Standard Dosing Schedule Research Articles

893P - Improved long-term clinical outcomes and safety profile of sunitinib dosing schedule with 4/2 switched to 2/1 in patients with metastatic renal cell carcinoma

Background: Adverse events (AEs) have been a key issue for sunitinib administration with a standard dosing schedule. We aimed to identify the survival benefit and safety of alternative dosage schedules for sunitinib in patients with metastatic renal cell carcinoma (mRCC). Methods: Clinicopathologic and survival data of patients treated with sunitinib as first-line therapy were retrospectively reviewed. Patients were classified into three groups: a standard dosing schedule (4/2 schedule), alternative dosing schedule (2/1 schedule), and switched dosing schedule (4/2-2/1 schedule). Treatment-related AEs were recorded and evaluated. Progression-free survival (PFS), overall survival (OS), and potential risk factors were also analyzed. Results: A total of 99 patients were included. Seventy-five (75.8%) patients were initially administrated with a 4/2 schedule of sunitinib, while 24 were started with the 2/1 schedule. During treatment, 45 (60.0%) patients with an initial 4/2 schedule switched to a 2/1 schedule (4/2-2/1 schedule) due to severe AEs or poor tolerance. The median follow-up time was 37 months. Compared to that with a 4/2 schedule, patients with a 2/1 schedule had a much lower incidence of grade 3/4 AEs (69.6% vs. 40.6%, p = 0.001). Overall, the 4/2-2/1 schedule was associated with the best survival benefits. Among the 4/2, 2/1, and 4/2-2/1 schedule groups, the median PFS was 12.5, 11.0, and 25.0 months, respectively (p = 0.003), and the median OS was 21.0, 28.0, and 52.0 months, respectively (p = 0.030). Multivariate analysis identified the 4/2-2/1 schedule as an independent factor predicting favorable PFS. Although without statistical significance, 4/2-2/1 schedule could decrease 55% risk of death. Furthermore, patients with unfavorable IMDC risk seemed to have more opportunity to achieve better survival from the 4/2-2/1 dosing schedule. Conclusions: Among the three dosing schedules in the treatment of mRCC, patients with a 4/2-2/1 schedule could minimize treatment-related toxicities; more importantly, patients with 4/2-2/1 schedule could achieve a superior survival benefit. However, prospective clinical trials are required to identify the optimal sunitinib schedule. Legal entity responsible for the study: Sichuan University Funding: This work was supported by Natural Science Foundation of China (NSFC 81402110 from Pengfei Shen and NSFC 81672547 from Hao Zeng) and Science and Technology Support Program of Sichuan Province (2015SZ0230-3, Hao Zeng). Disclosure: All authors have declared no conflicts of interest.

Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients

Regorafenib was approved as third-line therapy for advanced Gastrointestinal Stromal Tumour (GIST) at a starting dose of 160 mg daily 3 weeks on, 1 week off, based on improvement in progression free survival over placebo (4.8 vs. 0.9 months), but the response rate was low at 4.5%. Given the high toxicity rate in GIST patients, there is variability in the post-marketing dosing of regorafenib. We aimed to summarize our experience regarding prescribing patterns, efficacy and toxicity of regorafenib and determine the role of response assessment by Choi criteria in GIST patients. We included 28 patients who received regorafenib from our pharmacy. Baseline patient characteristics and treatment outcomes were recorded and an independent radiologist assessed response using Choi and RECIST. Seventy-nine percent of patients started at a 120 mg continuous daily dosing schedule, different from the standard intermittent dosing schedule. Grade 3/4 adverse events were experienced by 43% of patients. Median progression-free survival was 8.7 months. Continuous dosing with regorafenib at 120 mg daily is the preferred prescribing pattern and appears to be better tolerated and with comparable efficacy to the current standard dose. Similar to imatinib, the partial response rate for regorafenib by Choi (29%) was higher compared to RECIST (4%).

Feasibility of extended dosing intervals of denosumab.

Purpose Denosumab is a crucial supportive care agent for patients with advanced cancers affecting the bone. Despite the importance of treatment, logistical and financial obstacles hinder the ability to maintain long-term adherence. This analysis was designed to provide preliminary data regarding the feasibility of extended denosumab dosing intervals. Methods This retrospective, case cohort study was conducted on patients receiving treatment with denosumab for malignancies with bone involvement. A total of 60 patients were identified for analysis and were divided into cohorts according to the average number of days between denosumab doses. The standard interval group was comprised of patients receiving treatment once every 27-30 days ( n = 29), whereas the deviated interval group was comprised of patients with an interval of 31-56 days between injections ( n = 31). The primary outcome was the percentage of patients developing a skeletal-related event. Secondary efficacy outcomes included rate of pathologic fracture, spinal cord compression, radiation therapy, surgery, and hypercalcemia. Results Patients in the deviated interval arm experienced significantly more skeletal-related events compared to the standard interval group (61% vs. 31%, respectively; p = 0.02). Secondary efficacy endpoints trended in favor of the standard therapy arm except for requirement for surgery (results were virtually equivalent) and hypercalcemia (no events in either group). Conclusions Non-adherence with the standard denosumab dosing schedule demonstrated an increased risk of experiencing a skeletal-related event. Preservation of denosumab dose density appears imperative to maintain efficacy and as such extending the dosing interval should be discouraged.

Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. The virus is known to be transmitted fecal-orally, resulting in symptoms ranging from asymptomatic infection to fulminant hepatitis. HAV can also be transmitted through oral-anal sex. Residents from regions of low endemicity for HAV infection often remain susceptible in their adulthood. Therefore, clustered HAV infections or outbreaks of acute hepatitis A among men who have sex with men and injecting drug users have been reported in countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in human immunodeficiency virus (HIV)-positive individuals compared to HIV-negative individuals with acute hepatitis A. Current guidelines recommend HAV vaccination for individuals with increased risks of exposure to HAV (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis). The seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) are lower among HIV-positive individuals compared to HIV-negative individuals. While the response rates may be augmented by adding a booster dose at week 4 sandwiched between the first dose and the 6-mo dose, the need of booster vaccination remain less clear among HIV-positive individuals who have lost anti-HAV antibodies.

Tigecycline Treatment for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review and Meta-Analysis.

Carbapenem-resistant Enterobacteriaceae (CRE) infections are prevalent worldwide; they have few effective treatments and this jeopardizes public health. Clinicians often use tigecycline to combat CRE, but its clinical efficacy remains controversial. Therefore, to compare the efficacy and safety of tigecycline in treating CRE infections compared with that of other antimicrobial agents, and to evaluate whether combination therapy and high-dose regimens are beneficial, we performed a systematic review and meta-analysis.PubMed and Embase were searched for controlled trials or cohort studies reporting the efficacy and/or safety of tigecycline-based regimens to treat CRE infections. Statistical analyses were performed using the Comprehensive Meta-Analysis V2.2. All meta-analyses were performed based on fixed- or random-effects model, and the I2 method was used to assess heterogeneity.Twenty-one controlled studies and 5 single-arm studies were included in this systematic review. With regard to the controlled studies, the tigecycline groups did not differ significantly from the control groups in terms of overall mortality (Odds ratio (OR) = 0.96 [95% confidence interval (CI) = 0.75–1.22; P = 0.73]), clinical response rate (OR = 0.58 [95% CI = 0.31–1.09; P = 0.09]), or microbiological response rate (OR = 0.46 [95% CI = 0.15–1.44; P = 0.18]). Subgroup analyses showed that 30-day mortality was significantly lower in patients who received tigecycline combination therapy than in those who received monotherapy (OR = 1.83 [95% CI = 1.07–3.12; P = 0.03]) and other antibiotic regimens (OR = 0.59 [95% CI = 0.39–0.88; P = 0.01]), respectively. In addition, high-dose tigecycline regimens differed significantly from standard dose schedules in terms of ICU mortality (OR = 12.48 [95% CI = 2.06–75.43; P = 0.006]). The results of the 5 single-arm studies corroborated the findings of the controlled studies.Our results indicated that the efficacy of tigecycline in treating CRE infections is similar to that of other antibiotics. Tigecycline combination therapy and high-dose regimens may be more effective than monotherapy and standard-dose regimens, respectively. Nonetheless, considering that the current available evidence is limited, well-designed randomized controlled trials are urgently needed to clarify the comparative efficacy of tigecycline in treating CRE infections.

Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer

BackgroundThe present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. Patients and MethodsPostmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m2 orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of ≥ 85%, with a lower 95% confidence boundary > 70%. ResultsThe mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. ConclusionEribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m2 on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation.

The Future of Sublingual Immunotherapy in the United States.

Sublingual immunotherapy (SLIT) is a safe and effective treatment for allergic rhinitis (AR) and allergic rhinoconjunctivitis (ARC). The Food and Drug Administration (FDA) in the USA has approved three SLIT tablets for the treatment of AR and ARC in relation to pollen. Specifically, Grastek® and Oralair® are two formulations approved to treat patients suffering with AR/ARC to grass pollen, and Ragwitek™ is a formulation approved to treat patients suffering with AR/ARC to ragweed pollen. Although these approvals provide support for physicians to prescribe SLIT, barriers to prescribing SLIT still remain such as FDA approval for additional formulations, a standard dose and dosing schedule, and cost/insurance coverage. In order to further support the use of SLIT, research is currently being conducted to expand the indication for SLIT to other common comorbidities to AR/ARC. For example, allergic asthma, food allergies, and atopic dermatitis are other diseases which are being explored. The future of SLIT in the USA is unknown; however, education will be necessary for both providers and patients.

Care of the infant with neonatal abstinence syndrome: strength of the evidence.

There is little empirical evidence that guides management of infants with neonatal abstinence syndrome. The standard of care first described in the 1970s is still prevalent today, although it has never been tested in this population. Standard of care interventions include decreasing external stimulation, holding, nonnutritive sucking, swaddling, pressure/rubbing, and rocking. These interventions meet the goals of nonpharmacologic interventions, which are to facilitate parental attachment and decrease external stimuli. Many nursing interventions used in infants with neonatal abstinence syndrome have been tested in low-birth-weight infants, whose treatment often includes the same goals. Those interventions include music therapy, kangaroo care, massage, and use of nonoscillating water beds. Nursing attitude has also been shown to be impactful on parental attachment. The American Academy of Pediatrics recommends breast-feeding in infants whose mothers are on methadone who do not have any other contraindication. It also provides guidelines for pharmacologic management but cannot provide specific recommendations about a standard first dose, escalation, or weaning schedule. Buprenorphine has some evidence about its safety in newborns with neonatal abstinence syndrome, but high-powered studies on its efficacy are currently lacking. There are many opportunities for both evidence-based projects and nursing research projects in this population.

Prise en charge des accidents vasculaires cérébraux dans un service de médecine interne de la banlieue de Dakar

Co-trimoxazole is widely used in treatment of paediatric pneumonia in developing countries, but drug resistance may decrease its effectiveness. We studied the effectiveness of co-trimoxazole compared with that of amoxycillin in pneumonia therapy, and assessed the clinical impact of co-trimoxazole resistance.We recruited 595 children, aged 2–59 months, with non-severe or severe pneumonia (WHO criteria) diagnosed in the outpatient wards of two urban Pakistan hospitals. Patients were randomly assigned on a 2:1 basis co-trimoxazole (n=398) or amoxycillin (n=197) in standard WHO doses and dosing schedules, and were monitored in study wards. The primary outcome was inpatient therapy failure (clinical criteria) or clinical evidence of pneumonia at outpatient follow-up examination.There were 92 (23%) therapy failures in the co-trimoxazole group and 30 (15%) in the amoxycillin group (p=0·03)—26 (13%) versus 12 (12%) among children with non-severe pneumonia (p=0·856) and 66 (33%) versus 18 (18%) among those with severe pneumonia (p=0·009). For patients with severe pneumonia, age under 1 year (p=0·056) and positive chest radiographs (p=0·005) also predicted therapy failure. There was no significant association between antimicrobial minimum inhibitory concentration and outcome among bacteraemic children treated with co-trimoxazole.Co-trimoxazole provided effective therapy in non-severe pneumonia. For severe, life-threatening pneumonia, however, co-trimoxazole is less likely than amoxycillin to be effective.

Superior Tolerability of Altered Dosing Schedule of Sunitinib with 2-Weeks-on and 1-Week-off in Patients with Metastatic Renal Cell Carcinoma--Comparison to Standard Dosing Schedule of 4-Weeks-on and 2-Weeks-off

Poor tolerability to sunitinib with the standard dosing schedule has become an issue. We retrospectively analyzed the treatment efficacy and the profile of adverse events of 2 weeks of sunitinib treatment followed by 1-week-off (Schedule 2/1) and compared the results with the standard dosing schedule with 4 weeks of treatment followed by 2-weeks-off (Schedule 4/2). From January 2010 until December 2012, 48 patients with metastatic renal cell carcinoma who received at least two cycles of sunitinib as first-line therapy were the subjects of this study. After 2011, we switched to Schedule 2/1 for most patients. Schedule 2/1 included 26 patients and Schedule 4/2 had 22. The incidence of most adverse events was not significantly different between the two groups except for hand-foot syndrome and diarrhoea, which were observed more frequently in Schedule 4/2 and reached statistical significance. A dose interruption due to adverse events in the first three cycles was significantly lower in Schedule 2/1 patients than in those on Schedule 4/2 (27 versus 53% P = 0.04). With respect to treatment efficacy, the objective response rate tended to be higher in Schedule 4/2 than in Schedule 2/1 (50 versus 32%), and median progression-free survival was longer in patients on Schedule 2/1 than those on Schedule 4/2 (18.4 versus 9.1 months). These differences, however, did not reach statistical significance (P = 0.14, P = 0.13). Alteration in dosing schedule of sunitinib with 2-weeks-on and 1-week-off showed a lower incidence of dose interruption and a similar oncological outcome compared with the standard dosing schedule of 4-weeks-on and 2-weeks-off.

Abstract P3-14-18: Dose-dense neoadjuvant chemotherapy in locally advanced breast cancer. Long term results of a cooperative retrospective study

Abstract BACKGROUND: Dose-dense chemotherapy results in better overall (OS) and disease free survival (DFS) in women with hormone receptor-negative early breast cancer as shown with a systematic review and meta-analysis by Bonilla et al (JNCI 2010). Aim of our study was to compare neoadjuvant dose-dense chemotherapy with standard dose schedule in T4 patients in terms of DFS and OS, according to hormone-receptor status. PATIENTS AND METHODS: we analysed, retrospectively, 160 consecutive T4 patients, of median age 52 ys (range 29-73) who received neoadjuvant anthra-based chemotherapy with and without taxanes, observed from 1989 to 2009; 74 patients (46%) received dose-dense schedule (q14) and 86 (54%) conventional dose (q21); 68 (42%) patients were ER-negative (32 q14; 36 q21) and 92 (58%) patients were ER-positive (42 q14; 50 q21). No Trastuzumab was allowed during neoadjuvant treatment. RESULTS: at a median follow-up of 130 months (range 8-241 months), overall, 10 y DFS was 41.9% and 30.2% on q14 and q21 schedules, respectively (p = 0.085); 10 y OS was 48.6% on q14 and 44.2% on q21 schedule, (p = 0.343). ER-negative patients who received q14 schedule had better DFS (46.9%) than those on q21 schedule (16.7%), (p = 0.007) [Relative Risk 0,63 and Odds Ratio 0,22] and better OS (50%) than those on q21 schedule (30.6%) (p = 0.083) [Relative Risk 0,61 and Odds Ratio 0,44]. DFS and OS did not differ on q14 and q21 schedules in ER- positive patients. CONCLUSIONS: Our findings are consistent with published data and suggest that there is no appreciable survival benefit from increasing dose density among T4 ER-positive patients. Dose-dense neoadjuvant chemotherapy may be justified in LABC patients with T4 ER-negative tumors. DFS OS q 14q 21pq 14q 21pER-46,9%16,7%0.00750%30,6%0.083ER+38,1%40,0%0.51247,6%54,0%0.344 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-18.

A Survivin-Associated Adaptive Response in Radiation Therapy

Adaptive responses can be induced in cells by very low doses of ionizing radiation resulting in an enhanced resistance to much larger exposures. The inhibitor of apoptosis protein, survivin, has been implicated in many adaptive responses to cellular stress. Computerized axial tomography used in image-guided radiotherapy to position and monitor tumor response uses very low radiation doses ranging from 0.5 to 100 mGy. We investigated the ability of these very low radiation doses administered along with two 2 Gy doses separated by 24 hours, a standard conventional radiotherapy dosing schedule, to initiate adaptive responses resulting in the elevation of radiation resistance in exposed cells. Human colon carcinoma (RKO36), mouse sarcoma (SA-NH), along with transformed mouse embryo fibroblasts, wild type or cells lacking functional tumor necrosis factor receptors 1 and 2 were used to assess their relative ability to express an adaptive response when grown either to confluence in vitro or as tumors in the flank of C57BL/6 mice. The survival of each of these cells was elevated from 5% to 20% (P ≤ 0.05) as compared to cells not receiving a 100 mGy or lesser dose. In addition, the cells exposed to 100 mGy exhibited elevations in survivin levels, reductions in apoptosis frequencies, and loss of an adaptive response if transfected with survivin siRNA. This survivin-mediated adaptive response has the potential for affecting outcomes if regularly induced throughout a course of image guided radiation therapy.

Replication of hepatitis C virus in peripheral blood mononuclear cells in patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin

Hepatitis C virus (HCV) is a primarily hepatotropic virus, but hepatocytes are not the only localization of its replication. It is still unclear if extrahepatic HCV replication, measured as the detection of HCV RNA negative strand in peripheral blood mononuclear cells (PBMCs) before initiation of treatment, has an influence on therapy response. Detection of HCV RNA in extrahepatic sites for assessment of therapy efficacy is not routinely used in clinical practice. The aim of the study was to evaluate whether the replication of HCV in PBMCs affects the rate of sustained virological response (SVR). The study group comprised 55 patients with chronic hepatitis C, originally treatment naive. They were treated with pegylated interferon (PEG-IFN) alpha 2a and ribavirin, with the standard dosing schedule. Parallel serum samples for HCV RNA and PBMC samples for HCV RNA negative strand were obtained at baseline, at the end of treatment and 24 weeks after finishing therapy. Undetectable HCV RNA in serum at the end of therapy was found in 48 patients (87.3%), while 33 patients (60.0%) achieved sustained virological response (SVR) (51% for HCV genotype 1 and 78% for genotype 3, respectively). Fifteen individuals (31.3%) were relapsers. Factors associated with significantly higher rate of SVR were young age, mild or no fibrosis and infection with HCV genotype 3. HCV RNA negative strand in PBMCs before treatment was found in 21.8% (12 out of 55 patients). HCV RNA negative strand was detected at baseline more frequently in patients who later achieved SVR. Relapse appeared significantly more often in patients with negative strand at the end of therapy: in 2 out of 15 individuals compared to 0 out of 33 patients (p=0.03). Presence of negative HCV RNA strand in PBMCs before treatment may be suggested as a potential marker of good treatment response. Detection of negative strand at the end of therapy is a predictor of relapse.

Pharmacokinetics of Meropenem in Critically Ill Patients With Severe Infections

Meropenem is an effective β-lactam antibiotic that is frequently used to treat serious infections in both intensive care unit (ICU) and febrile neutropenic hematology/oncology (Hem/Onc) patients. Studies suggest that to be effective, meropenem concentrations must be maintained above the inhibitory concentrations for the majority of a dosing interval. However, the pharmacokinetics (PK) of meropenem seem to differ in critically ill patients compared with healthy or less ill subjects used to select labeled dosing regimens. This study was designed to investigate meropenem PK in critically ill patients and to see how often standard dosing regimens produced adequate plasma concentrations. A secondary objective was to investigate how achieved concentrations were related to outcomes (morbidity and mortality) in these patients. Meropenem plasma concentrations over time were measured using a high pressure liquid chromatography assay in febrile Hem/Onc and ICU patients who were treated with standard meropenem dosing schedules. Outcomes such as fever control and survival were assessed in these patients and compared with individual meropenem PK data and with recommended target concentrations. A total of 25 subjects including 10 febrile Hem/Onc and 15 ICU patients with a variety of serious illnesses and baseline renal function were studied. Mean peak concentrations were less variable than were pre-dose concentrations. Post peak and trough concentrations were often below recommended minimum inhibitory concentrations. Both clearance and volumes of distribution were greater than reported in less ill subjects, only in part explained by increased renal clearance. Therefore, serum concentrations often did not exceed recommended concentration targets even for moderately sensitive organisms. Inadequate concentrations were especially common in the mostly ill, febrile neutropenic Hem/Onc subjects and seemed to explain at least some therapeutic failures. Conversely, drug accumulation occurred in ICU subjects with decreased renal function. Standard meropenem dosing regimens were inadequate in many critically ill febrile, neutropenic Hem/Onc, and septic ICU patients. These data suggest a role for meropenem concentration monitoring in such patients.

Current Advances in Radiotherapy for Newly Diagnosed Glioblastoma Multiforme

Glioblastoma multiforme is the most common adult primary brain tumor that is associated with very poor survival. The current standard therapy for newly diagnosed glioblastoma multiforme includes surgical resection and a combination of radiotherapy and chemotherapy with temozolomide. This treatment strategy leads to better overall survival; however, majority of tumor recurrences occur within the irradiated field. To overcome this problem, dose intensification is being tested in the management of glioblastoma multiforme. In recent years, technological development of radiotherapies, such as intensity-modulated radiation therapy, stereotactic radio surgery, stereotactic radiation therapy, boron neutron capture therapy, and particle beam therapy, has improved dose distribution. Several prospective studies using these radiotherapies have shown that dose escalation is feasible and appears to be effective. Although the number of patients with glioblastoma multiforme in each study was not large, the survival times in these studies tended to be better than in those with standard dosing schedules. Dose escalation radiotherapy could be a hopeful strategy for patients with glioblastoma multiforme. In this review, we review advances in current radiotherapies for patients with newly diagnosed glioblastoma multiforme.

Pharmacokinetic and Pharmacodynamic Analysis of Ocaratuzumab in 50 Patients with Relapsed Follicular Lymphoma and Low-Affinity FcγRIIIa (CD16a) Polymorphisms.

Abstract 2750Ocaratuzumab, previously known as AME-133v, is a Fc- and Fab-engineered humanized anti-CD20 monoclonal antibody designed for optimized affinity to the CD20 antigen as well as to the FcγRIIIa (CD16a) receptor on effector cells. It demonstrates 13–20 fold higher affinity for CD20 and 6-fold higher antibody-dependent cellular cytotoxicity compared to rituximab.In a Phase II study, 50 patients received IV ocaratuzumab at 375 mg/m2 weekly for 4 doses, the standard dosing schedule of rituximab. The median age (range) was 61 (39–83) years and the median number of prior systemic therapies (range) was 2 (1–9). Two patients were rituximab naïve.This abstract describes the pharmacokinetics (PK) and pharmacodynamics of ocaratuzumab. The steady state concentration of ocaratuzumab was reached by the 2nd dose and started to decline 1 week after the last dose. The PK of ocaratuzumab is best characterized by a 2-compartment model with a typical clearance estimate of 0.26 L/day. The typical volume estimates for the central and peripheral compartments were 3.15 L and 3.31 L respectively, which corresponds to a terminal half-life of approximately 19 days.As expected, there was significant inter-patient variability in the clearance of ocaratuzumab. Analysis of the serum concentration of ocaratuzumab revealed no correlation between serum ocaratuzumab concentration and progression free survival (PFS) as some patients with low concentrations had prolonged PFS and some patients with high concentrations had short PFS (Figure 1).Only 2 patients developed high titers of human anti-human antibody. These 2 patients maintained very low concentrations of ocaratuzumab and were amongst 3 total patients who demonstrated progressive disease in the study.All patients had rapid and sustained B-cell depletion for at least 90 days after the last infusion. A retrospective analysis of B-cell recovery and response showed a direct correlation between time to B-cell recovery and PFS duration. Patients with prolonged B-cell depletion stayed in remission longer than patients who recovered their circulating B-cells more quickly.In conclusion, clinical efficacy was seen across a wide range of serum concentrations of ocaratuzumab, suggesting significant potency of the drug even at low serum concentration levels. Despite all patients having low-affinity FcγRIIIa polymorphisms, the overall response rate was 32% with a median PFS of 38 weeks. Although a weekly dose of 375 mg/m2 for 4 doses was used in this trial, lower doses of ocaratuzumab, such as 100 mg/m2 given once weekly for 4 doses, may potentially be effective. [Display omitted] Disclosures:Du:Mentrik Biotech, LLC: Employment. O’Reilly:Mentrik Biotech, LLC: Employment. Le:Mentrik Biotech, LLC: Employment. Jain:Mentrik Biotech, LLC: CEO Other, Employment, Equity Ownership, Patents & Royalties.

393 - Vinorelbine with or without Trastuzumab in Metastatic Breast Cancer

ABSTRACT Background Vinorelbine is one of the most widely used drugs in metastatic breast cancer. We report a single center experience with vinorelbine with or without trastuzumab in patients with metastatic breast cancer. Patients and methods All patients with metastatic breast cancer receiving vinorelbine with or without trastuzumab during a six years period were retrospectively reviewed. Demographic data and data on response, time to progression (TTP) and survival were collected. Patients received vinorelbine IV 25-30 mg/m2or PO 60-80 mg/m2 in days 1 and 8 of a 21 days cycle. In patients who received concomitant trastuzumab a standard dosing schedule with 8 mg/kg loading dose followed by 6 mg/kg in subsequent administrations every three weeks was used. Results Eighty seven women were included. The median age was 63 years (range 32 to 85). Sixty two patients received vinorelbine alone and 25 patients received vinorelbine with trastuzumab. In 67 patients this was the first line treatment for metastatic disease and in 20 patients it was 2nd or later line of treatment. Seventy patients were evaluable for response while the remaining seventeen patients were not evaluable due to early progression (n = 6) or early termination of treatment for adversary effects (n = 11). The response rate of evaluable patients was 37.1% [1.4% Complete Response (CR) and 35.7% Partial Response (PR)]. Eighteen additional patients (25.7%) had Stable Disease (SD) for three or more months resulting in a Disease Control Rate of 62.8%. Twenty four of 54 (44.4%) patients receiving first line treatment had a response while in the second and subsequent lines setting two of 16 (12.5%) patients responded (x2 = 9.66, p = 0.001). A response was obtained in 63.6% of patients receiving concomitant trastuzumab and in 25% of patients receiving vinorelbine alone (x2 = 13.63, p = 0.0002). The median TTP was six months (range 1-45). Sixty six patients of the cohort have died and the median overall survival was 11.5 months (range 1-83). Adverse effects necessitating interruption of treatment were observed in 18.5% of patients. Conclusion This retrospective study of vinorelbine in metastatic breast cancer confirms a high disease control rate. Response rate is higher in first line treatment compared to subsequent lines and with the combination with trastuzumab. Disclosure All authors have declared no conflicts of interest.

Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function

BackgroundCisplatin-based combination chemotherapy is the mainstay of treatment for locally advanced or metastatic urothelial carcinoma. However, standard dose schedule of cisplatin cannot be used in patients with impaired renal function. We evaluated the safety and efficacy of gemcitabine and a split dose administration of cisplatin in patients with renal dysfunction. Patients and methodsPatients with locally advanced or metastatic urothelial carcinoma with creatinine clearance between 35 and 59ml/min received gemcitabine 2500mg/m2 and cisplatin 35mg/m2 on day 1 and day 15 for an every 28day schedule. ResultsBetween March 2004 and November 2009, 38 patients were treated. Median creatinine clearance was 49ml/min. Median number of cycles per patient was 3 (1–7). There were 15 partial responses (39%) and 12 patients had stable disease (31%). Median progression free survival and overall survival were 3.5 and 8.5months (mo), respectively.Grade 3–4 haematological toxicities were: neutropenia 9%, anaemia 6% and thrombocytopenia 16%. No patient developed renal toxicity. ConclusionsBiweekly gemcitabine and cisplatin is an active and feasible regimen in this subset of patients and could be an option for unfit patients. However, results seem not to be superior to those obtained with carboplatin based regimens in this population of patients.

Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer

S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

Management of bleeding disorders in children

Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules.