospital visit in the past 2 weeks) (stage 1), a 24 hour infusion in adults at baseline (stage 2), a 24 hour infusion in adults during a painful vaso-occlusive crisis (VOC) (stage 3), and a 24 hour infusion in children (≥ 14 years) during a painful VOC (stage 4). Three dose levels of infusional regadenoson have been evaluated thus far: 0.24 (level 0), 0.6 (level 1) and 1.44 mcg/kg/hour (level 2). Samples for plasma levels and iNKT cell activation are obtained at 0, 6, 12, 18 and 30 hours after start of infusion. Two methods are used to identify iNKT cells: 1) CD1d tetramers, loaded with the α-GalCer-like glycolipid PBS57 (defined as tetramer+CD3+), and 2) 6B11 antibody to the invariant T cell receptor (defined as CD45+6B11 high). NF-kB activation is measured using phospho-Ser536-p65 antibody (phospho-NF-kB). To date, 15 subjects have received infusional regadenoson. Regadenoson appears to be safe (devoid of cardiovascular or other side effects) and biologically active in reducing iNKT cell activation markers during a 12 hour infusion at dose levels 1 and 2, and we are currently evaluating the safety of a 24 hour infusion at dose level 2. No dose limiting toxicities occurred in the 15 subjects at dose levels 0, 1 or 2. Pharmacokinetic analyses showed mean peak plasma concentrations of regadenoson for dose levels 0, 1 and 2 were 0.37 ng/ml, 1.16 ng/ml and 2.19 ng/ml, respectively. Based on animal models, we suspect that biologically active plasma concentrations are approximately 1 ng/ml. At baseline, iNKT cells were activated in patients with SCD as defined by elevated levels of phospho-NF-kB expression and A2AR expression as assessed by anti-A2AR immunoreactivity. In particular, CD4+ iNKT cells showed increased phospho-NF-kB expression whereas CD4- iNKT cells were not activated. At dose levels 1 and 2, regadenoson decreased iNKT cell activation in patients with SCD. For example, when pre- and post-12 hour regadenoson infusion measurements were compared at dose level 2 (N=5), mean percent of cells expressing phospho-NF-kB in the activation gate was 40% (90% CI 23–58) at baseline and decreased by 53% at the end of infusion to 19% (90% CI 6–33). Similar results were found in measurements of A2ARs. We conclude that infusional regadenoson administered at 0.6 and 1.44 mcg/kg/hour is safe during a 12 hour infusion and decreases activation of iNKT cells. Our next steps are to determine whether infusions of a longer duration (24 and 48 hours) are safe and similarly biologically effective during a VOC. We then intend to conduct a clinical trial to measure the clinical efficacy of regadenoson infusion during VOC and acute chest syndrome episodes. Disclosures: Off Label Use: Regadenoson is an adenosine 2A receptor agonist that is FDA approved for use during myocardial stress imaging. We are examining the safety of regadenoson in patients with sickle cell disease. Nathan:Astellas: Research Funding.