Surrogate Efficacy Research Articles

Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival.

Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate-specific antigen (PSA) levels as a marker of efficacy. The clinical relevance of prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. The University of Washington Caisis database was queried for radical prostatectomy patients who received 6-12 months of ADT after biochemical recurrence (BCR), defined as PSA ≥0.2 ng/mL and no radiographically detectable metastasis. Proportions of men with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death were evaluated by log-rank tests. After ineligibility exclusions, 23/93 (25%; 95%CI 16-35%; P < 0.001) and 14/93 (15%; 95%CI 9-24%; P < 0.001) had undetectable PSA 12 and 24 months after ending ADT, respectively. Detectable PSA at 12 months was associated with increased risk of metastasis (P = 0.006), prostate cancer-specific death (P = 0.028), and death from any cause (P = 0.065). Being 1 year older at diagnosis was associated with a 14% (95%CI 5-24%; P = 0.006) decrease in the odds of having a detectable PSA after controlling for PSA at diagnosis, PSA doubling time, grade group, and time from initial therapy to BCR. This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. No baseline prognostic characteristic other than age was associated with a durable (12 month) undetectable PSA. Because a durable undetectable PSA was associated with lower risks of metastasis and prostate cancer-specific death, it may be a reasonable clinical trial endpoint.

Association of undetectable PSA with time to metastasis and survival after short-course androgen deprivation therapy for biochemically-recurrent prostate cancer patients.

e17073Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Durable undetectable prostate-specific antigen ...

Prediction of hosts who are more likely to respond to PD-1 inhibitors/blocking antibodies

Abstract A major challenge in the development of immune checkpoint blockades (ICB) is the variability in outcome of such therapeutics. This leads to a large number of non-responder patients receiving costly therapies that are also associated with some toxicities. Surrogates of efficacy are needed both to select the right patient population for the clinical trials and in later stages, to identify the right patients for the right ICB, ideally with assays that are rapid, high throughput and noninvasive. T cell clonal expansions caused by ICB are mainly local. As a result, the expanded T cells are mostly found in the tumor deposit and hard to detect in the peripheral blood. We optimized an antigen recall assay that assesses the ability of PD-1 blocking antibody to further enhance antigen specific CD8 T cell expansion and thereby discriminates responders from non-responders. A simple version of this assay has been used for functional screening of ICBs. By improving each component of the assay and its readout, we have increased the “signal to noise” window allowing us to rapidly detect PD-1 blockades’ effects on the host. We use a cocktail of optimized recall peptides, a characterized conditioned media and 96-well plates to support rapid (7 days) expansion of memory T cells. Finally, as a readout system, cocktail of MHC class I tetramers generated by peptide exchange was used to detect the overall expanded clonotypes. Currently, we have optimized the assay with commercially available anti-PD-1 and anti-PD-L1 antibodies. This assay system has the potential to assist in predicting those who are more likely to respond to ICB therapies. We have initiated blinded studies using clinical samples for clinical validation.

Implementing Liquid Biopsies in Clinical Trials: State of Affairs, Opportunities, and Challenges.

A primary goal of personalized medicine is to develop tumor-specific biomarkers to aid in treatment selection and to better evaluate response to targeted therapies. The assessment of circulating blood markers as surrogate real-time biopsies of disease status, termed liquid biopsies, has been under investigation. There are many different types of liquid biopsies each with different functionalities and limitations. These include tumor markers, circulating tumor cells, cell-free DNA, and extracellular vesicles including exosomes. Multiple clinical trials have evaluated liquid biopsies as prognostic biomarkers with positive results. Additional studies are underway to evaluate liquid biopsies as predictive biomarkers, pharmacodynamic biomarkers, and surrogate efficacy endpoints for treatment response evaluation. There are several challenges in and barriers to implementation of liquid biopsies into clinical trials and subsequently into routine clinical practice, which are addressed in this review.

Proportion of biochemically-recurrent prostate cancer patients with durable undetectable PSA after short-course androgen deprivation therapy.

207 Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate specific antigen (PSA) levels as a marker of efficacy. The proportion of patients and clinical relevance of those with a prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. Methods: The University of Washington Caisis database was queried for radical prostatectomy patients who received 6–12 months of ADT after biochemical recurrence (BCR), defined as PSA ≥ 0.2 ng/mL and no radiographically detectable metastasis. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death from any cause were evaluated by log-rank tests. Results: After ineligibility exclusions, data were abstracted from 93 patients. Proportions of patients with undetectable PSA 12 and 24 months after ending ADT were n=23/93 (24.7%; 95% CI 16.4–34.8%; P&lt;0.001) and n=14/93 (15.1%; 95% CI 8.5–24.0%; P&lt;0.001), respectively. Proportions of patients with undetectable PSA 12 and 24 months after testosterone recovery ≥ 50 ng/dL were n=16/65 (24.6%; 95% CI 14.8-36.9%) and n=10/65 (15.4%; 95% CI 7.6-26.5%), respectively. Being 1 year older at diagnosis was associated with an 11.5% (95% CI 3.1–21.9%; P=0.01) increase in the odds of having a detectable PSA after controlling for PSA at diagnosis, Gleason sum and time from initial therapy to BCR. Detectable PSA was associated with increased risk of metastasis (P=0.006) with marginal evidence of association with death from any cause (P=0.07). Conclusions: This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. Additional analysis is needed to demonstrate the clinical value of this measure as a surrogate for prostate cancer outcomes and for consideration as a trial endpoint.

Just chill—it's worth it!

Just chill—it's worth it!

Abstract P424: Assessment of the RAAS-status Using Triple-A-Testing: Combining Molecular Profiling of Hypertension With Advanced Screening for Primary Aldosteronism in a Single Blood Test

Triple-A testing is a novel mass spectrometry based approach providing a comprehensive biochemical evaluation of the circulating renin-angiotensin-system (RAS) on the basis of equilibrium angiotensin levels and circulating aldosterone levels. In contrast to previous technologies involving complex sampling procedures, RAS-Equilibrium-Analysis combines the robustness and accuracy of LC-MS/MS based quantification with the versatility of serum sampling to generate a highly accurate readout containing multiple layers of information regarding the biochemical features of the circulating RAAS. Equilibrium Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone were simultaneously quantified in 500μl of standard collected serum samples from healthy volunteers or hypertensive patients receiving different anti-hypertensive first-line therapies. Stable-isotope labeled internal standards were used to control for analyte recovery. Following analyte extraction, samples were subjected to UPLC-MS/MS analysis and diagnostic ratios were calculated. ACE inhibitor therapy resulted in a significant reduction of the Ang II-to-Ang I-Ratio in equilibrium analysis, which was accompanied by an up-regulation of renin, as expected. Surprisingly, PRA showed a high correlation with the sum of equilibrium Ang I and Ang II, which was independent of ACE inhibitor treatment. While the ARR was strongly suppressed in the presence of ACE inhibitor treatment, the Aldosterone-to-Angiotensin II-Ratio (AA2-Ratio) was not affected, suggesting superior applicability in screening for primary aldosteronism (PA). Triple-A testing is a mass spectrometry based multiplex assay combining Ang I, Ang II and Aldosterone to diagnostic values that draw a comprehensive picture of a patient’s "RAAS Status" . While the sum of Ang I and Ang II serves as a strong PRA surrogate marker, ACE activity and ACE inhibitor therapy efficacy can be monitored using the Ang II/Ang I-Ratio. On top, the AA2-Ratio serves as an advanced diagnostic marker for PA that might pave the way for patient screening without the need of withdrawing anti-hypertensive therapies.

Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).

Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5years. There were no new safety signals. Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.

Associations between regorafenib-induced adverse events (AEs) and efficacy in metastatic colorectal cancer (mCRC).

556 Background: It is occasionally recognized that, in molecular targeted therapy, target-specific AEs can surrogate its efficacy, such as skin toxicities and anti-EGFR antibodies. Because of multikinase inhibitor, regorafenib is involved in various kinds of adverse events; however, the clinical associations between AEs and efficacy remain unclear. The aim of this study is to reveal what AEs could surrogate efficacy of regorafenib. Methods: AEs were graded according to CTCAE ver. 4.0. We defined as “CRP increased”, if CRP increased more than 5 mg/dl during treatment compared with the baseline level. Time to treatment failure (TTF) and overall survival (OS) were estimated using Kaplan-Meier methods and compared by the log-rank test. Covariates which were significant in univariate analysis were included in multivariate analysis. Results: One-hundred and two patients were enrolled in this study. Almost all patients were PS 0-1 and received 160mg of regorafenib as an initial dose. The median TTF and the median OS were 2.0 and 8.0 months, respectively. Major AEs were Hand-foot skin reaction (HFSR) in 82.4% (≥Gr3:38.2%), Hypertension (HT) in 39.2% (16.7%), Rash in 23.5% (8.8%), Blood bilirubin increased (BBI) in 58.8% (2.9%), Thrombocytopenia in 48.0% (3.9%), Neutropenia in 20.5% (0%), and CRP increased in 46.1%. Regarding TTF, in univariate analysis, BBI, AST increased Gr0-1, neutropenia, absence of CRP increased, Diarrhea, HFSR, and Rash Gr0-2 were associated with longer TTF. In multivariate analysis, HFSR (HR 0.34 95%CI 0.19-0.63, p = 0.001) and Rash ≥Gr3 (HR 2.43 95%CI 1.13-5.21, p = 0.023) retained to be significant. With respect to OS, in univariate analysis, AST increased Gr0-1, ALT increased Gr0-1, neutropenia, absence of CRP increased, HFSR, and Rash Gr0-2 were associated with longer OS. In multivariate analysis, HFSR (HR 0.47 95%CI 0.24-0.91, p = 0.026), neutropenia (HR 0.54 95%CI 0.30-0.95, p = 0.032) and AST ≥Gr2 (HR 5.72 95%CI 2.11-15.63, p = 0.023) retained to be significant. Conclusions: HFSR and neutropenia might surrogate regorafenib efficacy in mCRC. Elucidation of the mechanisms of these AEs may help to understand which the pathway is the key role of regorafenib treatment in mCRC.

Treatment responses with once-weekly teriparatide therapy for osteoporosis.

SummaryMonitoring bone mineral density is useful to assess treatment response for osteoporosis, but it does not always reflect fracture prevention. Two types of bone mineral density thresholds were used to analyze data from a once-weekly teriparatide trial, and they appear to be useful indicators of treatment success for osteoporosis.IntroductionThis study aimed to clarify whether the criteria of treatment response could be used to evaluate treatment success with once-weekly teriparatide.MethodsThe data of subjects whose lumbar or femoral neck bone mineral density (BMD) was measured in the TOWER study were included. The least significant change (LSC) and the absolute change were used as the criteria for judgment of treatment success. The correlation between the incidence of fractures and the treatment response was also assessed.ResultsThere was no significant difference in baseline characteristics between the placebo and teriparatide groups. Once-weekly teriparatide therapy for 72 weeks showed treatment success in 79.2 % of the subjects for lumbar BMD and 44.1 % for femoral neck BMD by LSC and in 50.5 and 39.6 % by absolute change, respectively. A lower incidence of vertebral fracture was observed in patients who achieved treatment success for lumbar BMD. With the LSC, some treatment success was observed in the early phase of treatment, and it increased with treatment duration.ConclusionsIt appears that the LSC could be used as a surrogate efficacy indicator at an earlier stage of treatment, and the absolute criterion of −2.5SD was confirmed as a useful marker of long-term treatment success.

Pharmacokinetic (PK) Comparison of Two Fibrinogen Concentrates in Patients with Congenital Fibrinogen Deficiency: Final Analysis

IntroductionPatients with congenital afibrinogenaemia and hypofibrinogenaemia, experience frequent severe bleeding episodes starting at birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is a plasma derived, highly purified, lyophilized, fibrinogen concentrate, which has been double virus safeguarded using two dedicated virus inactivation/removal steps. In this study, the (PK) profile of this new concentrate is compared to a commercially available product.MethodsThis study was a prospective, randomized, open-label, multinational, crossover PK comparison of Octafibrin to an existing marketed product (Haemocomplettan¨ P/RiaSTAPTM) in adult and adolescent afibrinogenemic patients, including comparison of a surrogate efficacy endpoint Maximum Clot Firmness (MCF) measured by ROTEM¨. Patients were randomized to either product and received a single dose of 70mg/kg b.w. and blood samples were collected over 14 days followed by an observational period up to 45 days. Afibrinogenemia was confirmed by baseline fibrinogen activity plasma level of < 0.20. All fibrinogen and MCF testing was performed in a central lab using validated methods. Primary objective was to show bioequivalence between both products based on the Normalized Area Under the Curve (AUCnorm).ResultsTwenty two adult and adolescent patients were included in the final analysis. Mean AUCnorm) for Octafibrin was 1.62, and for the marketed concentrate 1.35 (hákgág/L/mg) and mean clearance 0.67 and 0.82 mL/h/kg, respectively. Both showed a statistically significant differences between the groups (see figure and table below). Other PK parameter were comparable between the products. Comparable haemostatic efficacy of the two products was demonstrated based on their ability to significantly increase MCF from baseline. There were no reports of adverse events (AE) related to the infusion of this novel concentrate.ConclusionsIn conclusion, this study showed a statistically significantly higher AUCnorm and lower clearance for Octafibrin compared to the comparator. Other PK parameters were in general comparable. Change in MCF compared to baseline as a surrogate efficacy parameter, was similar to that of the licensed comparator used in this study, and there was no related AE or SAE for Octafibrin after single-dose administration.TableRatios of Octafibrin Relative to Haemocomplettan¨ P/RiaSTAPTM for AUC and AUCnorm (PK Population, N=22)Fibrinogen activityParameter ratioMean90% CI ofmean ratiop-valueAUC1.34(1.23, 1.41)<0.0001AUCnorm1.21(1.25, 1.44)0.0002 [Display omitted] DisclosuresRoss:Octapharma: Other: Investigator. Rangarajan:Octapharma: Other: Investigator. Karimi:Octapharma: Other: Investigator. Schwartz:Octapharma: Employment. Knaub:Octapharma: Employment. Peyvandi:LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding; Octapharma: Other: Investigator.

Nivolumab dose selection: challenges, opportunities and lessons learned for cancer immunotherapy

Meeting abstracts Dose selection for immuno-oncology (I-O) treatments presents unique challenges and opportunities. Surrogate efficacy endpoints in early clinical studies (typically objective anti-tumor response) may not fully represent the potential for improved overall survival in pivotal trials

Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rγnull Immunodeficient Mice.

A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4(+) T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations.

A Time-Trend Economic Analysis of Cancer Drug Trials.

Scientific advances have led to the discovery of novel treatments with high prices. The cost to publicly fund high-cost drugs may threaten the sustainability of drug budgets in different health care systems. In oncology, there are concerns that health-benefit gains are diminishing over time and that the economic evidence to support funding decisions is too limited. To assess the additional costs and benefits gained from oncology drugs over time, we used treatment protocols and efficacy results from U.S. Food and Drug Administration records to calculate cost-effectiveness ratios for drugs approved to treat first- and second-line metastatic or advanced breast, colorectal, and non-small cell lung cancer during the years 1994-2013. We assessed reimbursement recommendations reached by health technology assessment agencies in the U.K., Australia, and Canada. Cost-effectiveness ratios were calculated for 50 drugs approved by the U.S. regulator. The more recent approvals were often based on surrogate efficacy outcomes and had extremely high costs, often triple the costs of drugs approved in previous years. Over time, the effectiveness gains have increased for some cancer indications; however, for other indications (non-small cell lung and second-line colorectal cancer), the magnitude of gains in effectiveness decreased. Reimbursement recommendations for drugs with the highest cost-effectiveness ratios were the most inconsistent. Evaluation of the clinical benefits that oncology drugs offer as a function of their cost has become highly complex, and for some clinical indications, health benefits are diminishing over time. There is an urgent need for better economic evidence from oncology drug trials and systematic processes to inform funding decisions. High-cost oncology drugs may threaten the ability of health care systems to provide access to promising new drugs for patients. In order to make better drug-funding decisions and enable equitable access to breakthrough treatments, discussions in the oncology community should include economic evidence. This study summarizes the extra benefits and costs of newly approved drugs from pivotal trials during the postgenomic era of drug discovery. The reader will gain an appreciation of the need for economic evidence to make better drug-reimbursement decisions and the dynamics at play in today's oncology drug market.

Pharmacokinetic (PK) Comparison of Two Fibrinogen Concentrates for the Treatment of Congenital Fibrinogen Deficiency

Patients with congenital afibrinogenaemia and hypofibrinogenaemia, experience frequent severe bleeding episodes starting at birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is plasma derived, highly purified, lyophilized, fibrinogen concentrate, which has been double virus safeguarded using two dedicated virus inactivation/removal steps. In this study, the (PK) profile of this new concentrate is compared to a commercially available product (Haemocomplettan® P/RiaSTAPTM). This ongoing study is a prospective, randomized, open-label, multinational, crossover PK comparison of Octafibrin to an existing marketed product with planned interim data in 9 adult and adolescent patients, including comparison of a surrogate efficacy endpoint Maximum Clot Firmness (MCF) measured by ROTEM®. The study includes a crossover design where both products are given a single dose in a randomized fashion separated by an observation period and washout of any fibrinogen product prior to infusion. Patients are confirmed afibrinogenemic with baseline fibrinogen activity plasma level of &lt; 0.20. All fibrinogen and MCF testing was performed in a central lab using validated methods. Nine patients completed the study until the end of May 2014. There have been no reports of adverse events (AE) related to the infusion of this novel concentrate. Comparable PK profiles between the products were seen but in key parameters, Normalized Aria Under the Curve (AUCnorm) (h·mg/mL/(mg/kg) Octafibrin 0.994, Haemocomplettan® P/RiaSTAPTM 0.731 p-value 0.014) and clearance (mL/h/kg Octafibrin 0.522, Haemocomplettan® P/RiaSTAPTM 0.594 p-value 0.033), significant differences were observed between the groups. Comparable haemostatic efficacy of Octafibrin and Haemocomplettan® P/RiaSTAPTM was demonstrated based on their ability to significantly increase MCF. Mean (± SD) Fibrinogen Levels (g/L) during PK Assessment after Octafibrin and Haemocomplettan® P/RiaSTAPTM Administration, Standardized to 70 mg/kg (PK Population, n=9) Figure 1 Figure 1. Ratios of Octafibrin Relative to Haemocomplettan® P/RiaSTAPTM for AUC and AUCnorm (PK Population, N=9) Table 1 Baseline Characteristics of Patients with and without Cardiac Complications in TTP Fibrinogen activity Parameter ratio Mean 90% CI of mean ratio p-value AUC 139.11 79.25, 246.13 0.0173 AUCnorm 139.96 80.26, 245.94 0.0144 In conclusion, this study showed in general a comparable PK profile for Octafibrin and Haemocomplettan® P/RiaSTAPTM in patients with congenital fibrinogen deficiency. Octafibrin showed a significantly higher AUCnorm and lower clearance than the comparator. The haemostatic efficacy of Octafibrin, as measured by change in MCF as a surrogate parameter, was similar to that of the licensed comparator used in this study, and there was no related AE or SAE for Octafibrin after single-dose administration. Disclosures Schwartz: Octapharma: Employment. Knaub:Octapharma: Employment.

Monitoring Warfarin with the Fiix-Prothrombin Time Improves Anticoagulation Stability and Long-Term Clinical Outcome. the Fiix-Trial

▪Introduction: Experiments suggest that the anticoagulation effect of warfarin is mainly influenced by a reduction in coagulation factor (F) II and X activity and that FVII may have relatively little effect. Due to the short half-life of FVII but its strong influence on the prothrombin time (PT), monitoring warfarin using PT may therefore confound warfarin dosing. The Fiix-prothrombin time is specially designed to circumvent measuring FVII activity and is only sensitive to the activity of FII and FX in the sample. The Fiix-trial was a single center randomized prospective and blinded non-inferiority clinical trial that examined monitoring warfarin with the Fiix-PT compared to the PT.Methods: All community dwelling patients 18 years and older with an INR target of 2-3 managed by our center´s anticoagulation management service were eligible for participation. A PT ratio adapted for thromboplastin sensitivity (INR) was calculated for both tests and results were reported by the laboratory as R-INR (“research INR”) to the dosing staff that was blinded to each patient´s test method. Warfarin dosing was software assisted using the DAWN anticoagulation software. Protocols designed for monitoring with PT were used, including a recommended maximum six week interval between tests. The major efficacy endpoint was fatal and non-fatal thromboembolism (TE) rate and the major safety endpoint was major bleeding per patient year (ppy). Surrogate efficacy parameters included number of tests, tests in range, time within target range 2-3 (TTR), monitoring test interval and dose adjustment rate.Results: After exclusion of 4 patients in each group, 573 patients were evaluable in the Fiix-PT arm and 575 in the control arm. About 69% had atrial fibrillation (AF) and 21% had venous thromboembolism (TE). The median monitoring time was 1.7 (IQR 1.1-1.9) years per patient in both study arms. The TE rate was similar in the first six months but thereafter the event curves diverged (Figure 1) and therefore we specially examined events occuring after six months in a secondary analysis. In the primary analysis of events during days 1-720, the TE rate ppy was 1.2% in the Fiix-arm vs 2.3% in controls (-48%, p = 0.09) demonstrating at least non-inferiority of Fiix-PT monitoring compared to the PT in reducing TE. The major bleeding rate did not differ; 2.2% and 2.5%, respectively (p = n.s., non-inferior). In the secondary analysis, after excluding the first six observation months, the Fiix-PT lead to a superior long-term reduction in TE (1.1% vs 2.2% annual rate, -50%, p = 0.03) with major bleeding rate of 1.5% vs 2.3% respectively (p = 0.8). A subanalysis of patients with AF yielded similar results. The intracranial hemorrhage (ICH)/intracerebral hemorrhage rate was 0.26%/0.13% ppy in the Fiix-arm and 0.64%/0.38% ppy in the PT-arm. In the first six months the test volume was the same in both arms but therafter a 5.8% reduction occurred in the Fiix-arm. The dose adjustment rate was reduced 12% overall and 18% during long term monitoring (4.1 vs 5.0 ppy, p = 0.01). At six month intervals, the median percent TTR was 84.9 (79.9-86.7) in the Fiix-arm vs 80.3 (78.5-81.3%) in the PT-arm. [Display omitted] Conclusion: Monitoring warfarin with Fiix-PT is non-inferior and possibly superior to the PT in reducing long-term recurrent TE. Bleeding is not increased despite omitting FVII activity in the monitoring test. With the Fiix-PT, the warfarin effect fluctuates less than with standard PT as manifested by a higher TTR and reduced dose-adjustment need. Overall, the results suggest that the fluctuation typically observed during warfarin treatment is partly caused by the traditional prothrombin time itself. DisclosuresOnundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Gudmundsdottir:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.

Abstract 11963: Randomized Ivus Comparison Between a Durable and a Biodegradable-Polymer Second Generation Drug-Eluting Stents: The Bioactive Trial

Background: New generation drug-eluting stents (DES), biolimus-eluting stents (BES) and everolimus-eluting stents (EES) were conceived to minimize local coronary inflammation allowing better endothelial healing. The aim of this study is to compare the IVUS patterns observed with both stents at midterm follow-up. Methods: The Bioactive trial is a multicentre, randomized trial (1:1) comparing BES and EES based on surrogate safety and efficacy endpoints. Inclusion criteria was single, de novo lesions in native coronary arteries of 3.0 to 3.5mm and maximum lesion length of 20 mm. Patients with in-stent restenosis, lesion in grafts and treated in the setting of STEMI were excluded. The present analysis aims to compare the main IVUS findings for both DES at 9-month invasive follow-up. IVUS analyses were performed in an independent corelab blinded to the type of DES used. Results: A total of 40 patients were enrolled in the trial and 35 had IVUS performed. Procedure success was achieved in all cases. Baseline clinical characteristics as well as reference vessel diameter and lesion length did not significantly differ between the 2 cohorts. At 9 month, QCA measured in stent late loss was also comparable (0.15±0.18mm for BES vs. 0.20±0.47mm for EES, p=0.7). By IVUS, vessel volume (349±158mm3 for BES vs. 326±127mm3 for EES, p=0.6) and stent volume (178±78 for BESmm3 vs. 154±54mm3 for EES, p=0.4) did not significantly differ between the groups as well as neointimal tissue volume (3.6±2.8mm3 for BES vs 4.3±6.1mm3 for EES, p=0.4) and the % of stent obstruction (2.3±2.1% for BES vs. 2.5±2.8% for EES. OF note, the pattern of neointimal distribution was very similar between the two DES (figure). Conclusions: In this head-to-head to comparison, both second-generation DES were shown to be effective and safety in the treatment of coronary artery disease with no significant differences in terms of IVUS findings.

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

Background:Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS).Methods:Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay.Results:The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1–8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007).Conclusions:We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

Methylated glutathione s-transferase 1 (mGSTP1) as a potential plasma epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer (CRPC).

11 Background: GSTP1 is inactivated and displays aberrant CpG island promoter methylation in the majority of prostate cancers (PCs). The aim of this study was to assess whether changes in methylated glutathione s-transferase 1 (mGSTP1) levels are predictive of response to chemotherapy and overall survival (OS). Methods: Plasma samples were collected prospectively from a phase I exploratory cohort of 75 men with castration-resistant prostate cancer (CRPC) (40 treated with chemotherapy) and a phase II independent validation cohort (n=51). Plasma samples were collected at presentation with CRPC and pre- and post-cycle one of chemotherapy (90% Docetaxel). mGSTP1 levels were measured using a methylation-specific head-loop PCR assay from DNA isolated from either (1) immunomagnetic separation of circulating tumor cells (CTCs) or (2) free plasma DNA. The associations between plasma mGSTP1 levels, PSA response (defined by PCWG1 criteria), and OS were tested using non-parametric tests and survival analyses. Results: The ability to detect mGSTP1 was significantly higher for the plasma free DNA assay compared to DNA from CTCs (p&lt;0.0001), so for the remainder of the study the plasma free DNA assay was used. The phase I exploratory cohort identified that detectable mGSTP1 at CRPC presentation predicted for poorer OS (HR 4.2, 95% CI 2.1-8.2; p&lt;0.0001). In the 40 men treated with chemotherapy, a decrease in mGSTP1 levels after cycle one predicted a subsequent more than 50% decrease in PSA prior to cycle 4 (p=0.008). The phase II validation cohort demonstrated that undetectable plasma mGSTP1 after one cycle of chemotherapy predicted for a clinical benefit from treatment (PR+SD vs. PD) (p=0.007). Furthermore, an undetectable plasma mGSTP1after one cycle of chemotherapy was a better predictor of death within 12 months than change in PSA after three months (AUC 0.87, 95% CI 0.77-0.98; p=0.006). Conclusions: We have identified plasma mGSTP1 levels as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for cytotoxic chemotherapy and validated these findings in an independent phase II cohort. Prospective phase III assessment of mGSTP1 as a biomarker of therapeutic response is now warranted.

Ethacrynic Acid continuous infusions in critically ill pediatric patients.

The purpose of this study was to describe dosage regimens and treatment outcomes in critically ill children receiving ethacrynic acid continuous infusions (CI). This retrospective cross-sectional study evaluated patients less than 18 years of age who received ethacrynic acid CI with a duration exceeding 12 hours, from January 1, 2007, through January 31, 2012. The primary objective was to determine the mean/median doses of ethacrynic acid CI. Secondary objectives were to assess surrogate efficacy markers (e.g., urine output [UOP], fluid balance) and the number of patients with electrolyte abnormalities or metabolic alkalosis. Descriptive statistics were used. A series of repeated measures analyses of variance were conducted to assess differences in surrogate efficacy markers and in adverse events that occurred pre-, mid-, and posttherapy. Nine patients were included. The mean ± SD initial and maximum doses (mg/kg/hr) were 0.13 ± 0.07 (median 0.1; range, 0.08-0.3) and 0.17 ± 0.08 (median, 0.16; range 0.09-0.3), respectively. The median UOP (mL/kg/hr) pre-, mid-, and postinfusions (interquartile range [IQR]) were 2.4 (1.8-3.2), 4.2 (3.5-6), and 4 (3.4-5.3), respectively. The median fluid balance (mL; IQR) was 189 (90-526), -258 (-411.7 to 249) and -113.5 (-212.5 to 80.2), respectively. There were statistically significant differences in UOP and fluid balance pre- versus mid-therapy (0.014) and pre- versus posttherapy (p=0.010). No significant differences were noted with magnesium and potassium. Five children (55.6%) developed metabolic alkalosis. This study provides preliminary evidence for ethacrynic acid CI in children. The median initial dose and maximum dose in this cohort were 0.13 mg/kg/hr and 0.17 mg/kg/hr, respectively. Larger prospective studies are needed to confirm these findings.