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

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

A two-stage design with two co-primary endpoints.

Two-stage designs are commonly used in phase II oncology trial to mitigate the risk of exposing patients to an inefficacious drug. Typically, the decision of moving into stage 2 enrollment is made based on response rate in stage 1 patients; and trials are designed in the hypothesis testing framework. When the primary objective of a trial involves more than one efficacy endpoints it is desirable to extend the two-stage design to a setting that accommodates two hypotheses while controlling overall type I and II errors (α and ß). In this manuscript, we propose a simple method of searching stopping boundaries of both hypotheses simultaneously that satisfy α and ß constrains using binomial distribution. Several design characteristics of these selected boundaries are further examined in order to choose the most desirable design based on an objective function. Simulation is used to confirm the results. A trial design in metastatic breast cancer where both response rate and health-related quality of life are of interest is used as an example of the application of the proposed method. In conclusion, the proposed design is an extension of Simon Two-Stage Design. It can be applied to phase II oncology trials with two independent co-primary efficacy endpoints.

Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer.

Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m(2) IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1-43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3-42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.

A two-stage patient enrichment adaptive design in phase II oncology trials.

Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker-defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy.

Clinical trial design for mild-to-moderate community-acquired pneumonia--an industry perspective.

The use of noninferiority clinical trials is problematic unless one can establish the benefit of the active control versus no treatment. In community-acquired pneumonia, there are no placebo-controlled clinical trials establishing the benefit of antibiotic treatment, because the observed benefit of sulfapyridine and, subsequently, penicillin was established before the advent of randomized clinical studies. Historical data and observational cohort studies have established the marked decrease in mortality resulting from antimicrobial therapy; however, mortality is not a suitable end point for contemporary clinical trials for mild-to-moderate community-acquired pneumonia that is treated with oral antimicrobial drugs in ambulatory patients. There are historical clinical data that describe the timing of spontaneous recovery in patients with documented pneumonia caused by Streptococcus pneumoniae. In addition, there is one contemporary clinical trial that demonstrated superiority in clinical response of levofloxacin versus a cephalosporin regimen of ceftriaxone and/or cefuroxime for treatment of mild-to-moderate community-acquired pneumonia. Using either the historical data or the superiority study of levofloxacin, one can justify a noninferiority margin of 10% for the per-protocol population and 15% for the microbiologically evaluable population for future noninferiority clinical trials for mild-to-moderate community-acquired pneumonia.

Inference methods for saturated models in longitudinal clinical trials with incomplete binary data.

In the longitudinal studies with binary response, it is often of interest to estimate the percentage of positive responses at each time point and the percentage of having at least one positive response by each time point. When missing data exist, the conventional method based on observed percentages could result in erroneous estimates. This study demonstrates two methods of using expectation-maximization (EM) and data augmentation (DA) algorithms in the estimation of the marginal and cumulative probabilities for incomplete longitudinal binary response data. Both methods provide unbiased estimates when the missingness mechanism is missing at random (MAR) assumption. Sensitivity analyses have been performed for cases when the MAR assumption is in question.

Diagnostic criteria for postconcussional syndrome after mild to moderate traumatic brain injury.

This study evaluated the prevalence and specificity of diagnostic criteria for postconcussional syndrome (PCS) in 178 adults with mild to moderate traumatic brain injury (TBI) and 104 with extracranial trauma. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and International Classification of Diseases (ICD-10) criteria for PCS were evaluated 3 months after injury. The results showed that prevalence of PCS was higher using ICD-10 (64%) than DSM-IV criteria (11%). Specificity to TBI was limited because PCS criteria were often fulfilled by patients with extracranial trauma. The authors conclude that further refinement of the DSM-IV and ICD-10 criteria for PCS is needed before these criteria are routinely employed.

Limited agreement between criteria-based diagnoses of postconcussional syndrome.

The objectives of this study were to compare diagnoses of postconcussional syndrome between the International Classification of Diseases, 10th revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). The patient sample was comprised of 178 adults with mild-moderate traumatic brain injury (TBI). The study design was inception cohort, and the main outcome measure was a structured interview 3 months after injury. The results were that, despite concordance of DSM-IV and ICD-10 symptom criteria (kappa=0.73), agreement between overall DSM-IV and ICD-10 diagnoses was slight (kappa=0.13) because fewer patients met the DSM-IV cognitive deficit and clinical significance criteria. Agreement between DSM-IV postconcussional disorder and ICD-10 postconcussional syndrome appears limited by different prevalences and thresholds.

Subject ordered pointing task performance following severe traumatic brain injury in adults.

The utility of a non-verbal, untimed subject ordered pointing task for identifying memory deficit in adult patients with TBI was tested. Using a cross-sectional design, the working memory performance of 70 adults with severe traumatic brain injury (TBI) and 45 uninjured adults was investigated on a computerized, self-paced, non-verbal subject ordered pointing task. Persons with severe TBI were impaired on measures of working memory relative to the control subjects. In addition, the task appeared to be sensitive to severity of injury as measured by the Glasgow Coma Scale, even within a truncated range of severity (GCS scores 3-8). It was concluded that the subject ordered pointing task is useful in identifying memory deficits in persons with brain injury.

Sample size for K 2x2 tables in equivalence studies using Cochran's statistic.

This paper presents a new sample size formula for Cochran's test that uses additional information on stratum-specific success rates and requires fewer subjects for an equivalence study. Equivalence studies are common in clinical trials, where unlike superiority studies, the goal is to show whether a new drug therapy is as effective as a standard one. Stratification is typically used to adjust for differences among individual clinical trial centers with different success rates. The sample size is derived for a clinical trial design where two independent binomial proportions are compared within each stratum. Implementation of the sample size formula is described when the number of centers is large and the success rates of each individual center are not known exactly. The effect of variability of the success rates on the power of Cochran's test is shown through simulation. The variability of the success rates is measured by the intracluster correlation coefficient, which can be estimated by the ANOVA estimator of Donald and Donner. The simulation results show that the new sample size formula requires fewer subjects than sample size methods, which ignore stratification. The new method provides greater savings as the variability of success rates among centers increases.

An evaluation of methods for the stratified analysis of clustered binary data in community intervention trials.

A simulation study is conducted in a community intervention setting. Several methods of stratified analysis of clustered binary data are compared in terms of empirical significance and empirical power levels. They are the Mantel-Haenszel test statistic (chi(2) (MH)), the adjusted Mantel-Haenszel test statistic of Donald-Donner (chi(2) (DD)), Rao-Scott (chi(2) (RSN) and chi(2) (RSP)), and Zhang-Boos (chi(2) (ZBN) and chi(2) (ZBP)), Wald (chi(2) (W)), robust Wald (chi(2) (RW)), score (chi(2) (S)), robust score (chi(2) (RS)), and the test statistic based on generalized linear mixed model (GLMM) (chi(2) (GLMM)). When rho not equal 0, chi(2) (MH) has inflated type I error, and it should not be used when observations are correlated. The results also warn of the use of chi(2) (RSN) and chi(2) (RW) due to their poor performance in terms of empirical significance level. chi(2) (ZBP) and chi(2) (GLMM) have better empirical significance levels as compared to other statistics; however, chi(2) (ZBP) tends to have lower empirical powers than other statistics when the number of clusters (N) is less than 24. chi(2) (RSP) provides the highest empirical powers when rho > or = 0.1 and N < or = 12. When rho < or = 0.01, we recommend the use of chi(2) (RS) and chi(2) (GLMM) since they have better overall performance in terms of empirical significance levels and empirical power levels.