phase-III Trials Research Articles

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

Objectives:Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed.Methods:To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations.Results:The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies.Conclusion:Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.

Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-na\xefve, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial

BackgroundThe value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC.Methods/designThe trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy.DiscussionThis multicenter, prospective, randomized, exploratory phase-II trial will bring about new data regarding the efficacy and safety of abiraterone/prednisone treatment with or without continuation of LHRH therapy. In addition, further insight into the complex hormonal changes under treatment will be gained and the results of this trial may give rise to a larger phase-III trial to examine the possibility of withdrawing LHRH therapy in patients with CRPC.Trial registrationClinicalTrials.gov, ID: NCT02077634. Registered on 9 December 2013.

Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. A major breakthrough in treatment came when, after decades of clinical trials which failed to identify an efficacious treatment regimen, two therapies were successful in Phase-III trials. The advent of these therapies, nintedanib and pirfenidone, meant that for the first time IPF patients had two treatment options that could reduce disease progression. This review summarises the key lessons to be obtained from the clinical trials that led to the current international clinical practice guidelines for the treatment of IPF and provides insights for the design of future clinical trials that are needed if we are to improve outcomes that are clinically meaningful to IPF patients.

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice.

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n=24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3months compared to 2.3months in bortezomib-refractory patients (P<.001). Median overall survival was not reached vs 4.8months (P=.046) in bortezomib-sensitive and bortezomib-refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high-risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study

Background and purposeLocal recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. Material and methodsDose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. ResultsThe median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. ConclusionsFDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Abatacept: A Review in Rheumatoid Arthritis.

The biological DMARD (bDMARD) abatacept (Orencia®), a recombinant fusion protein, selectively modulates a co-stimulatory signal necessary for T-cell activation. In the EU, abatacept is approved for use in patients with highly active and progressive rheumatoid arthritis (RA) not previously treated with methotrexate. Abatacept is also approved for the treatment of moderate to severe active RA in patients with an inadequate response to previous therapy with at least one conventional DMARD (cDMARD), including methotrexate or a TNF inhibitor. In phaseIII trials, beneficial effects on RA signs and symptoms, disease activity, structural damage progression and physical function were seen with intravenous (IV) or subcutaneous (SC) abatacept regimens, including abatacept plus methotrexate in methotrexate-naive patients with early RA and poor prognostic factors, and abatacept plus methotrexate or other cDMARDs in patients with inadequate response to methotrexate or TNF inhibitors. Benefits were generally maintained during longer-term follow-up. Absolute drug-free remission rates following withdrawal of all RA treatments were significantly higher with abatacept plus methotrexate than with methotrexate alone. Both IV and SC abatacept were generally well tolerated, with low rates of immunogenicity. Current evidence therefore suggests that abatacept is a useful treatment option for patients with RA.

A randomized, double-blind phaseIII trial of niraparib maintenance treatment in patients with HRD+ advanced ovarian cancer after response to front-line platinum-based chemotherapy

A randomized, double-blind phaseIII trial of niraparib maintenance treatment in patients with HRD+ advanced ovarian cancer after response to front-line platinum-based chemotherapy

Children’s Oncology Group (COG) clinical trials as exemplars of pragmatism in clinical research.

e18188 Background: In 2016, President Obama announced the “Moonshot Cancer Initiative” to advance cancer research. One of the key components of this initiative is promoting enrollment in pragmatic clinical trials and data sharing. As described in 2009 by Thorpe et al, using the 9-domian PRECIS-2 tool, a ‘pragmatic’ trial, as opposed to an ‘explanatory’ trial used to confirm a physiologic hypothesis, is one in which the intervention can be immediately applied into real-world clinical practice (J of Clin Epi:2009). In the US, 60%-90% children are enrolled on COG research trials. State-of-the-art treatment for a child is derived from superior therapy identified in prior trials which then serves as the standard arm of subsequent phase-III trials and becomes the de facto practice guideline and ‘standard of care’ .To accomplish this goal, COG shares its data among the 242 member institutions.Our objective is to assess “pragmatism” in COG trials. Methods: We analyzed the 158 COG phase III clinical trials between 2006-2016 for all 9 domains of the PRECIS-2 (Table 1) and graded them from 1-5 (most explanatory to most pragmatic). Results: Out of 152 phase III clinical trials on the COG website, 138 (91%) scored 5/5 for all 9 PRECIS pragmatic domains and 148 (98%) scored &gt;4. The scoring for all 9 domains is in table 1. Conclusions: COG provides nearly all children in the United States access to pragmatic phase III research as outlined in the Moonshot Goals. Goal of merging evidence-based standard care accessible to all and conducting well- designed clinical research to identify the best therapies has been accomplished by COG and should serve as an example to other cancer organizations. 9 domains of PRECIS-2 to assess pragmatism in clinical trials. [Table: see text]

Third-line treatment: A randomized, double-blind, placebo-controlled phase III ALTER-0303 study—Efficacy and safety of anlotinib treatment in patients with refractory advanced NSCLC.

9053 Background: Anlotinib hydrochloride, an oral TKI targeting VEGFR, FGFR, PDGFR and c-Kit, showed promising efficacy in PhaseⅡstudy. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced NSCLC, a randomized, double-blind, placebo-controlled Phase Ⅲtrial (ALTER-0303). Methods: Eligible ⅢB/Ⅳ NSCLC pts who progressed after at least 2 lines of prior therapies were randomized 2:1 to receive anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression or intolerable toxicity. Enrolled pts harboring EGFR or ALK mutations must had failed in previous match-targeted therapies. The primary endpoint is OS; secondary endpoint includes PFS, DCR and ORR. Results: As of Aug 2016, total of 437 pts from 31 sites were randomized. The baseline characteristics of Anlotinib arm (N=294) and placebo arm (N=143) were well balanced in the age, gender, ECOG PS and gene states. With 292 OS events (66.82%), significant superiorities in OS, PFS, DCR and ORR were observed in Anlotinib arm according to investigator-assessed results. Grade ≥ 3 treatment-related AEs were hypertension, dermal toxicity and hypertriglyceridemia. There was no treatment–related death in either arm. (Data presented in the Table.) Conclusions: ALTER-0303 trial met its primary endpoint. Anlotinib significantly improved OS and PFS in advanced NSCLC with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced NSCLC. Clinical trial information: NCT02388919. [Table: see text]

A high level of estrogen-stimulated proteins selects breast cancer patients treated with adjuvant endocrine therapy with good prognosis

Background: Adjuvant endocrine therapy has significantly improved survival of estrogen receptor α (ER)-positive breast cancer patients, but around 20% relapse within 10 years. High expression of ER-stimulated proteins like progesterone receptor (PR), Bcl-2 and insulin-like growth factor receptor I (IGF-IR) is a marker for estrogen-driven cell growth. Therefore, patients with high tumor levels of these proteins may have particularly good prognosis following adjuvant endocrine therapy.Patients and methods: Archival tumor tissue was available from 1323 of 1396 Danish breast cancer patients enrolled in BIG 1-98, a randomized phase-III clinical trial comparing adjuvant letrozole, tamoxifen or a sequence of the two drugs. Immunohistochemical staining for ER, HER-2, PR, Bcl-2 and IGF-IR was performed and determined by Allred scoring (ER, PR and Bcl-2) or HercepTest (HER-2 and IGF-IR).Results: Data on all five markers were available from 969 patients with ER-positive, HER-2-negative tumors. These patients were classified in ER activity groups based on the level of PR, Bcl-2 and IGF-IR. High ER activity profile was found in 102 patients (10.5%) and compared with the remaining patients, univariate and multivariate analysis revealed HR (95% CI) and p values for disease-free survival (DFS) of 2.00 (1.20–3.22), 0.008 and 1.70 (1.01–2.84), 0.04 and for the overall survival (OS) of 2.33 (1.19–4.57), 0.01 and 1.90 (0.97–3.79), 0.06, respectively. The high ER activity profile did not disclose difference in DFS or OS according to treatment with tamoxifen or letrozole (p = .06 and .09, respectively).Conclusions: Stratifying endocrine-treated patients in ER activity profile groups disclosed that patient with high ER activity profile (10.5%) had significantly longer DFS and OS, and the profile was an independent marker for DFS. High ER activity is a marker for estrogen-driven tumor growth. We suggest further analyses to disclose whether the ER activity profile or other markers associated with estrogen-driven growth may be used to identify ER-positive high-risk breast cancer patients who can be spared adjuvant chemotherapy.

Current status and future perspectives of laparoscopic radical surgery for advanced gastric cancer.

Laparoscopic radical gastrectomy with lymph node dissection has widely penetrated to East Asian countries, where incidence of gastric cancer occurrence is higher than the rest of the world. Laparoscopic distal gastrectomy for cStageI disease is regarded as one of the option in daily practice in the latest Japanese guidelines; however its applicability to more advanced disease (Stage II/III) is still under debate. Actually, operative techniques of laparoscopic D2 dissection is being matured, but still, necessity of total omentectomy, splenic hilar dissection, management of bulky nodes or large primary tumor, high-level anastomosis in esophageal invasion cases, and extensive peritoneal lavage can be raised as technical limitations. In the future perspective, further technological innovation, including next generation surgical robot, may help surgeons overcome these difficulties. Currently, three large-scaled randomized phase-III clinical trials are ongoing in East Asia, in which patients' accruals have been already completed. With coming long-term outcomes of these well-designed studies, oncological validity of laparoscopic approach will be adequately elucidated.

Sorafenib for the treatment of breast cancer

ABSTRACTIntroduction: Breast cancer treatment includes many options depending on the tumor clinicopathological profile, which groups breast cancer into various subtypes. Bevacizumab is currently the only drug capable of targeting angiogenesis in breast cancer. Sorafenib has also been studied in combination with other agents.Areas covered: Pharmacological aspects of sorafenib, including results from preclinical studies on breast cancer cells; findings about clinical efficacy and safety in both single-arm and randomized clinical trials; ongoing trials.Expert opinion: Since sorafenib as a single agent has shown limited efficacy in breast cancer, its combination with other drugs is under investigation. Dose reduction is the main challenge when sorafenib is combined with chemotherapy or endocrine therapy. Although randomized phase-II trials on sorafenib plus chemotherapy versus chemotherapy alone have shown potential benefits in progression-free survival, preliminary results from a phase-III study in combination with capecitabine are negative. The definitive results of this trial and results from other ongoing phase-II trials will determine further developments of sorafenib in breast cancer. Although these additional data could help determine the most appropriate dose, drug combination and patient settings, a confirmation of the preliminary negative results reported in the phase-III trial are likely to discourage further use of sorafenib in breast cancer, given its non-negligible toxicity, lack of predicting markers, and the number of more promising drugs for breast cancer.

Teduglutide: A Review in Short Bowel Syndrome.

Subcutaneous teduglutide (Revestive®), a glucagon-like peptide-2 analogue that increases intestinal absorption, is approved in the EU for the treatment of short bowel syndrome (SBS) in patients aged ≥1year who are stable following a period of postsurgical intestinal adaptation. In a phaseIII trial in adults with SBS intestinal failure (IF) dependent on parenteral support (PS), a significantly greater proportion of teduglutide 0.05mg/kg/day than placebo recipients achieved a ≥20% reduction in weekly PS volume from baseline to week20 and maintained it to week24. The proportion of patients who had a reduction in one or more days on PS was also significant with teduglutide compared with placebo. Improved intestinal absorption and reduced PS requirements were generally maintained in the longer term. Results from a phase III trial in paediatric patients with SBS-IF dependent on PS were consistent with those in adults. Adverse events were mostly of mild to moderate severity and generally consistent with the underlying condition or known mechanism of the drug (e.g. central line-related issues, gastrointestinal events). Teduglutide is therefore a useful treatment option in children (aged ≥1year), adolescents and adults with SBS.

VP107 Pharmaceutical Industry's Experiences with the German Health Technology Assessment Scientific Advice

INTRODUCTION:The early benefit assessment of drugs was introduced in Germany with the ‘Act to Reorganize the Pharmaceuticals’ Market in the SHI’ (AMNOG) in 2011. Before submitting the manufacturer's dossier, optional scientific advice is offered by the Federal Joint Committee (G-BA). The objective was to elicit manufacturers experience with the scientific advice offered by the Federal Joint Committee.METHODS:To prepare the survey, several manufacturers were interviewed on their experience with the scientific advice offered by the Federal Joint Committee. Subsequently, a questionnaire was developed to collect information for this purpose, comprising eight items on different topics aimed at understanding the perceived quality of the scientific advice provided.RESULTS:The qualitative part comprised seven manufacturers who had received between one and ten advisories before the end of 2012. With regard to the quantitative elicitation part, a total of sixty-one completed questionnaires from nineteen manufacturers were included until the beginning of 2015 (corresponding to almost 25 percent of the overall implemented scientific advice). Fourteen cases were about so called “early” scientific advice in terms of relating to evidence before commencing phase-III trials, forty-four cases concerned “late” scientific advice (pivotal trials were just conducted or already terminated), another two concerned repeated scientific advice and finally, four referred to miscellaneous contents (multiple answers possible). Both, the preceding qualitative and the following quantitative part of the elicitation, highlighted points about the process as well as the content shortcomings from an industry's point of view: inconsistencies, lacking expertise with conducting clinical trials, partially incomplete answers and a low readiness to engage in dialogue were criticized. On the other hand, the majority of respondents showed a positive attitude concerning unambiguousness, completeness, traceability, atmosphere and the protocol of the advice. Over the course of time, propositions on study design, agreement with the determined appropriate comparative therapy and subgroup definitions improved significantly.CONCLUSIONS:A more active involvement of further stakeholders and the incorporation of procedural elements from other health are systems with longer experience could improve the scientific advice provided.

Treatment of Acute VTE with Rivaroxaban - Results of the Prospective Dresden Noac Registry (NCT01588119)

Background: The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be evaluated in unselected patients treated under daily care conditions.Patients and methods: The Dresden NOAC registry is a prospective regional registry in which patients with oral anticoagulation undergo prospective follow- up (FU). So far, more than 3200 patients have been enrolled, including 772 VTE patients with rivaroxaban treatment. For this analysis, only patients with acute VTE who started rivaroxaban within 14 days after diagnosis of VTE and who were enrolled within these 14 days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. All reported outcome events were centrally adjudicated based on source documentation and standard definitions.Results: Between December 1st 2011 and March 31st 2016, 407 patients received rivaroxaban for acute VTE treatment (51.6% female, 80.8% DVT; 19.2% PE±DVT, mean age 61.4 years). Mean time between VTE diagnosis and initiation of rivaroxaban was 1.7±3.3 days (median 0d; 25th/75th percentile 0; 1d). At baseline, rivaroxaban doses consisted of 15 mg BID in 93.1%, 20 mg OD in 3.4%, 15 mg OD in 3.2% and 10 mg OD in 0.2% of patients. Reasons for not using 2x15 mg rivaroxaban BID were pre-treatment with therapeutic parenteral anticoagulants for ≥7 d in 14 cases, comorbidities (e.g. bleeding history, renal impairment) in 4 cases and unknown in 10 cases.During FU (mean 762.4±462.7d), the mean rivaroxaban exposure was 357.7±385.9 days. During treatment with rivaroxaban, 4/407 patients (1.0%) experienced a recurrent VTE, which translated into a recurrence rate of 1.0/ 100 pt. years.During treatment, 172/407 (42.3%) patients reported bleeding complications, which in 13 cases (3.2%; 3.3/100 pt. years) were major bleeding according to ISTH definition, including one fatal intracranial bleeding.Patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) had similar rates of recurrent VTE during rivaroxaban treatment (1.01 and 1.01/100 pt. years) but PE patients had numerically higher rates of major bleeding (3.99/100 pt. years compared to 3.09/100 pt.years in the DVT group).Effectiveness and safety profiles were consistent across relevant subgroups (table 1).18 patients died during FU (2.12/100 pt.years), of which 8 deaths occurred during or within 3 days after last intake of rivaroxaban. Most common causes of death were fatal cardiovascular event (n=7) and terminal malignant disease (n=4), followed by sepsis/infection (n=3), age related death (n=1), fatal bleeding (n=1) and other reasons (n=2).At 6 months (FU completed in 365 pts.), 61.4% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (28.8%) or were switched to other anticoagulants (7.1%). Therefore, the rate of unplanned complete discontinuation at 6 months was 2.7%.At 12 months (FU completed in 289 pts.), 41.5% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (45.0%) or were switched to other anticoagulants (8.3%). Therefore, the rate of unplanned complete discontinuation at 12 months was 5.2%.After rivaroxaban interruption for more than 3 days or permanent discontinuation, 21 patients experienced a recurrent VTE (9 PE±DVT, 12 DVT) with a mean time between last intake of rivaroxaban and VTE recurrence of 351.2±282.6 days (range 7-926d). PE was a common manifestation of VTE recurrence and, despite numerically lower bleeding rates after discontinuation, 2 cases of intracranial haemorrhage occurred (table 2).Conclusions: In unselected patients in daily care, rivaroxaban treatment for acute VTE has high effectiveness and acceptable rates major bleeding. Initial dosing was according to label in over 90% of patients and, at 6 and 12 months, persistence to rivaroxaban therapy was excellent with low rates of unplanned complete discontinuation. Fatal VTE and fatal bleeding are rare events during rivaroxaban therapy and all-cause mortality is mostly related to underlying diseases, age or acute co-morbidities. Treatment discontinuation resulted in a relevant increase in VTE recurrence, of which more than 40% manifested as PE. In contrast, major bleeding rates declined after discontinuation but with 1%/year remained at a clinically relevant level, probably due to co-morbidities. [Display omitted] [Display omitted] DisclosuresMarten:Bayer: Honoraria; Daichii Sankyo: Honoraria. Werth:Pfizer: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; OmniaMed: Honoraria; LEO-Pharma: Honoraria. Beyer-Westendorf:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding.

Replacing 5-fluorouracil by capecitabine in localised squamous cell carcinoma of the anal canal: systematic review and meta-analysis

BackgroundThe standard treatment for localised squamous cell carcinoma of the anal canal (SCCAC) is chemoradiotherapy (CRT) with infusional 5-fluorouracil (5-FU) and mitomycin. Because 5-FU and capecitabine have offered similar efficacy in many phase-III trials of solid tumours, studies have tested capecitabine in this setting of SCCAC. However, these studies are small and have reported variable results. Therefore, a systematic review and meta-analysis was performed.MethodsMedline, Scopus and Embase were searched for studies that evaluated the efficacy outcomes of capecitabine used as a substitute of 5-FU in the CRT of localised SCCAC. The primary endpoint was complete response rate (CRR) at 6 months. Metaprop analysis of reported CRR-based on pooled estimates of proportions with corresponding 95% confidence intervals (95%CI) were calculated on the base of the Freeman-Tukey double arcsine transformation.ResultsWe retrieved 300 studies, of which six met our eligibility criteria. The capecitabine dose ranged from 500 mg/m2 to 825 mg/m2 BID for 5 days per week during radiation. With a total of 218 patients, the median follow-up was 21.5 months (14–23). The pooled analysis of three trials (N = 132 patients) reported a CRR at 6 months of 88% (83%–94%), considering all clinical stages. The pooled analysis of overall CRR (N = 218 patients), evaluated at different intervals, showed an overall CRR of 91% (87%–95%). Rates of locoregional relapse varied from 3.2% to 21%. The majority of patients completed the planned radiotherapy dose (93.5%–100%) and any chemotherapy interruption was reported in up to 55.8% of patients.ConclusionsCapecitabine is an acceptable and more convenient alternative to infusional 5-FU in the CRT for localised SCCAC, offering similar clinical CRR to those reported by phase-III trials.

The Efficacy and Safety of the Fentanyl Iontophoretic Transdermal System (IONSYS®) in the Geriatric Population: Results of a Meta-Analysis of PhaseIII and IIIb Trials.

Background and ObjectivesAcute postoperative pain management in the geriatric patient can be challenging, including their response to medications. The purpose of this analysis was to evaluate whether the efficacy and safety profile of fentanyl iontophoretic transdermal system (ITS) (IONSYS®) was similar in geriatric (≥65 years) and non-geriatric (<65 years) patients.MethodsEfficacy and safety data from three randomized, double-blind, placebo-controlled trials and four randomized, open-label, active-comparator trials were utilized for this analysis. Efficacy was assessed via the patient global assessment (PGA) and the investigator global assessment (IGA) scales. The PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment success defined as excellent or good. Safety was evaluated via adverse events.ResultsA total of 1763 patients were assigned to the fentanyl ITS treatment group. Of the 1763 patients in the fentanyl ITS group, 499 patients were ≥65 years of age; 65.1% were 65–74 years of age, 31.7% were 75–84 years of age, and 3.2% were ≥85 years of age. In the fentanyl ITS treatment groups, there were no statistically significant differences between the non-geriatric and geriatric patients in terms of patients reporting success on the PGA at 24 h (80.0 vs. 83.0%, respectively; p = 0.3415). There were no statistically significant differences between the groups in success rates on the IGA at study discharge (82.8 vs. 87.5%, respectively; p = 0.1195). The safety profile was similar between the age groups.ConclusionsOverall, efficacy and safety of the fentanyl ITS were similar between the geriatric and non-geriatric patients.

Translation Elongation Factor eEF1A2 is a Novel Anticancer Target for the Marine Natural Product Plitidepsin.

eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a KD of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding [14C]-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.

What is new in basal cell carcinoma?

Basal cell carcinoma (BCC) is the most common skin cancer in fair-skinned individuals. Although lymph node or visceral metastases are observed in less than 0.5 % of all cases, BCC can have afatal course due to its highly invasive growth pattern. To provide acomprehensive update on diagnosis, treatment, and prevention of BCC. We review the current literature and recommendations of the German guidelines on treatment and prevention of skin cancer. The most pertinent developments are summarized in this review article. The use of optical coherence tomography and reflectance confocal microscopy can significantly improve the diagnosis of BCC compared with clinical assessment and dermoscopy alone. Mohs micrographic surgery remains the therapeutic gold standard for tumors in the head and facial area and tumors with high-risk features. The application of imiquimod, 5‑fluorouracil, or photodynamic therapy should be restricted to low-risk superficial tumors. Topical inhibitors of the sonic hedgehog (SHH) pathway are currently being evaluated in early clinical trials. In contrast, vismodegib and sonidegib have been approved for the systemic treatment of locally advanced and metastatic BCC with good response rates. The most common adverse events of both agents are muscle cramps, dysgeusia, diffuse alopecia, weight loss, and fatigue. In an Australian phaseIII trial, oral nicotinamide (vitamin B3) reduced the occurrence of new BCC by 20 % in skin cancer patients. Targeted therapy with SHH inhibitors has improved the prognosis of locally advanced and metastatic BCC, albeit at the cost of asignificant number of adverse events.

Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis

ABSTRACTIntroduction: Despite recent advances in pharmacological management, multiple sclerosis (MS), an autoimmune disease of the central nervous system, remains a leading cause of disability. In relapsing-remitting (RR)MS, neurologists most commonly utilize immunomodulatory or immunosuppressive agents to benefit their patients. With the introduction of humanized monoclonal antibodies (mAbs) ablation of distinct immune populations has become possible. Depletion of B cells by anti-CD20 mAbs has repeatedly proven to be a very rapid and effective means to diminish disease activity in RRMS.Areas covered: We discuss the biological rationale, development, and recent clinical study results of the second generation anti-CD20 mAb ocrelizumab.Expert commentary: The topline results of two phase-III randomized clinical trials demonstrate superiority of ocrelizumab over interferon beta in RRMS patients with regards to clinical and paraclinical outcome parameters. The short term adverse events profile appears favorable. However, long-term effects of repeated B cell depletion are currently unknown.