In oncology, the aim of dose-finding phase I studies is to find the maximum tolerated dose for further studies. The use of combinations of two or more agents is increasing. Several dose-finding ...designs have been proposed for this situation. Numerous publications have however pointed out the complexity of evaluating therapies in combination due to difficulties in choosing between different designs for an actual trial, as well as complications related to their implementation and application in practice.
In this work, we propose R functions for Wang and Ivanova's approach. These functions compute the dose for the next patients enrolled and provide a simulation study in order to calibrate the design before it is applied and to assess the performance of the design in different scenarios of dose-toxicity relationships. This choice of the method was supported by a simulation study which the aim was to compare two designs in the context of an actual phase I trial: i) in 2005, Wang and Ivanova developed an empirical three-parameter model-based method in Bayesian inference, ii) in 2008, Yuan and Yin proposed a simple, adaptive two-dimensional dose-finding design. In particular, they converted the two-dimensional dose-finding trial to a series of one-dimensional dose-finding sub-trials by setting the dose of one drug at a fixed level. The performance assessment of Wang's design was then compared with those of designs presented in the paper by Hirakawa et al. (2015) in their simulation context.
It is recommended to assess the performances of the designs in the context of the clinical trial before beginning the trial. The two-dimensional dose-finding design proposed by Wang and Ivanova is a comprehensive approach that yields good performances. The two R functions that we propose can facilitate the use of this design in practice.
Purpose Observational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and ...unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC). Patients and methods Causal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative. Results In the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model. Conclusion Unmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.
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:
Pain is a common symptom of hemophilia that may adversely affect patients’ quality of life (QoL). Previous post hoc analyses of prophylaxis with recombinant factor IX Fc fusion protein ...(rFIXFc) have been published for adults and adolescents, demonstrating improvements in health-related QoL (HRQoL) when assessed by the haemophilia-specific QoL (HaemAQoL) questionnaire.
Objective:
To describe in depth the evolution of QoL, pain- and activity-related domains and questions for pediatric, adolescent, and adult patients with hemophilia B treated with rFIXFc prophylaxis.
Design:
A post hoc analysis of data from a series of clinical trials.
Methods:
This post hoc, long-term analysis assessed patient-reported outcomes (PROs) from the Kids B-LONG (NCT01440946: pediatric) and B-LONG (NCT01027364: adults and adolescents) parent studies and the B-YOND (NCT01425723: all age groups) extension study.
Results:
Ninety-two adult and adolescent patients that started in the B-LONG study were assessed, with a median (range) duration of follow-up of 58.9 (0.0–78.4) months. The Haem-A-QoL total score was significantly reduced from baseline by 4.45 (p ⩽ 0.01), as were the subdomains ‘physical health’ (9.10; p = 0.001), ‘sports and leisure’ (11.25; p ⩽ 0.01), ‘treatment’ (2.69; p = 0.05), and ‘view of self’ (5.81; p = 0.002). Thirty pediatric patients that started in the Kids B-LONG study were assessed, with a median (min–max) duration of follow-up of 36.7 (9.0–59.9) months. The high level of satisfaction demonstrated by the PROs at baseline was maintained.
Conclusion:
rFIXFc prophylaxis reduced perceived pain and increased levels of physical activity with sustained, long-term improvements in QoL in adult and adolescent patients with hemophilia B and maintained high QoL scores in pediatric patients.
Plain language summary
Helping to reduce pain and increase physical activity in patients with hemophilia B
People with hemophilia B do not produce factor IX (FIX) that works properly, so they need to be given additional FIX to help their blood clot. Recombinant factor IX Fc fusion protein (rFIXFc), is an extended half-life (meaning it remains active for longer than standard, unmodified FIX) treatment for hemophilia B. People with hemophilia B can experience episodes of bleeding, which can result in other symptoms, including pain, difficulty participating in sport, and poor mental health. This study shows that regularly taking rFIXFc over approximately 5 years to prevent or treat bleeds could also help to make these other symptoms better.
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.
•Overall survival (OS) of metastatic breast cancer patients has slightly improved over the past decade.•OS improvement was confined to Epidermal Growth Factor (HER)-2-overexpressing metastatic breast cancer patients.•The uptake of therapeutic innovations was lower than expected.
The optimal dose of targeted treatment in oncology may not be the maximal tolerated dose. Evaluating jointly toxicity and efficacy data is then desirable. We propose an adaptive dose finding approach ...to identify a dose based on repeated binary toxicity and continuous efficacy outcomes from the first two cycles. Probit and linear Gaussian models are used for the toxicity and efficacy at each cycle respectively. The correlation between toxicity and efficacy outcome is modelled via a latent Gaussian variable. Maximum likelihood estimators are used. Two steps in this design are defined: dose escalation with decision rules based only on toxicity observed at the first cycle; the expansion cohort with decision rules based on both repeated toxicity and efficacy outcomes by using the joint model. We perform simulation studies to assess the operating characteristics of our design. The design has good performance for different scenarios. The percentage of correct selection dose varies from 54% to 84%. There is no effect on the estimation parameters with missing data of toxicity or efficacy at cycle 2. The design then has similar performance. Using repeated toxicity and efficacy data in dose finding trials provides more reliable information to estimate the optimal dose for further trials.
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.
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 i.t. administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic (PK) study. With a population PK approach, we described the fate of trastuzumab after i.t. administration in 21 women included in a phase I–II clinical trial. Trastuzumab was administered by i.t. 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/day) whereas estimated half‐life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single i.t. administration of 150 mg of trastuzumab corresponded to median mean residence times 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 i.t. route, is rapidly transferred to the serum.
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