Anlotinib in chemotherapy-refractory metastatic esophageal squamous cell carcinoma (ESCC): A randomized, double-blind, multicenter phase II trial.
Jing HuangJuxiang XiaoWentao FangPing LuQingxia FanYongqian ShuJ. FengShu ZhangYi BaYing LiuChunmei BaiYuxian BaiYong TangYan SongJie He
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95 Background: The treatment option for ESCC patients (pts) progressing after chemotherapy is still uncertain. Anlotinib is a multi-target tyrosine kinase inhibitor involved in tumor angiogenesis and growth, such as vascular endothelia growth factor receptor (VEGFR) 2/3, etc. Methods: Eligible pts were advanced ESCC who had progressed after platinum or taxane containing chemotherapy. Between January 6, 2016 and May 22, 2018, a total of 165 pts from 13 centers in China were randomly assigned (in a 2:1 ratio) to anlotinib arm (n=110), and placebo arm (n=55). Pts were given anlotinib (12 mg/day) or placebo orally from day 1 to day 14 in a 21-day cycle until disease progression or had unacceptable toxic effects. The primary end point was progression-free survival (PFS). Results: Median PFS was 3.0 months with anlotinib and 1.4 months with placebo (HR 0.5, 95% CI, 0.3-0.7; P<0.0001). Complete response occured in 2 pts with anlotinib and 0 pt with placebo. The objective response rates were 7% in the anlotinib group and 4% in the placebo group (P=0.498), and the disease control rates (DCR) were 64% and 18%, respectively (P<0.0001). In anlotinib arm, median duration of response was 5.8 months (range, 3.1-19.7+). Grade 3/4 treatment-related adverse events (TRAE) were reported in 36.7% and 11.0% of the two group pts, and grade 5 TRAE were 2.8% and 0%, respectively. The most common grade 3/4 TRAE (>5%) in anlotinib arm were hypertension (15.6%) and loss of appetite (5.5%). Median overall survival were similar between the groups (6.1 months vs 7.2 months; HR 1.2, 95%CI 0.8-1.8, P=0.4261). The ratio of pts received post study treatments was 41.2% (40/97) in anlotinib arm and 72.7% (40/55) in placebo arm (P=0.0002), including chemotherapy (23.7% vs 54.6%), PD-1 inhibitors (4.1% vs 11.0%), and Apatinib, a VEGFR inhibitor, (10.3% vs 20.0%), etc. Conclusions: In pretreated advanced ESCC pts, anlotinib significantly improved PFS and DCR compared with placebo, with a manageable safety profile. Clinical trial information: NCT02649361.Keywords:
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The use of auxiliary endpoints may provide efficiencies for clinical trial design, but such endpoints may not have intrinsic clinical relevance or clear linkage to more meaningful endpoints. The purpose of this study was to generate a novel endpoint that considers both overall survival (OS) and earlier events such as progression-free survival (PFS) and determine whether such an endpoint could increase efficiency in the design of glioblastoma clinical trials.Recognizing that the association between PFS and OS varies depending on therapy and tumor type, we developed a statistical model to predict OS based on PFS as the trial progresses. We then evaluated the efficiency of our model using simulations of adaptively randomized trials incorporating PFS and OS distributions from prior published trials in neuro-oncology.When treatment effects on PFS and OS are concordant, our proposed approach results in efficiency gains compared with randomization based on OS alone while sacrificing minimal efficiency compared with using PFS as the primary endpoint. When treatment effects are limited to PFS, our approach provides randomization probabilities that are close to those based on OS alone.Use of OS as the primary endpoint, combined with statistical modeling of the relationship between OS and PFS during the course of the trial, results in more robust and efficient trial designs than using either endpoint alone.
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FigureThough overall survival has traditionally been considered the benchmark endpoint in determining efficacy of a treatment in large randomized controlled trials, new data analyzing outcomes of trials in soft tissue sarcomas where progression-free survival and response rate were the primary endpoints found those endpoints to be appropriate surrogates in trials. The findings were published online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2015.64.3437). “Soft tissue sarcomas are a cluster of rare and heterogenic tumors, making trial design and interpretation particularly challenging,” the study's lead author, Alona Zer, MD, of the Division of Medical Oncology at Princess Margaret Cancer Center in Toronto, explained in an email. “Many sarcoma randomized controlled trials used progression-free survival as a primary endpoint. We found that overall survival—the most definitive endpoint in oncology—was used as primary endpoint in only four percent of randomized controlled trials. “It was reassuring to discover that progression-free survival is a good surrogate for overall survival,” she said. The data also showed that other endpoints increasingly being used in clinical trials—three-month progression-free survival and six-month progression-free survival—have no correlation with overall survival. Study Details For the study, the researchers analyzed data from 52 randomized controlled trials in locally advanced/metastatic soft tissue sarcoma. The studies included 9,762 patients and 45 of the studies evaluated cytotoxic agents—and 11 studies included three arms (two experimental arms and one control arm), bringing the total number of comparisons in the analysis to 63. Some of the key findings and trends about the soft tissue sarcoma randomized controlled trials that the researchers reported were the following: The number of trials in soft tissue sarcoma has increased substantially over time with 19 studies being published between 1974 and 1994 and 33 from 1994 to 2014. Overall survival was the primary endpoint in two studies, whereas 23 studies used other time-to-event primary endpoints. Over time, there was an increase in the frequency of progression-free survival as a primary endpoint, as well as a reduction in the use of response rate as an endpoint. Secondary endpoints included overall survival in 39 studies, toxicity/safety in 35 studies, other time-based events in 24 studies, and response rate in 23 studies. Three studies included quality of life as a secondary endpoint. Sponsorship was reported in 42 studies, with 10 studies being sponsored by industry, 23 being sponsored by a cooperative group or an institution, and nine receiving combined funding. Compared with studies published between 1974 and 1994, the studies published in the past two decades were more likely to be supported by industry. Toxicity was reported comprehensively in 20 studies and reported poorly in six studies—with no observed changes in toxicity reporting over time. Surrogacy Analysis The researchers analyzed the surrogacy of the progression-free survival and response rate endpoints for overall survival using weighted linear regression (including only those studies reporting the hazard ratio for overall survival and the hazard ratio for either progression-free survival or data allowing the calculation of overall response for response rate, three-month progression-free survival, or six-month progression-free survival). The data showed a highly significant correlation between overall survival and progression-free survival, a substantially significant correlation between response rate and overall survival, and no significant correlation between three-month progression-free survival and overall survival or between six-month progression-free survival and overall survival. The eligible trials included in this study were found by a search of the MEDLINE, MEDLINE in-process, and EMBASE clinical trial databases, as well as meeting abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. The search included studies conducted between 1974 and December 2014. Because of their distinct biologic characteristics, trials involving bone sarcoma or gastrointestinal stromal tumors were excluded. The researchers also excluded review articles, meta-analyses, systematic reviews, phase I and II nonrandomized clinical trials, observational studies, and case reports. Key Messages “The main message from this study is that the new emerging endpoints—three- and six-month progression-free survival—should be used with caution, and probably not as the primary endpoint in randomized controlled trials for soft tissue sarcomas,” Zer said. “And overall survival is still the ultimate primary endpoint, even though it requires larger, longer, and more expensive studies. “And if a surrogate endpoint is chosen in place of overall survival, our data support the use of progression-free survival.” Additionally, Zer noted that a practical message from the study is that when reading a phase III randomized controlled trial abstract clinicians should pay attention to what primary endpoint was chosen for the study, she said. “Is it legitimate? Does it represent effectiveness of the treatment? Was it validated?” In an accompanying editorial also published online ahead of print in JCO, Fengmin Zhao, MHS, PhD, of the Department of Biostatistics & Computational Biology at Dana-Farber Cancer Institute, discusses a few limitations of the study by Zer et al., including cautions about properly validating surrogate endpoints (doi: 10.1200/JCO.2016.66.4581). But, he notes in the editorial: “Continuous efforts to improve the validation of surrogate endpoints are important in several ways. “In this era of personalized medicine and rapid development of oncology drugs, many drugs are in the pipeline, waiting for testing in phase III clinical trials. It is difficult, if not impossible, to conduct a phase III trial with overall survival as the primary endpoint for a rare disease. Surrogate endpoints usually allow for smaller trials and shorter completion times and, once validated, could help resolve these issues.” Sarah DiGiulio is a contributing writer.
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4072 Background: Pts with advanced or metastatic cholangiocarcinoma (CCA) have limited response to current chemotherapy regimens and poor overall survival (OS). Nab-Paclitaxel (nabPAC) can increase the intra-cellular concentration of gemcitabine (GEM) through depletion of its metabolizing enzyme, cytidine deaminase (CDA). We investigated the nabPAC+GEM combination in a ph II single arm trial in advanced or metastatic CCA pts with exploratory biomarker evaluation, including CDA, hENT1, SPARC and circulating tumor cells (CTCs). Methods: Key eligibility criteria: advanced or metastatic CCA with no prior systemic chemotherapy, age > 18, ECOG PS 0-1 and Child-Pugh < 8. Pts received nabPAC (125 mg/m2 IV) and GEM (1000 mg/m2 IV) days 1, 8 and 15 Q4 weeks until progression. Primary endpoint: progression-free survival (PFS) rate at 6 months. Secondary endpoints: safety, time to progression (TTP), objective response (ORR) and disease control rates (DCR), median PFS and OS, as well as correlation of change in CA 19-9 to clinical efficacy. The study required > 43 of 67 evaluable patients alive and progression-free at 6 months to conclude the 6-month PFS rate is at least 70% against a null hypothesis of 55% based on historical data. Results: 73 eligible patients (41.1% male, 91.8% Caucasian, 45.2% ECOG PS 0) were enrolled across 22 sites with a median age of 62 (range 36-87) years and received a median of 6 (range 1-18) cycles. The primary endpoint of PFS rate at 6 months was 54.7% on intention to treat analysis. Response evaluation is underway and will be reported at the meeting. The median PFS and OS were 6.5 (95% CI, 5.1-7.7) and 10.3 (95% CI, 9.1-14.6) months, respectively. The safety profile of nabPAC+GEM was similar to that reported in ph III MPACT trial. The most common treatment-related G3/4 toxicities were neutropenia (24.3%), fatigue (13.5%) and anemia (12.2%). Five patients remain on the trial. Exploratory analyses are pending. Conclusions: The observed PFS rate at 6 months with nabPAC+GEM in CCA is insufficient to reject the null hypothesis of 55% PFS at 6 months, and appears to be as effective as the historical control. Clinical trial information: NCT02181634.
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Drug repurposing is a promising strategy to develop new treatments for glioblastoma. In this phase II clinical trial, we evaluated the addition of chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol in patients with unmethylated
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Abstract Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. Clin Cancer Res; 19(10); 2607–12. ©2013 AACR.
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The main objective of this project was to estimate progression-free survival rates at different fixed time points in order to design future phase-II trials targeting the progression-free survival rate as primary endpoint in mesothelioma. Response rate has traditionally been used as an endpoint in many phase-II trials of oncology therapies. However, progression-free survival could be a more appropriate endpoint in rapidly progressing disease, at least in three situations: (1) when testing cytostatic agents, (2) when the response to a regimen is difficult to assess, (3) when the response is expected to be low. The use of progression-free survival as an endpoint instead of the response rate is relevant in mesothelioma for two primary reasons. Firstly, the global incidence of mesothelioma is increasing and current treatments yield disappointingly poor results. The development of more active treatments is thus highly desirable and new targeted therapies, including cytostatic agents, are currently the main focus of mesothelioma research. Secondly, in mesothelioma the assessment of response is difficult and not reproducible, and the response rate is usually low. In order to evaluate a novel therapy using progression-free survival rate as the primary endpoint, we need data about the progression of patients and especially about the progression-free survival rate at fixed time point. Data on 523 patients included in 10 mesothelioma trials conducted by the European Organisation for Research and Treatment of Cancer were analysed. Values of progression-free survival rate at 3, 4, 5 and 6 months in groups of different levels of therapeutic activity and in different risk groups were calculated. Our work also provides a prognostic index which allows the definition of more homogeneous groups of patients that avoids dilution of results between groups. Based on these results, the size of future mesothelioma trials can be calculated and designs can be adapted to improve the assessment of the activity of a new therapy. Furthermore the use of progression-free survival rate rather than response rate as a primary endpoint would not require much more time to assess the endpoint. It would also decrease the probability to reject a potentially interesting therapy by considering non-progressive diseases as successes.
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