A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors

PURPOSE: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors. METHODS: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.5-mg/kg dose was given before the first dose in the 3-mg/kg cohort to determine pharmacokinetics (PK) and pharmacodynamics under unsaturated conditions. After completion of dose escalation in the QW cohorts, patients were enrolled in two additional cohorts and received MEDI-575 25 or 35 mg/kg every 3 weeks (Q3W). Secondary measures included assessments of PK, immunogenicity, and antitumor activity. RESULTS: A total of 35 patients received MEDI-575 QW (n = 23) or Q3W (n = 12). Most treatment-related adverse events were grade 1 or 2 in severity across all dose levels, with fatigue (n = 12) and nausea (n = 8) being reported most frequently. With no reports of dose-limiting toxicities (DLTs), the MTD was not reached. MEDI-575 exhibited a nonlinear PK profile and increased plasma platelet-derived growth factor-AA levels in a dose-dependent manner with limited immunogenicity. Stable disease was reported as the best tumor response in 9 of 29 evaluable patients; however, no objective responses were reported. CONCLUSION: Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

AbstractBackgroundFor patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering 90Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.MethodsFifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N=29, 90Y-clivatuzumab tetraxetan, weekly 6.5mCi/m2doses×3, plus gemcitabine, weekly 200mg/m2 doses×4 starting 1week earlier) or Arm B (N=29, 90Y-clivatuzumab tetraxetan alone, weekly 6.5mCi/m2doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.ResultsCytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1year.ConclusionsClinical studies of 90Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting

Darinaparsin a Novel Organic Arsenic Molecule Active in Lymphoma: Development of An Oral Form

Abstract Abstract 4759 Introduction Darinaparsin is an organic arsenic molecule constructed of dimethylated arsenic linked to glutathione (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine). It has a multifaceted mechanism of action, inducing G2/M cell cycle arrest and apoptosis mediated through disruption of mitochondrial functions, increased reactive oxygen species production, and modulation of signal transduction pathways. In addition, darinaparsin has anti-angiogenic activity. It has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models, including human cell lines resistant to arsenic trioxide. It is active in heavily treated patients with refractory lymphoma when administered IV 300 mg/m2 for 5 days on a 28 day cycle, and is very well tolerated. Preclinically it is orally highly bioavailable. Oral administration may be of importance in potential utility in lymphoma in continuous metronomic dosing. Methods Two Phase I studies of oral darinaparsin are being conducted in patients diagnosed with relapsed or refractory advanced tumors. The first protocol is a Phase I, dose-escalation, oral administration study designed to determine the MTD of darinaparsin capsules. The dosing schedule is a regimen of 2 doses per week for 3 weeks followed by 1 week of rest, starting at 300 mg twice weekly. A second Phase I study, having a similar design and objective, evaluates several dosing regimens, including dosing capsules three times per week increasing dosing frequency to daily dosing for 3 weeks, with 1 week of rest. For each study 28 days constitutes one cycle. Standard methods for evaluation of toxicity, escalation and efficacy are being used. Results These two studies have thus far enrolled 19 and 17 patients, respectively. In total there are 24 male and 12 female patients. The median age is 59 years, with a range from 38 to 82 years. To date, MTD has not been reached in either study. The dose continues to be escalated and is currently at 900mg / day twice weekly in the 1st study, and 300 mg daily every day in the 2nd study. Bioavailability has been very high (>75%). All patients were heavily pretreated and refractory. Of 27 evaluable patients thus far in the two trials, 2 had a partial response and 15 had prolonged stable disease, including lymphoma (NHL), head and neck, colon, and pancreatic cancers. The duration of responses has been 3 – 8 + months. Safety and tolerability has been very good and comparable to that of IV darinaparsin. SAEs were atrial fibrillation and congestive heart failure, each occurring in one patient, and dyspnea, occurring in two patients. No QT prolongation has been observed. Dose escalation continues in both studies and updated results will be presented. Conclusion Darinaparsin is a novel organic arsenic molecule that has demonstrated clinical activity in refractory lymphoma when given IV. When given orally by capsule, the drug is well tolerated and demonstrates early signs of activity. Disclosures: Buck: ZIOPHARM Oncology: Employment. Wallner:ZIOPHARM Oncology: Employment. Lewis:ZIOPHARM Oncology: Employment, Membership on an entity's Board of Directors or advisory committees

Wildlife in Airport Environments: Appendix, Index and Back Cover

In 1990, the 190 member nations of the International Civil Aviation Organization (ICAO) adopted, in Annex 14 to the Convention on Civil International Aviation, three recommended management practices regarding bird hazards to aviation. The recommended practices required that aviation authorities within each nation (1) assess the extent of the hazard posed by birds at and in the vicinity of airports certificated for passenger traffic, (2) take necessary action to decrease the number of birds, and (3) eliminate or prevent the establishment of any site in the vicinity of the airport that could attract birds and thereby present a danger to aviation. Because of the increasing threat posed by birds to aviation worldwide, member states voted to make these recommendations mandatory ICAO standards, effective November 2003. In 2009, ICAO expanded these standards to include terrestrial wildlife such as large mammals and reptiles that pose a risk at airports (ICAO 2009)