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Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro-oncology, especially in leptomeningeal carcinomatosis of HER2-overexpressing breast cancer. Case reports of intrathecal (IT) administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic study. With a population pharmacokinetic approach, we described the fate of trastuzumab after IT administration in 21 women included in a phase I-II clinical trial. Trastuzumab was administered by IT route every week for 8 weeks and both cerebrospinal fluid (CSF) and serum were sampled to measure trough concentrations. Some patients showed noticeable CSF concentration fluctuations predicted using a target-mediated drug disposition. This target was latent and produced with a delayed feedback. Apparent volumes of distribution were close to physiological volumes (V1 = 3.25 L, V2 = 0.644 L, for serum and CSF, respectively). Estimated (constant) transfer from serum to CSF was very slow (k12 = 0.264 mg.d-1 ) while estimated half-life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single IT administration of 150 mg of trastuzumab corresponded to median mean residence times (MRT) of 3.8 days and 15.6 days in CSF and serum, respectively. Survival without neurological relapse was not related to trastuzumab exposure. This study confirms that transfer of trastuzumab from serum to CSF is very limited and that this monoclonal antibody, when administered by IT route, is rapidly transferred to the serum.

INTRODUCTION: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL). AIM: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity. METHODS: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL. RESULTS: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL. CONCLUSION: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc.

Background: Pain, a common symptom of hemophilia, begins early in life primarily due to joint bleeding. Recurrent bleeding adversely affects patients’ pain-related physical functioning, which can negatively impact their quality of life (QoL). Objective: Post hoc analysis of data from the A-LONG study (NCT01181128), to assess change over time in pain-related QoL in patients with severe hemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein (rFVIIIFc). Methods: Patients who completed Haem-A-QoL (17–65 years) and EQ-5D-3L (⩾12–65 years) questionnaires at baseline (BL) and end of study (EoS). Individual-level changes were assessed using three pain-related items of the Haem-A-QoL ‘Physical Health’ domain and the pain/discomfort item of EQ-5D-3L. Distributions of responses (EoS versus BL) were compared using McNemar’s test. Results: A significantly greater proportion of patients reported they did not experience painful swellings ( n = 87; 66% versus 46%, p < 0.01) or pain in their joints ( n = 89; 42% versus 27%; p < 0.05) at EoS versus BL. The proportion of patients who did not find it painful to move numerically increased at EoS versus BL ( n = 86; 47% versus 38%; p = NS). A significantly greater proportion of patients reported no pain/discomfort at EoS versus BL ( n = 116; 45% versus 34%; p < 0.05). Conclusion: This study reports the effect of FVIII prophylaxis on patient-reported measures of pain over time in patients with severe hemophilia A. The results of this post hoc analysis showed improvements in pain from BL to EoS in patients receiving rFVIIIFc individualized prophylaxis indicating effective pain management, a key component of patient care.

Background New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. Methods This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). Results Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7–29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9–23.7), and the disease control rate was 85.3% (95% CI, 68.9–95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2–53.67). Conclusions Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

Phase I oncology trials are designed to identify a safe dose with an acceptable toxicity profile. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle, although patients continue to receive treatment for multiple cycles. In addition, the toxicity data from multiple types and grades are typically summarized into a single binary outcome of dose-limiting toxicity. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades. In this work, we propose to account for longitudinal repeated measures of total toxicity profile over multiple treatment cycles, accounting for cumulative toxicity during dosing-finding. A linear mixed model was utilized in the Bayesian framework, with addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design is evaluated using simulation studies and compared with the previously proposed quasi-likelihood continual reassessment method (QLCRM) design. Twelve clinical scenarios incorporating four different locations of maximum tolerated dose and three different time trends (decreasing, increasing, and no effect) were investigated. The proposed repeated measures design was comparable with the QLCRM when only cycle 1 data were utilized in dose-finding; however, it demonstrated an improvement over the QLCRM when data from multiple cycles were used across all scenarios. Copyright © 2016 John Wiley & Sons, Ltd.

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

PurposeThe currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme.ParticipantsAll consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually.Finding to dateWith a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort.Future plansThese real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings.Trial registration numberNCT03275311; Pre-results.

Phase I oncology trials are designed to identify a safe dose with an acceptable toxicity profile. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle, although patients continue to receive treatment for multiple cycles. In addition, the toxicity data from multiple types and grades are typically summarized into a single binary outcome of dose-limiting toxicity. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades. In this work, we propose to account for longitudinal repeated measures of total toxicity profile over multiple treatment cycles, accounting for cumulative toxicity during dosing-finding. A linear mixed model was utilized in the Bayesian framework, with addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design is evaluated using simulation studies and compared with the previously proposed quasi-likelihood continual reassessment method (QLCRM) design. Twelve clinical scenarios incorporating four different locations of maximum tolerated dose and three different time trends (decreasing, increasing, and no effect) were investigated. The proposed repeated measures design was comparable with the QLCRM when only cycle 1 data were utilized in dose-finding; however, it demonstrated an improvement over the QLCRM when data from multiple cycles were used across all scenarios. Copyright © 2016 John WileySons, Ltd.

LBA100 Background: ProfiLER (NCT01774409) is a molecular profiling clinical trial exploring cancer cell genomic alterations in pts with advanced disease to guide treatment. Methods: Pts with confirmed diagnosis of advanced cancers are eligible. DNA extracted from either archival or fresh collected tumor samples was analyzed by targeted exon sequencing of 60 cancer related genes and whole genome array comparative genomic hybridization (CGH). A multidisciplinary molecular board analyzes genomic data and recommends molecular targeted therapies (MTT) when actionable alterations are found. Results: As of Jan 2017, 2490 pts (55% female, median age 59, range 1-90) were consented; 1826 (73.3%) tumors were analyzed, 301 (12%) are ongoing (not done in 363 pts (14.6%) for technical issues). Tumor types were colorectal (10.3%), gyneco (9.5%), breast (8.8%), head & neck (7.1%) carcinomas, sarcomas (7.1%) and brain tumors (6.5%). 940/1826 pts (51.5%) had at least 1 actionable mutation (AM): 579 pts with only one AM, while 358 with 2 or more AM (up to 6). Mutations (including substitutions and small indels), amplifications and homozygous deletions (HD) were observed respectively in 55.3%, 42.1% and 25.5% of tumor samples. The most common AM were on KRAS (n = 156; 8.5%), PIK3CA (n = 150; 8.2%), CDKN2A HD (n = 174; 9.5% ), PTEN HD (n = 49, 2.7%), CCND1 (n = 97; 5.3%), FGFR1 (n = 56; 3.1%), MDM2 (n = 53; 2.9%), HER2 (n = 42; 2.3%) and HER1(n = 41; 2.2%). MTT were recommended in 644 pts. Among them, 101 (gyn [28%], GI [18%], breast [12%]) initiated a recommended MTT. Collection of treatment data is ongoing for 202 pts. MTT received were mTOR inhibitors (39%), anti-angiogenic TKI (21%), EGFR TKI (9.8%), inhibitors of cell cycle (6.9%). Best responses were CR (n = 2, 2.3%), PR (n = 13, 15.1%), SD (n = 29, 33.7%), PD (n = 42, 48.8%), with a median PFS of 2.8 months (95% IC: 2.2-3.5). 24% are alive progression free at 6 months. Updated data will be presented at the meeting. Conclusions: In this series of 2490 cancer pts, CGH and NGS identified actionable alterations on 51% of pts, with treatment recommendation in 35%. Most patients treated derived benefit from the recommended MTT, but these represent a minority of the whole population screened. Clinical trial information: NCT01774409.

1078 Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity at cycle 1, although toxicity is repeatedly measured over cycles on an ordinal scale. Recently, a proportional odds mixed-effect model for ordinal outcomes has been proposed to (i) identify the optimal dose accounting for repeated events and (ii) to provide some framework to explore time trend. We compare this approach to a method based on repeated binary variables and to a method based on an under-parameterized model of the dose-time toxicity relationship. We show that repeated binary and ordinal outcomes both improve the accuracy of dose-finding trials in the same proportion; ordinal outcomes are, however, superior to detect time trend even in the presence of nonproportional odds models. Moreover, less parameterized models led to the best operating characteristics. These approaches are illustrated on two dose-finding phase I trials. Integration of repeated measurements is appealing in phase I dose-finding trials.

Introduction The staging of node-negative non–small-cell lung cancer is modified in the 7th edition TNM classification. Here, we pool data from the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Cancer and Leukemia Group B-9633 trial to explore the prognostic and predictive effects of the new T-size descriptors and KRAS mutation status. Methods Node-negative patients were reclassified as T2a (>3–⩽5 cm), T2b (>5–⩽7 cm), T3 (>7 cm) or T ⩽ 3 cm (⩽3 cm, but other T2 characteristics). Results Of 538 eligible patients, 288 (53.5%) were T2a, 111 (21%) T2b, 62 (11.5%) T3, whereas 77 (14%) T⩽3 cm were excluded to avoid confounding. KRAS mutations were detected in 104 of 390 patients (27%). T-size was prognostic for disease-free survival ( p = 0.03), but borderline for overall survival (OS; p = 0.10), on multivariable analysis. Significant interaction between the prognostic value of KRAS and tumor size was observed for OS ( p = 0.01), but not disease-free survival ( p = 0.10). There was a nonsignificant trend ( p = 0.24) for increased chemotherapy effect on OS with advancing T-size (hazard ratio [HR] T2a 0.90, [0.63–1.30]; T2b 0.69, [0.38–1.24]; and T3 0.57, [0.28–1.17]). The HR for chemotherapy effect on OS in T2a patients with KRAS wild-type tumors was 0.81 ( p = 0.36), whereas a trend for detrimental effect was observed in those with mutant tumors (HR 2.11; p = 0.09; interaction p = 0.05). Similar trends were observed in T2b to T3 patients with wild-type (HR 0.86; p = 0.62), and KRAS mutant tumors (HR 1.16; p = 0.74; interaction p = 0.58). Conclusion Chemotherapy effect seems to increase with tumor size. However, this small study could not identify subgroups of patients who did or did not derive significant benefit from adjuvant chemotherapy based on T-size or KRAS status.

The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.

2577 Background: The emergence of MTA in oncology has revolutionized the phase I design paradigm. The usual dose-limiting toxicity (DLT) endpoint is an oversimplification of the complex toxicity profile resulting in loss of information. Moreover, MTAs can induce less DLTs but more multiple moderate toxicities that may lead to dose reduction in long lasting treatment. We thus sought to develop a new toxicity endpoint, the Total Toxicity Profile (TTP), to incorporate multiple toxicities. Methods: We reanalysed the phase I trial that evaluated erlotinib (75, 100, 125, 150 mg/m2) in children with brain stem glioma (NCT00418327). Only 2/21 patients experienced protocol defined DLTs, but multiple moderate toxicities were observed. The TTP endpoint is a weighted combination of all toxicities experienced by the patient (Euclidean norm of the weights), where the weights (ranging from 0 to 10) reflect the clinical importance of each grade and type of toxicity. The weights and the acceptable toxicity target (target TTP) were elicited from 3 clinicians using hypothetical patient cohorts with various toxicity outcomes. They were asked to make a decision of where the next cohort of patients would be treated: higher, lower or same dose level. The target TTP was defined as the mean of TTPs of the cohorts associated with a decision to repeat the dose. We used the TTP-driven Quasi-Likelihood Continual Reassessment Method (QL-CRM) to re-estimate the recommended dose. Results: Clinicians identified 5 main dermatological toxicity types possibly attributable to erlotinib. The consensus weights (table below) as well as the target TTP (set at 4.66) were easily obtained, confirming the feasibility of the process. The weights differed from the CTCAE grades, confirming the interest of the approach. The recommended dose based on the retrospective analysis of all grades toxicity was lower than that identified by the DLT-driven CRM (100 instead of 125mg/m2). Conclusions: By neglecting multiple moderate toxicities, DLT-driven designs may over-estimate the recommended dose when investigating MTA. Our proposal is an appealing alternative design for MTA. [Table: see text]