Preliminary Toxicity Data Research Articles

Potential impacts of titanium dioxide nanoparticles on the biochemical and behavioural status of the amphipods Talitrus saltator (Amphipoda, Talitridae)

ABSTRACT Titanium dioxide nanoparticles (TiO2 NPs) are among the most universally engineered nanomaterials and widely used nanomaterials in the world. In order to predict the environmental impact and interaction between these NPs and coastal organisms, the amphipod Talitrus saltator was exposed to TiO2 NPs C1 = 151.5 µg.L−1 and TiO2 NPs C2 = 303 µg.L−1. Catalase activity increased significantly and reaches a maximum of about 0.8 ± 0.02 µMol/min/mg proteins after exposure to TiO2 NPs C2 showing possible oxidative mechanisms. In addition, acetylcholinesterase activity reduced significantly (p < 0.05) after exposure to the highest TiO2 NPs concentration, indicating neurotransmission disturbance treated with 303 µg.L−1 of TiO2 NPs. Locomotor behaviour for untreated and treated specimens with TiO2 NPs was studied under constant darkness (DD). Results revealed the existence of ultradian and circadian components. In addition, locomotor activity patterns were generally bimodal for untreated specimens and became multimodal for treated ones. We noted also a slippage of the activity peak from the middle of the subjective night for the control until the subjective day after TiO2 NPs exposure. Furthermore, the most important stability was observed for control individuals who were more active than treated ones. Overall, this laboratory study provides preliminary toxicity data for Talitrus saltator exposed to TiO2 NPs.

Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats.

Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in environmental samples around the world. Human exposure primarily occurs via oral ingestion with reported higher concentrations in children. Currently, there are no data to evaluate potential risk from exposure to either TPHP or IPP during fetal development. These short-term perinatal studies in rats provide preliminary toxicity data for TPHP and IPP, including information on transfer to fetus/offspring and across the pup blood-brain barrier. In separate experiments, TPHP or IPP were administered via dosed feed at concentrations 0, 1000, 3000, 10 000, 15 000, or 30 000 ppm to time-mated Hsd:Sprague Dawley SD rats from gestation day (GD) 6 through postnatal day (PND) 28; offspring were provided dosed feed at the same concentration as their dam (PND 28-PND 56). TPHP- and IPP-related toxicity resulted in removal of both 30 000 ppm groups on GD 12 and 15 000 ppm IPP group after parturition. Body weight and organ weights were impacted with exposure in remaining dams. Reproductive performance was perturbed at ≥10 000 ppm TPHP and all IPP exposure groups. In offspring, both TPHP- and IPP-related toxicity was noted in pups at ≥10 000 ppm as well as reduction in bodyweights, delays in pubertal endpoints, and/or reduced cholinesterase enzyme activity starting at 1000 ppm TPHP or IPP. Preliminary internal dose assessment indicated gestational and lactational transfer following exposure to TPHP or IPP. These findings demonstrate that offspring development is sensitive to 1000 ppm TPHP or IPP exposure.

A prospective observational study of combinatorial abiraterone (AA) and radical radiotherapy (RT) in node-positive (N+) prostate cancer (PCa).

e17555 Background: The conventional treatment backbone of N+ PCa has been hormonal therapy (HT) alone. Nonetheless, evidence from the STAMPEDE trial suggests that there could be survival benefit with the addition of local RT or AA, and there may be synergy between RT and AA in these advanced patients. We therefore conducted a prospective observational study to evaluate the efficacy of combination AA+HT+RT in patients with N+ PCa. Here, we report the preliminary biochemical response and toxicity data. Methods: Patients with N+M0/N+M1a, biopsy-proven adenocarcinoma of the prostate were enrolled. Patients were staged by 68Ga-PSMA-PET or whole body MRI. Exclusion criteria were i) ECOG ≥2; ii) cardiac event of &lt; 6 mo interval; iii) bone and visceral metastasis. Treatment protocol entailed 18 mo of combination AA (1000 mg plus 5 mg prednisolone once daily) and HT (LHRH agonist/antagonist); RT was delivered to the prostate (78 Gy) +/- pelvis (54 Gy with simultaneous boost of 60-66 Gy to grossly involved lymph nodes in M0 patients). This was matched against a control group that received long-term HT +/- RT (N = 38). Primary endpoint of this analysis was PSA ≤0.1 ng/ml at 6 mo; secondary endpoints were PSA ≤0.1 ng/ml, testosterone ≤0.7 nmol/l at 12 mo, and toxicity outcomes. Germline genetic profiling was performed in all patients. Results: From Feb 2017 to Aug 2019, 18 men were recruited to this study, with a median fu of 15 mo (range 6.0-35.0 mo). Median age was 66.0 y (IQR 62.0-71.0y); median baseline PSA was 18.2 ng/ml (range 3.0-272); 66.7% had GS 8-10 disease; and 22.2% had M1a disease. Combination AA+HT+RT achieved PSA of ≤0.1 ng/ml in 80.0% (N = 12) and 93.3% (N = 14) of patients at 6 mo and 12 mo, respectively, in contrast to 29.4% and 25.0% of patients who were treated with HT+RT and HT alone, respectively. We observed profound castration of 87.5% (N = 14) at 6 mo, and 91.7% (N = 11) at 12 mo. Four and 6 patients experienced acute G2 genitourinary and gastrointestinal toxicities during RT, respectively; 2 patients reported late G2 GU. One patient experienced G2 fatigue and G1 liver enzyme dysfunction, resulting in dose reduction of AA. Genetic testing revealed a patient with BRCA2 frameshift mutation; interestingly, this patient failed to achieve a PSA of ≤0.1 ng/ml at 12 mo. Conclusions: We demonstrate that combinatorial AA+HT and definitive RT is well tolerated, and yield a pronounced early PSA response in N+ PCa. Long-term data will inform if this early efficacy signal leads to improved survival in these patients.

Short-term perinatal toxicity study in sprague Dawley rats with the plasticizer and emerging contaminant N-Butylbenzenesulfonamide

N-Butylbenzenesulfonamide (NBBS) is a plasticizer and emerging contaminant that has been detected in a wide array of environmental samples. There are very little toxicity data available with which to evaluate potential risk from exposure to NBBS or other structurally-related sulfonamide plasticizers. To address this knowledge gap, NBBS was selected by the National Toxicology Program for evaluation. The current short-term pre- and post-natal (perinatal) study aims to provide preliminary toxicity and gestational transfer data for NBBS. NBBS was administered via dosed feed at concentrations of 0, 625, 1250, 2500, 5000, and 10,000 ppm to time-mated Sprague Dawley (Hsd:Sprague Dawley SD®) rats from gestation day (GD) 6 through postnatal day (PND) 28. The high concentration of 10,000 ppm NBBS was overtly toxic to dams, and the group was removed on GD 17-18. Exposure to NBBS resulted in lower maternal weights during the gestational period in the 5000 and 10,000 ppm groups as compared to control weights. Dams also displayed lower weights in the lactational period, which resolved to control levels by PND 28. NBBS exposure did not affect pregnancy or littering parameters in F0 dams. However, pup survival was lower in the 5000 ppm group, and pup weights were dose-responsively lower than control pup weights with the difference expanding over the postnatal period. The lowest observed effect level (LOEL) based on significantly lower body weights was 5000 ppm NBBS for F0 dams and 2500 ppm NBBS for F1 pups. Preliminary data for NBBS levels indicated that the chemical was transferred from dams to offspring during the gestational period.

A90 A UTILITY-BASED BAYESIAN OPTIMAL INTERVAL (U-BOIN) PHASE I/II DESIGN TO IDENTIFY THE OPTIMAL BIOLOGICAL DOSE FOR TARGETED AND IMMUNE THERAPIES

Abstract Background In the era of targeted therapy and immunotherapy, the objective of dose finding is often to identify the optimal biological dose (OBD), rather than the maximum tolerated dose (MTD). Aims To develop a utility-based Bayesian optimal interval (U-BOIN) phase I/II design to find the OBD. Methods We jointly model toxicity and efficacy using a multinomial-Dirichlet model, and employ a utility function to measure dose risk-benefit trade-off. The U-BOIN design consists of two seamlessly connected stages. In stage I, the Bayesian optimal interval (BOIN) design is used to quickly explore the dose space and collect preliminary toxicity and efficacy data. In stage II, in light of accumulating efficacy and toxicity from both stages I and II, we continuously update the posterior estimate of the utility for each dose after each cohort, and use this information to direct the dose assignment and selection. Compared to existing phase I/II designs, one prominent advantage of the U-BOIN design is its simplicity for implementation. Once the trial is designed, it can be easily applied using predetermined decision tables, without complex model fitting and estimation. Results Our simulation study shows that, despite its simplicity, the U-BOIN design is robust and has high accuracy to identify the OBD. Conclusions The U-BOIN design provide a practical, easy-to-implement method to identify the OBD for phase I-II clinical trials. It has great potential to accelate the drug development for GI diseases. Funding Agencies NIH

A utility-based Bayesian optimal interval (U-BOIN) phase I/II design to identify the optimal biological dose for targeted and immune therapies.

In the era of targeted therapy and immunotherapy, the objective of dose finding is often to identify the optimal biological dose (OBD), rather than the maximum tolerated dose. We develop a utility-based Bayesian optimal interval (U-BOIN) phase I/II design to find the OBD. We jointly model toxicity and efficacy using a multinomial-Dirichlet model, and employ a utility function to measure dose risk-benefit trade-off. The U-BOIN design consists of two seamless stages. In stage I, the Bayesian optimal interval design is used to quickly explore the dose space and collect preliminary toxicity and efficacy data. In stage II, we continuously update the posterior estimate of the utility for each dose after each cohort, using accumulating efficacy and toxicity from both stages I and II, and then use the posterior estimate to direct the dose assignment and selection. Compared to existing phase I/II designs, one prominent advantage of the U-BOIN design is its simplicity for implementation. Once the trial is designed, it can be easily applied using predetermined decision tables, without complex model fitting and estimation. Our simulation study shows that, despite its simplicity, the U-BOIN design is robust and has high accuracy to identify the OBD. We extend the design to accommodate delayed efficacy by leveraging the short-term endpoint (eg, immune activity or other biological activity of targeted agents), and using it to predict the delayed efficacy outcome to facilitate real-time decision making. A user-friendly software to implement the U-BOIN is freely available at www.trialdesign.org.

Preliminary toxicity data from the combination of pembrolizumab and definitive-dose radiotherapy for locally advanced head and neck cancer with contraindication to cisplatin therapy.

6069Background: Bolus cisplatin in combination with radiation therapy is a standard of care for the treatment of locally advanced SCCHN, but contraindications such as hearing loss, tinnitus, inadeq...

PDCT-10. FIRST IN PEDIATRICS PHASE I STUDY OF CRENOLANIB BESYLATE (CP-868,596-26) ADMINISTERED DURING AND AFTER RADIATION THERAPY (RT) IN NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND RECURRENT HIGH GRADE GLIOMA (HGG)

Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor tissue analyzed from approximately 70 % of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective antagonist of the PDGF pathway with in vitro IC50 of 35- and 185- fold lower than observed with dasatinib and imatinib, respectively. We used a rolling-6 design to study the MTD of once-daily crenolanib administered during and after local RT in children with newly diagnosed DIPG (Stratum A), and in recurrent/progressive HGG, including DIPG (Stratum B).We have completed accrual of 55 patients, 30 and 20 evaluable in Stratum A and B, respectively. Serum pharmacokinetic analyses were performed using non-compartmental techniques on all patients for samples collected on days 1 and 28 of course 1. Fifty evaluable patients were enrolled on the two strata and the maximum tolerated dosage (MTD) of 170 mg/m2has been established in each stratum. Dose limiting toxicities (DLTs) were primarily elevated liver enzymes in both strata (<15% of patients), and the most common Grade 3 toxicity seen on Stratum A was leukopenia that resolved with drug interruption. PFS and OS at 2 years were 8% (± 4.5%) and 22% (±7%) for Stratum A, and 5% (± 3.5%) and 30% (± 9%) for stratum B. The PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children at doses slightly higher than the established MTD from Phase I trial in adults (280 mg/day).The spectrum of toxicities observed in children is similar to those observed in adults, though leukopenia is a novel toxicity.

Effects of in vivo exposure to polyfluorinated dibenzo-p-dioxins on organo-somatic indices and ethoxyresorufin-O-deethylase activity in mice (Mus musculus)

ABSTRACTIn this study, five different congeners of polyfluorinated dibenzo-P-dioxins (PFDDs) (1,8-di-FDD, 1,3,8-tri-FDD, 1,3,6,8-tetra-FDD, 2,3,7,8-tetra-FDD and 1,2,3,4,5,6,7,8-octa-FDD), representing different numbers and positions of fluorine substituents of all 75 PFDD congeners, were synthesized and purified to evaluate their potential environmental impact on living organisms. Their toxicity was evaluated by determining the impact on the organo-somatic indices (OSI) and ethoxyresorufin-O-deethylase (EROD) activity in mice (Mus musculus) after intragastric administration with different doses (0.5–100 μg/kg body weight) for 3 days. The results showed that these PFDDs significantly inhibited the growth and changed the OSI in mouse tissues. Notably, hepatic EROD activity was markedly induced in mice after exposure to these PFDDs, probably indicating a high affinity of binding to the aryl hydrocarbon receptor. Overall, these findings provided some preliminary but alarming toxicity data of PFDDs, and filled information gaps in the toxicological databases for living organisms.

Abstract 4399: Utilizing cobalt coordination chemistry as a traceless prodrug strategy in targeted drug delivery

Abstract We recently reported the synthesis of albumin nanoparticles using cobalt as a traceless, reductively labile crosslinker. Here, we report in vitro characterization of particle uptake for fluorescently labeled cobalt crosslinked albumin nanoparticles (Co-Alb-FITC NPs) via image-based flow cytometry as well as preliminary toxicity data. Uptake of Co-Alb-FITC NPs by gastric carcinoma cells (SNU-5) was rapid, but could be dramatically reduced through the addition of an inhibitor of macropinocytosis. High levels of non-specific uptake of other particle types were also observed suggesting SNU-5 cells possess high macropinocytic activity. Cancers harboring mutated Ras (&amp;gt;20% of all cancers) are known to take up protein via macropinocytosis to satisfy metabolic demands. Because SNU-5 cells are not known harbor mutated Ras, our findings may indicate that other cancers rely on this mechanism as well, which would have important implications for observing selectivity in active nanoparticle targeting strategies. The Co-Alb NPs themselves were found to exhibit no inherent toxicity. Based on these initial findings, Co-Alb NPs were loaded with the active metabolite of camptothecin, SN-38, to explore their potential as a delivery vector for hydrophobic drugs. An albumin-topotecan prodrug conjugate was also synthesized by crosslinking the amine group in topotecan with lysine residues in the protein, which should be applicable to other amine-containing therapeutics. Characterization of drug loading and release will be discussed along with preliminary in vitro characterization. Citation Format: Robby A. Petros, Duong T. Nguyen, Ronaldo J. Cavazos, Clifford S. Morrison, Jana B. Lampe, Alesha N. Harris, Brian K. McFarlin. Utilizing cobalt coordination chemistry as a traceless prodrug strategy in targeted drug delivery. [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 4399. doi:10.1158/1538-7445.AM2015-4399

The Evaluation of Bac7 Labeled Nanocarriers to Deliver Antiretrovirals as a Pre‐Exposure Prophylaxis (PrEP) Therapy for HIV Prevention

ObjectiveThe objective of this study is to engineer nanocarriers (NCs) capable of translocating through colorectal mucus and tissue and delivering drugs into cells of the distal colon. NCs will be delivered in quickbreak foams to provide sufficient colorectal coverage and be used as a colorectal PrEP therapy to prevent HIV transmission.MethodsFITC‐labeled poly(ethylene glycol) NCs were conjugated to the protease inhibitor amprenavir (APF) or cell‐penetrating peptide (CPP) Bac7 (BPF). APF and BPF were used to treat Caco‐2 cells in vitro and cell uptake was studied via flow cytometry. Mice were also treated with enemas containing APF or BPF and tissue retention was investigated. Foam formulations were studied for their ability to distribute NCs evenly throughout the distal colon. Histology and toxicity studies were also completed to assess the safety of the foam formulation.ResultsBPF uptake was shown to be 4‐fold higher than APF in vitro. Similar results were seen in vivo and BPF was retained within colorectal tissue for up to 5 days suggesting transport into the lamina propria. Ex vivo tissue samples show complete coverage of the distal colon by foams and NCs. Preliminary toxicity data of foam components display promising results based on histological observations.ConclusionBac7 CPP increased the translocation of NCs across the colorectal mucus and increased uptake into colonic cells both in vitro and in vivo. The current foam formulation is effective in providing uniform coverage of the distal colon and causes minimal tissue damage.AcknowledgementsFunding by NIH Grants T32GM8339, 1R01AI084137 and R37AI/DK‐051214

Focal radiotherapy as focal therapy of prostate cancer

Focal radiotherapy treatment procedures play an increasingly important role in function-preservation and organ-preservation treatment techniques. As an alternative to traditional whole-gland radiotherapy regimes, focal prostate radiotherapy may be of benefit for both primary tumor as well as locally recurrent disease. This is a review of the current literature on the topic, including patient selection, preliminary toxicity, and outcome data as well as a technical overview on treatment delivery techniques. Partial organ treatment in early prostate cancer (PCa) is now technically feasible with both newer external-beam and brachytherapy technology. To date, only small and generally monoinstitutional series have been published in the literature. Early feasibility and toxicity data are encouraging, and demonstrate potential advantages for the role of focal brachytherapy in early PCa. Although some advanced external-beam techniques can also be used to deliver focal therapy within the prostate, there is no relevant publication in the literature. Radiotherapy, especially interventional radiotherapy (brachytherapy), is a technically feasible treatment technique to deliver focal radiotherapy for PCa. To date, only preliminary results are available for all forms of interventional radiotherapy (high dose rate, low dose rate, and pulsed dose rate) for focal PCa treatment and no large cohort comparative results are published. As interventional radiotherapy (brachytherapy) as yet lacks any such long-term studies, comparative outcome data are not available to suggest differences in efficacy for one form of brachytherapy or another.

HDR brachytherapy as monotherapy for prostate cancer: Preliminary toxicity data

HDR brachytherapy as monotherapy for prostate cancer: Preliminary toxicity data

347 Efficacy of Dasatinib in Targeting Diffuse Intrinsic Pontine Glioma (DIPG) Specific Pathway Activation in Vitro

70% of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective and potent antagonist of the PDGF pathway with in vitro IC50 of 35and 185-fold lower than observed with Dasatanib and Imatinib, respectively. Methods: We are conducting a Phase I study using rolling-6 design of crenolanib during and after local RT in children with DIPG, and in recurrent/progressive HGG. We are presently accruing patients to the second dose level (130mg/m) in ND-DIPG receiving concurrent RT (Stratum A), and to the fourth dose level (220mg/m) for the recurrent/ progressive HGG (Stratum B). The dose-limiting toxicity (DLT) evaluation period was comprised by the first 8 weeks of therapy (Stratum A) and the first 4 weeks of therapy (Stratum B). Serum pharmacokinetic studies were performed on all patients on days 1 and 28 of course 1, and for select patients on day 28 of cycles 3 and 5 both on and off dexamethasone therapy. Pharmacodynamic and mutational analyses of peripheral blood mononuclear cells and tumor tissue are ongoing. Tumor autopsy studies are also being conducted to attempt to establish cell lines from a subset of patients that will be used for investigation of mechanisms of drug resistance and pharmacodynamic modulation of PDGF pathway. Results: Thirty-three patients have been enrolled on study (Stratum A: n = 12 at 100mg/m2, n = 6 at 130mg/m2; Stratum B: n = 3 at 100, n = 6 at 130 and n = 4 at 170, n = 2 at 220mg/m2), with anticipated accrual of 54 patients. One patient in Stratum A experienced neutropenia (Grade 4) and no DLTs have yet been observed in Stratum B. The most common Grade 3 toxicity seen in a subset of patients is leucopenia that resolves with drug interruption. Mild (Grade 2) elevation in liver enzymes was observed in fewer than 15% of patients. The maximum tolerated dose (MTD) has not yet been reached in either cohort and we have exceeded the adult MTD of 340mg/day in Stratum B patients. On day 1, median crenolanib AUC0−∞ values for 100mg/m dosage were 7997 nM*hr (2971−16,207) for Stratum A and Stratum B combined, which is comparable to adult Phase I data. We have successfully established cell lines from autopsy tissue at intervals of >36 hours post mortem. Conclusions: While the MTD has not yet been reached in this ‘first in pediatrics’ study, the PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children (age 21 years) at doses approaching (Stratum A) and exceeding (Stratum B) the established MTD from Phase I trial in adults (200mg/day). The spectrum of toxicities observed in children differs from those observed in adults.

Feasibility and Preliminary Rectal Toxicity Data of Transperineal Polyethylene Glycol Gel Spacer Implantation Prior to Hypofractionated VMAT in Prostate Cancer

Feasibility and Preliminary Rectal Toxicity Data of Transperineal Polyethylene Glycol Gel Spacer Implantation Prior to Hypofractionated VMAT in Prostate Cancer

High-Dose-Rate Brachytherapy as Monotherapy Delivered in Two Fractions Within One Day for Favorable/Intermediate-Risk Prostate Cancer: Preliminary Toxicity Data

To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy × 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy × 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of ≤12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24-27 Gy in two fractions within 1 day have excellent tolerance with minimal acute and chronic toxicity. Longer follow-up is needed to confirm these encouraging early results.

P2-18-04: Pilot Evaluation of Bevacizumab (Bev) in Combination with Docetaxel (T) and Cyclophosphamide (C) as Adjuvant Treatment (AdjRx) for Patients (pts) with Early Stage (ES) Breast Cancer (BrCa).

Abstract Background The combination of Bev + chemotherapy (CRx) has been shown to produce superior response rates and progression free survival compared to CRx alone, providing a rationale for the study of Bev with AdjCRx for pts with ESBrCa. As Bev can cause hypertension (HTN) and may increase the risk of cardiac failure, there is a rationale for studying a standard non-anthracycline (Anth) AdjCRx with Bev, e.g. TC (docetaxel-cyclophosphamide). We performed a pilot phase II study to evaluate the feasibility and toxicity of TC+Bev in pts with ESBrCa in preparation for participation in a random assignment trial. We have previously reported preliminary toxicity data. Methods: Eligibility criteria included: ESBrCa which was HER-2 normal, node+ or, N- and primary tumour (T) &amp;gt;2 cm and receptor negative, or T &amp;gt;3 cm, normal left ventricle ejection fraction (LVEF), no active/uncontrolled cardiovascular disease, normal organ and marrow function. Treatment consisted of four 3-weekly cycles of docetaxel 75 mg/m2 together with cyclophosphamide 600 mg/m2. Patients commenced Bev 15 mg/kg i.v. on day 1, and then every 3 weeks to a total of 18 cycles of treatments. Pts were monitored clinically, with echocardiograms and with serial estimations of BNP and troponin. Results: A total of 106 female pts were accrued in 9 ICORG sites between 11/2008 and 7/2010. Ages ranged from 25–75 (median 52). On 20/06/2011, 105 pts have completed study Rx, 1 will finish 7/2011. A total of 36 serious adverse events (SAEs) have been reported so far, 33 involving hospital admission, 3 serious for other reasons. In 25 (24%) pts study Rx was discontinued due to: HTN-9, intestinal perforation-2, consent withdrawl-7, infection-2, proteinuria-1, anaphylaxis-1, cancer relapse-1, arthralgia-1, anal fistula-1. The two perforations occurred at cycles 1 and 16 of Bev respectively. Neither pt with perforation had history of prior abdominal surgery. The median number of cycles achieved by the discontinued pts was 9. HTN of any grade occurred in 49 out of 103 (48%) pts who had no HTN at baseline (BL) and 42 of them required Rx. Among pts who experienced HTN on study Rx and completed Bev, 34 (81%) were still on anti-hypertensive 4 weeks after last infusion of Bev. Forty-one (39%) pts had LVEF drop &amp;gt;10% from BL during study Rx. In 8 (7.5%) pts LVEF declined below 50%, 6 are documented to have recovered to normal, 2 had no further LVEF measurements (1 declined, 1 unknown reason). No episodes of CCF were reported. Troponin and BNP levels were normal in all 57 pts with serial measurements. Fourteen pts required treatment for neutropenia-related infection or for abscess/fistula. Conclusions: In this study Bev overall toxicity in ESBC pts was similar to that reported for pts with MBC, and Bev discontinuation due to toxicity was relatively frequent. Although no pt developed CCF 7.5% of decline in LVEF&amp;lt;50% was observed. Intestinal perforation can occur in ESBC pts in absence of prior intestinal surgery and in the post-CRx phase of Bev. Pts receiving Bev with non-Anth AdjCRx require careful monitoring for toxicity. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-04.

Self-assembling perfluorocarbon nanoemulsions for drug delivery and imaging

The purpose of this project is to create a stable, perfluorocarbonbased drug delivery agent that can be imaged by magnetic resonance in vivo. Perfluorocarbon (PFC)-based nanoemulsions have a long research history as blood substitutes, MRI tracers, and ultrasound agents. PFCs can also provide a biologically inert platform for controlled drug delivery and release and act as a highly specific 19F MRI tracer for in vivo monitoring. PFCs alone cannot serve as drug delivery vehicles due to their high lipophobicity and hydrophobicity. To improve their drug carrying potential, PFCs are formulated with surfactants or hydrocarbons into nanoemulsions. In this study, a previously synthesized compound, perfluoropolyether-tyramide (PFPE-tyramide, 4-(2-aminoethyl) phenol conjugated to perfluoropolyether)1 was formulated into nanoemulsions in the presence of various surfactants by selfassembly or high shear techniques such as sonication and microfluidization. Olive oil was introduced into selected formulations as a potential carrier of lipophilic drugs. Preliminary toxicity and stability data are also shown.

The feasibility of carboplatin-based intraperitoneal chemotherapy in ovarian cancer

Objective To reduce toxicities in cisplatin-based intraperitoneal (IP) chemotherapy, we substituted carboplatin for cisplatin. The purpose of this study was to provide preliminary toxicity data of carboplatin-based IP chemotherapy and to evaluate the feasibility of this chemotherapy regimen in patients with ovarian cancer after primary debulking surgery. Study design The toxicity data of 19 primary ovarian cancer patients (IP group) who underwent carboplatin-based IP and intravenous (IV) combination chemotherapy (IP carboplatin AUC 5 on day 1, IV paclitaxel 175 mg/m 2 on day 2, and IP paclitaxel 60 mg/m 2 on day 8) after primary debulking surgery were retrospectively analyzed and compared to 34 patients (IV group) who were treated with standard platinum-based IV chemotherapy during the same period. Results The toxicity data in a total of 118 cycles were analyzed. Grade 3 or 4 leukopenia, neutropenia, and pain were more common in the IP group than the IV group. There were seven catheter-related complications. Fourteen patients (73.7%) were able to complete six cycles or more of IP chemotherapy. Survival results in the IP group were compared with those from the IV group; a prolonged progression-free survival was observed (26.6 vs. 20.7 months; p = 0.038). Compared to the previous results with cisplatin-based IP chemotherapy, there was no significant difference in hematologic events. However, gastrointestinal, neurologic, and metabolic events in this study were definitely lower compared to those of cisplatin-based IP chemotherapy. Conclusions Carboplatin-based IP and IV combination chemotherapy is feasible in patients with ovarian carcinoma after primary debulking surgery.

Abstract 3573: The novel FASN inhibitor UCMG028 overcomes resistance to trastuzumab and lapatinib

Abstract The vast majority of Her-2 positive advanced breast cancer patients develop resistance to trastuzumab based therapies within the first year of treatment. We have shown that inhibition of Fatty Acid Synthase (FASN) activity, an enzyme overexpressed and hiperactivated in breast carcinoma, shows marked synergic anticancer activity combined with anti-HER drugs. To examine the molecular mechanisms of acquired resistance to HER2, we have generated clones of FASN+ and HER2+ cell lines (AU565 and SK-Br3) resistant to trastuzumab (TTZ) and lapatinib (LAP) for longer than 9 months, and have evaluated the anticancer effect of UCMG028. We further characterized the effect of UCM028 in a mice model of HER2+ xenograft (BT474). TTZ and LAP-resistant cells displayed an increased sensitivity to UCMG028 compared to previously known FASN inhibitors (C75 and EGCG). Gene expression profiling of LAP and TTZ-resistant cells showed a significant differential expression in different sets of genes involved on cell cycle pathways. Mice BT474 xenografts showed tumor regression after long-term exposure to UCMG028. Preliminary toxicity data showed no weight loss, and histological studies (H&amp;E, Masson's Tricromic, Sudan Black B and Picrosirius Red Stains) showed no structural myocardial abnormalities in treated mice with UCMG028-treated mice. Thus, UCMG028 is an effective anticancer treatment for HER2 + breast cancer and its activity remains unchanged in TTZ and LAP resistant cells. Taken together, these data suggest that FASN activity inhibition by UCMG028 could be a new therapeutic strategy in HER2 + breast cancer with potential to overcome resistance to standard anti-HER2 therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3573.