Independent Data Safety Monitoring Committee Research Articles

Protect peripheral intravenous catheters: a study protocol for a randomised controlled trial of a novel antimicrobial dressing for peripheral intravenous catheters (ProP trial)

IntroductionPeripheral intravenous catheters (PIVCs) are the most commonly used vascular access device in hospitalised patients. Yet PIVCs may be complicated by local or systemic infections leading to increased healthcare costs....

0624 Samelisant (SUVN-G3031), Baseline Characteristics from a Phase-2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction Histamine H3 receptor (H3R) antagonists/inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent H3R inverse agonist and exhibits very high selectivity over other targets. In orexin knockout mice, samelisant produced wake-promoting and anticataplectic effects suggesting its potential therapeutic utility in the treatment of excessive daytime sleepiness and cataplexy associated with narcolepsy. It showed dose-dependent H3R occupancy at efficacy doses. Safety and tolerability studies in animals and healthy human volunteers suggested a favorable risk/benefit profile for samelisant.Samelisant is being evaluated in a Phase-2, multicenter, double-blind, placebo controlled, parallel-group study in patients with narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Eligibility criteria for the study include subjects diagnosed with narcolepsy as per ICSD-3, aged between 18 to 50 years with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean maintenance of Wakefulness Test (MWT) time of <12 min. A total of 171 subjects will be randomized into 3 treatment arms (placebo, samelisant 2 mg and samelisant 4 mg) in a fixed 1:1:1. Further, the randomization will be stratified according to the type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks. The primary efficacy endpoint is change in MWT score from baseline to week 2. Secondary endpoints are change in ESS and Clinical Global Impressions of Severity (CGI-S) from baseline to week 2. Safety will be monitored throughout the study by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results At the data cutoff date of Nov30, 2021, a total of 108 subjects were randomized in the study. The median age of subjects was 30 years (range: 18-50 years) with mean BMI of 26.4 (range: 18.3- 43.1 kg/m2). Overall, 58% subjects were of narcolepsy type-1, 69% were female and 74% were Caucasian. Mean (SD) baseline values of MWT and ESS were 6.20 (4.53) and 17.17 (2.93), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling subjects with narcolepsy and the data readout is expected in Q3 2022. Support (If Any) None

Middle Cerebral Artery Aneurysm Trial (MCAAT): A Randomized Care Trial Comparing Surgical and Endovascular Management of MCA Aneurysm Patients

Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty. The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is "Treatment Success": (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS <3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377. Patients with MCA aneurysms can be optimally managed within a care trial protocol.

Tre-P-16 - Phase II trial evaluating resminostat for maintenance treatment of patients with advanced stage (stage IIB–IVB) mycosis fungoides (MF) or Sézary syndrome (SS): RESMAIN study

<h3>Background:</h3> Patients with advanced CTCL disease ((stage IIB–IVB) mycosis fungoides (MF) or Sézary syndrome (SS)) have a poor prognosis and suffer from profound symptom burden. These patients require systemic treatment. However, it is still a key challenge to achieve durable remissions with the available treatment options. CTCL is characterized by the presence of malignant clonal T-cells in the skin and/or blood, lymph nodes or visceral organs. Epigenetic alterations in malignant T cells are known to play a key role in the pathogenesis of the disease. Resminostat is an orally available HDAC-inhibitor, which induces changes in gene expression resulting in growth inhibition, modified cell differentiation and enhanced tumor immunogenicity. The purpose of the RESMAIN study is to investigate resminostat as maintenance treatment for patients with advanced stage mycosis fungoides (MF) or Sézary syndrome (SS) that have achieved disease control with systemic therapy. <h3>Methods:</h3> The RESMAIN study is a multicenter, double blind randomized, placebo controlled, prospective efficacy trial. Patients are randomized 1:1 to the resminostat and the placebo arm. Furthermore, patients are stratified according to their remission status and their disease stage immediately prior to the last systemic therapy. Patients will be treated until disease progression. Patients of the placebo arm have the option to receive resminostat treatment. In addition, exploratory biomarker analyses will be performed. <h3>Results:</h3> The study is conducted in 11 European countries at 51 sites and at 5 sites in Japan. The first patient was enrolled in January 2017. Recruitment was impacted by the COVID-19 pandemic but continued slowly in 2020 and is now in its final stage. The independent data safety monitoring committee (DSMB) recommended continuation of the ongoing RESMAIN study without modification after a pre-specified review of cumulative safety data of the first 50, 100, ,150 and 175 patients which had completed at least one treatment cycle. The poster will present an actual status update of the RESMAIN study. <h3>Conclusion and objectives:</h3> The primary objective is to determine if maintenance treatment with resminostat increases progression free survival (PFS) compared to placebo. As a key secondary end point the effect of resminostat on time to symptom worsening (TTSW) of pruritus compared to placebo will be assessed. Further secondary endpoints are TTP, TTNT, ORR, OS and HrQoL among others. To our knowledge, this is the first randomized study that investigates the potential of an HDAC inhibitor as maintenance therapy in advanced CTCL.

Dropless penetrating keratoplasty using a subconjunctival dexamethasone implant: safety pilot study

Background/aimRejection is the main cause of graft failure after penetrating keratoplasty (PK). Its prevention by repeated instillation of steroid eye-drops has not evolved in decades. Poor adherence and discontinuous nature...

Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma

Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma

506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of &amp;lt; 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

MO042LNP023: A NOVEL ORAL COMPLEMENT ALTERNATIVE PATHWAY FACTOR B INHIBITOR FOR THE TREATMENT OF GLOMERULAR DISEASE

Abstract Background and Aims The alternative complement pathway (AP) provides the central amplification loop of complement activation and is critically involved in a number of diseases including C3 glomerulopathy (C3G), paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uremic syndrome. There is also evidence for AP dysregulation in IgA and membranous nephropathies (IgAN, MN). Novartis has developed a highly selective oral low molecular weight inhibitor of complement Factor B, a key AP protease. LNP023 potently blocks AP activation in vitro and in vivo and is efficacious in passive Heymann nephritis in rats, suggesting an important role of the AP in classical-pathway mediated nephropathies. Method LNP023 was tested at increasing single or multiple ascending doses in a Phase I safety, tolerability, pharmacokinetic (PK) and pharmacodynamic study in healthy volunteers. Complement inhibition was measured by the ex vivo Wieslab assay and by quantifying fragment Bb level. Results LNP023 was well tolerated at all doses from 5 mg to 400 mg (single dose) and from 25 mg to 200 mg bid for 14 days (multiple dose). There were no deaths, SAEs or AEs leading to study drug discontinuation in LNP023-treated subjects. LNP023 dose-dependently inhibited the AP complement system. Based on the Wieslab assay, maximal inhibition of AP activity (80% or more) was observed 2 hours after a single dose of 10 mg or higher. The level of Bb decreased until 12 hours post-dose. Approximately 30% to 50% decrease in Bb, relative to baseline, was achieved for subjects receiving a single dose of LNP023 of 5mg or higher. For both assays, the duration of this inhibition was dependent upon the dose administered. Persistent inhibition was obtained in the multiple dose cohorts, the magnitude of inhibition being dose-dependent for the Wieslab assay but not for Bb. PK studies showed rapid drug absorption and no evidence of food effect. The plasma clearance was moderate and the terminal half-life was around 20h. There was an under-proportional dose-exposure relationship. Among other mechanisms, binding to highly expressed target (Factor B) is believed to affect clearance and thus exposure. Following a successful proof of concept Phase 2 study in PNH (data not shown), LNP023 is currently being investigated in three ongoing Phase 2 studies in IgAN (NCT03373461), C3G (NCT03832114) and MN (NCT04154787). The IgAN study has an adaptive seamless design; the first part has recently completed, 46 patients having received 3 months of one of three LNP023 doses or placebo. The study remains blinded; however, similar to the FIH study safety appears excellent, with only one treatment-emergent SAE (inhalation of chlorine gas) and two SAEs in the post-treatment follow-up period. No patient discontinued randomised treatment for any reason. There were no episodes of proven infection with encapsulated bacteria. The independent data safety monitoring committee have endorsed the study proceeding to the second part with the addition of a fourth LNP023 dose and recruitment is ongoing, completion being anticipated in mid-2020.

Stereotactic Radiation Therapy Combined With Immunotherapy Against Metastatic Melanoma: Long-Term Results of a Phase 1 Clinical Trial

To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy. Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression free (PFS) and overall survival (OS) of this cohort. Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than for those receiving 15 Gy, 8.3 months versus 2.1 months (P = .38). The only treatment-related factor associated with both improved PFS (HR 0.08, P < .01) and OS (HR 0.008, P ≤ .01) was receiving SABR with cycle 3. SABR dose (PFS P = .17, OS P = .50) was not significant. SABR at 10 Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimize synergism.

The RISE trial: A Randomized Trial on Intra-Saccular Endobridge devices.

Wide-necked bifurcation aneurysms (WNBA) are a difficult subset of aneurysms to successfully repair endovascularly, and a number of treatment adjuncts have been designed to improve on the results of coiling, including stenting and flow diversion of the parent vessel. Surgical clipping is commonly performed for certain WNBAs, such as middle cerebral aneurysms, in some centres. Intra-saccular flow diversion (ISFD) using the Woven Endo-Bridge (WEB) or similar devices, has been developed as a new endovascular alternative to coiling for WNBAs. Meta-analyses of case series suggest satisfactory results, both in terms of safety and efficacy, but in the absence of randomized evidence, whether ISFD leads to better outcomes for patients with WNBA remains unknown. There is a need to offer ISFD within the context of a randomized care trial. The proposed trial is a multicentre, randomized controlled care trial comparing ISFD and best conventional management option (surgical or endovascular), as determined by the treating physician prior to randomized allocation. At least 250 patients will be recruited in at least 10 centres over a four-year period, and followed for one year, to show that ISFD can increase the incidence of successful therapy from 75 to 90% of patients, defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS ≤ 2) at one year. The trial will be followed by an independent data safety monitoring committee to assure the safety of participants. Introduction of intra-saccular flow diversion can be accomplished within a care trial context.

A pre-specified statistical analysis plan for the VERIFY study: Vildagliptin efficacy in combination with metformin for early treatment of T2DM.

AimsTo ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial.Materials and MethodsVildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly‐diagnosed type 2 diabetes (T2DM) patients.ResultsThe SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine‐tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre‐specified subgroup analyses is provided here.ConclusionAccording to optimal trial practice, the details of the statistical analysis and data‐handling plan prior to locking the database are reported here. The SAP accords with high‐quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.

Stereotactic radiotherapy combined with immunotherapy is safe and effective: Results from a phase I clinical trial.

9557 Background: There is growing evidence to suggest synergism between stereotactic ablative radiotherapy (SABR) and immunotherapy (IO) against metastatic melanoma. The optimal timing and dosing of SABR for this purpose has not been established. Here, we report results from a Phase I trial, finding the best outcomes with low dose SABR delivered late. Methods: Metastatic melanoma pts with at least two metastases received SABR to a single metastatic site. All pts had standard dose IO with anti-PD1 and/or anti-CTLA4. Following a standard 3+3 design, pts were escalated through three SABR doses (10Gy, 15Gy and 20Gy) delivered at three different time points (Cycle 1, 2, or 3 of IO). Dose limiting toxicity (DLT) were defined as Grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or cox regressions were used to assess the impact of SABR dose, timing and use of combination IO on toxicity, progression-free (PFS) and overall survival (OS) while controlling age, gender and baseline performance status. Results: Between April 2016 and August 2018, 24 pts were enrolled. The median age was 66 years and most were ECOG 0-1 (92%). The median follow-up was 10 months. Three pts (12.5%) developed DLTs (enterocolitis, hepatitis and liver function derangement). None occurred at SABR treated sites and all were in pts receiving 15Gy. DLTs were not associated with SABR timing (p = 0.44) or use of combination IO (p = 0.72). On this basis the IDSMC recommended stopping the trial and maximum tolerated SABR dose was defined at 10 Gy. The median PFS and OS were respectively 5.4m (95% CI 2.1m-NR) and 16.9m (95% CI 7.1m-NR). The median PFS for those receiving 10Gy was numerically higher than those receiving 15Gy (11.8m vs 2.6 m, p = 0.42). The only treatment related factor associated with improved PFS (HR = 0.14, p = 0.02) and OS (HR = 0.09, p = 0.04) was receiving SABR with Cycle 3. SABR dose (PFS p = 0.75, OS p = 0.67) and IO type (PFS p = 0.13, OS p = 0.06) were not significant. Conclusions: SABR combined with IO is generally safe overall. We found the optimal therapeutic index may be achieved with 10Gy delivered with the third cycle of IO; a strategy that warrants further testing. Clinical trial information: ACTRN12616001064493.

Treatment of Bleeding in Severely Thrombocytopenic Patients with Transfusion of Dimethyl Sulfoxide (DMSO) Cryopreserved Platelets (CPP) Is Safe - Report of a Phase 1 Dose Escalation Safety Trial

Treatment of Bleeding in Severely Thrombocytopenic Patients with Transfusion of Dimethyl Sulfoxide (DMSO) Cryopreserved Platelets (CPP) Is Safe - Report of a Phase 1 Dose Escalation Safety Trial

Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer

Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). Patients (stage IIIB/IV or recurrent disease with nonadenocarcinoma histology) who had previously received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus erlotinib 150 mg/day or erlotinib alone every 3 weeks. The primary end point was overall survival (OS). Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.91-1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6 months for erlotinib alone (HR 1.08; 95% CI 0.90-1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatment-related deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab). The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma NSCLC. Clinical development of figitumumab has been discontinued. NCT00673049.

A Multicenter Phase-Ib/II Study of Ruxolitinib/Pomalidomide Combination Therapy in Patients with Primary and Secondary Myelofibrosis: Safety Data from the Mpnsg-0212 Trial (NCT01644110)

Background: Myelofibrosis (MF) is characterized by poor prognosis, and patients (pts) frequently present with constitutional symptoms, splenomegaly, and anemia. Although ruxolitinib (RUX) is available for the treatment of constitutional symptoms and splenomegaly, therapeutic options for the treatment of anemia are limited. Recent data indicate that immunmodulatory drugs such as lenalidomide or pomalidomide (POM) can improve anemia and/or thrombocytopenia. We designed a multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212) to evaluate potential synergistic effects in MF.Aims: Based on data from the first 6 pts,we performed a safety assessment to evaluate feasibility and toxicity of combination therapy. Primary study-endpoint is response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, response duration, quality of life, progression-free survival and overall survival.Study Design: Key inclusion criteria are primary or secondary (post-ET / post-PV) MF, anemia with hemoglobin level <10 g/dL, and splenomegaly. Key exclusion criteria are MF pts suitable for allotransplant, platelets <100x10E+9/L, and neutrophils <0.5x10E+9/L. POM is given at a fixed dosage of 0.5 mg QD. RUX was started at 10 mg BID. Dose modifications of RUX were allowed to increase efficacy and to manage myelosuppression. Safety assessment is done after treatment of the first 6 pts for ≥1 cycle. The safety profile is defined favourable if ≤1 of the first 6 pts had a treatment limiting toxicity associated with one of the study drugs (non-hematological toxicity CTCAE ≥°3 and/or hematological toxicity CTCAE ≥°4).Results: Between August 2013 and March 2014, 6 pts were registered. Database lock for the safety analysis was April 22, 2014. Median time on treatment was 4.3 months (range, 1.0-9.4 months). RUX dose was maintained at 10 mg BID in 5 pts, and increased stepwise to 20 mg BID until cycle 6 in 1 pt (ID001). POM was administered continuously. In total, 8 hematological toxicities CTCAE °3 (anemia) were recorded in the 6 pts over the total period of 26 cycles; 3 events already pre-existed before study entry and affected the same pt (ID005). In contrast, anemia increased in 5 pts and made RBC transfusions necessary. However, no CTCAE °4 anemia, no CTCAE °3/4 thrombocytopenia, and no CTCAE °3/4 neutropenia occurred.Study treatment was stopped in 2/6 pts, in ID003 at cycle 3 (cardiac decompensation) and in ID002 at cycle 6 (withdrawal). The following events of non-hematological toxicities CTCAE °3 (n=2) and °5 (n=1) were observed in these 2 pts: 2 SAEs (neuropathy and pneumonia) in ID002 and 1 SUSAR (cardiac decompensation) in ID003 who died during an in-hospital stay. No causal relationship with the study drugs was seen for pneumonia, whereas neuropathy was considered POM-associated. After discontinuation of POM, neuropathy resolved. ID003 was hospitalized for cardiac decompensation with immediate stop of study drugs and died 13 days later. Therefore, causal relationship between study treatment and the SUSAR is unlikely. Three additional unrelated non-hematological adverse events CTCAE °3 occurred in the remaining pts: 1 was pre-existing without aggravation (muscle cramps) and 2 represented MF symptoms not meeting seriousness criteria (musculoskeletal pain, reduced general condition).Conclusion: Based on our safety analysis, the combination therapy was well tolerated. The observed toxicities were within the expected range according to the reported toxicity profiles for the respective single agents and with regard to the general condition of the pts. Therefore, the safety profile of 6 pts treated within the MPNSG-0212 trial was favourably evaluated by the investigators and by an independent data safety monitoring committee. Recruitment of the study continues. An update on safety and first efficacy data will be presented. DisclosuresNo relevant conflicts of interest to declare.

Commentary

Commentary

On independent data monitoring committees in oncology clinical trials.

An independent data safety monitoring committee (IDMC) that is established to monitor the safety of participants in a clinical trial has, as its primary purpose, the protection of participants in the trial and the maintenance of the integrity of the trial. The IDMC should operate under a clear charter, with expectations understood by all its members. The investigators and sponsors should trust their IDMCs and give the IDMC the tools that it needs to operate effectively. The need to separate the investigators of randomized clinical trials from ongoing data has become widely appreciated. Especially when the study in question is a so-called 'phase III', or confirmatory, trial, knowledge of ongoing results can subtly or explicitly affect the care of participants in the trial, the methods of data collection, and the recruitment of new participants into the trial. These changes, if data-driven, can induce bias and therefore affect the scientific integrity of the trial. Failure to monitor the ongoing data, however, may put patients at undesirable risk, especially if emerging data indicate an unknown adverse consequence of therapy. The use of IDMCs has increased perhaps in response to the growing sophistication of the community of clinical trialists, the US Food and Drug Administration (FDA) draft guidance on data monitoring committees, the US National Institutes of Health (NIH)'s current rules for data monitoring plans, and the Data Monitoring Committees: Lessons, Ethics, Statistics Study Group from the UK National Health Service (DAMOCLES) recommendations. This article summarizes and describes the design and operations of IDMCs in oncology. IDMCs in oncology share many similarities with IDMCs in other disease areas, but the particular nature of cancer patients affects the operation of these committees. IDMC are important in oncology clinical trials because of the severity of illness and the often toxic effects of treatments.

Comparative Safety Profile of Levofloxacin in 2523 Children With a Focus on Four Specific Musculoskeletal Disorders

Fluoroquinolones, including levofloxacin, have not been recommended for use in children largely because studies in juvenile laboratory animals suggest there may be an increased risk of fluoroquinolone-associated cartilage lesions. A large prospective trial is needed to assess the risks associated with using levofloxacin in children. Assess the safety and tolerability of levofloxacin therapy in children based on observations for 1 year after therapy. Safety data were collected in children who participated in 1 of 3 efficacy trials (N = 2523) and a subset of these children who also subsequently participated in a long-term 1-year surveillance trial (N = 2233). Incidence of adverse events in children randomized to receive levofloxacin versus nonfluoroquinolone antibiotics was compared. Based on assessments by treating physicians and an independent data safety monitoring committee, events related to the musculoskeletal system were further categorized as 1 of 4 predefined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) considered most likely clinical correlates of fluoroquinolone-associated cartilage lesions observed in laboratory animals. Levofloxacin was well tolerated during and for 1 month after therapy as evidenced by similar incidence and character of adverse events compared with nonfluoroquinolone antibiotics. However, incidence of at least 1 of the 4 predefined musculoskeletal disorders (largely due to reports of arthralgia) was greater in levofloxacin-treated compared with nonfluoroquinolone-treated children at 2 months (2.1% vs. 0.9%; P = 0.04) and 12 months (3.4% vs. 1.8%; P = 0.03) after starting therapy. The incidence of 1 or more of the 4 predefined musculoskeletal disorders identified in nonblinded, prospective evaluations, was statistically greater in levofloxacin-treated compared with comparator-treated children.

Temozolomide in Non—Small-Cell Lung Cancer: Preliminary Results of a Phase II Trial in Previously Treated Patients

Virtually all patients with advanced non—small-cell lung cancer (NSCLC) relapse. Docetaxel has an established, Food and Drug Administration—approved role as salvage therapy in previously treated, platinum-exposed patients. However, the response rate in phase III studies is < 15%, and median survival is only 6-8 months. Temozolomide, a novel triazene derivative with activity in melanoma and anaplastic astrocytoma, has demonstrated activity in C26 adenocarcinoma, Lewis lung cancer, and in phase I studies. A phase II trial was mounted using a unique schedule of oral temozolomide 75 mg/m2 daily for 6 weeks every 8-10 weeks, in patients with previously treated, advanced, incurable NSCLC. Eligibility stipulated an Eastern Cooperative Oncology Group performance status (PS) of 0-2, adequate end organ function, up to 1 prior chemotherapy for advanced (relapsed or metastatic) disease, and up to 1 prior regimen in the context of radiosensitization, adjuvant therapy, or induction. From March 2000 through January 2002, 47 patients (24 male, 23 female) were enrolled. The median age was 67 years. Sixteen patients had a PS of 2, 22 had a PS of 1, and 9 had a PS of 0. It was too early to evaluate 9 patients. Toxicity, with the exception of mild nausea and thrombocytopenia, was negligible. Three patients had a delayed recovery of platelets prompting discontinuation of treatment. Of the 38 evaluable patients, 1 patient had a complete response, 2 patients had a partial response, 12 had stable disease, and 19 had disease progression. Four patients were not evaluable. Six patients died within 30 days of taking temozolomide; 5 of these deaths were not related to treatment upon review by an independent data safety monitoring committee. Temozolomide, using a unique 6-week continuous schedule, has demonstrated activity in the salvage therapy of advanced NSCLC. Toxicity is modest, and accrual to this study continues.