Characteristics and outcomes of patients with advanced non-small-cell lung cancer who declined to participate in randomised clinical chemotherapy trials

There are inadequate data on the outcomes of patients who declined to participate in randomised clinical trials as compared with those of participants. We retrospectively reviewed the patient characteristics and treatment outcomes of both participants and non-participants in the two randomised trials for chemotherapy-naive advanced non-small-cell lung cancer. Trial 1 compared four platinum-based combination regimens. Trial 2 compared two sequences of carboplatin plus paclitaxel and gefitinib therapies. Nineteen of 119 (16%) and 153 (37%) patients declined to participate in Trials 1 and 2, respectively. Among the background patient characteristics, the only variable associated with trial participation or declining was the patients'' attending physicians (P<0.001). Important differences were not observed in the clinical outcomes between participants and non-participants, for whom the response rates were 30.6 vs 34.2% and the median survival times were 489 vs 461 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 0.965 (95% confidence interval: 0.73–1.28). In conclusion, there was no evidence to suggest any difference in the characteristics and clinical outcomes between participants and non-participants. Trial designs and the doctor–patient relationship may have an impact on the patient accrual to randomised trials.     

CRAFT—A Proposed Framework for Decentralized Clinical Trials Participation in Canada

Canada’s vast geography, and centralized delivery of cancer care and clinical trials create barriers for trial participation for patients in remote and rural settings. The development and implementation of a framework that enables safe and regulatory compliant trial participation through local healthcare providers would benefit Canadian patients, clinicians, trial sponsors and the health care system. To address this issue, representatives of Canada’s cancer clinical trial community met to identify key challenges and develop recommendations for remote patient participation in trials. A structured literature review identified remote/rural trial delivery models. A panel of expert stakeholders reviewed the models and participated in a workshop to assess health system readiness, identify needed processes, tools and mechanisms, and develop recommendations for a Canadian framework for decentralized clinical trial conduct. The Canadian Remote Access Framework for clinical Trials (CRAFT) represents a risk-based approach used by site investigators to delegate responsibilities for a given trial to satellite health centres within a hub-and-spoke “trial cluster”. The Framework includes specific recommendations to ensure research experience, capacity, regulatory compliance and patient safety. Canada’s cancer care and telemedicine systems can be leveraged to enable broader access to clinical trials for patients who are geographically remote from cancer centres. CRAFT’s risk-based framework is based on other successful models of remote trial patient management and is in the pilot implementation phase in Canada.     

Phase II Trial of Combination Nab-paclitaxel and Gemcitabine in Non–squamous Non–small Cell Lung Cancer After Progression on Platinum and Pemetrexed

BackgroundBetter therapies are needed to improve survival in metastatic non–small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non–squamous (NSQ) NSCLC.Materials and MethodsThis single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m² and gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.ResultsThirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis.ConclusionCombination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning.Trial RegistrationClinicalTrials.gov Identifier: NCT02303977Micro-AbstractIn this phase II trial, 37 patients with metastatic non–squamous non–small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.     

New clinical trial designs in the era of precision medicine: An overview of definitions,strengths, weaknesses,and current use in oncology

With expanding knowledge in tumor biology and biomarkers, oncology therapies are increasingly moving away from the “one-size-fits-all” rationale onto biomarker-driven therapies tailored according to patient-specific characteristics, most commonly the tumor’s molecular profile. The advent of precision medicine in oncology has been accompanied by the introduction of novel clinical trial designs that aim to identify biomarker-matched subgroups of patients that will benefit the most from targeted therapies. This innovation comes with the promise of answering more treatment questions, more efficiently and in less time. In this article, we give an overview of the different biomarker-based designs, comparing the features of enrichment, randomize-all, umbrella, and basket trials, and highlighting their advantages and disadvantages. We focus more on the novel designs known as master protocols, which include umbrella and basket trials. We have also conducted a search in ClinicalTrials.gov for registered oncology-related protocols of ongoing or completed trials labeled as umbrella or basket trials for solid tumors; we also included additional relevant trials retrieved from other reviews. We present and discuss the key features of the 30 eligible basket trials and 27 eligible umbrella trials. Only a minority of them are randomized (2 and 9, respectively), including three trials with adaptive randomization. Five of these trials have been completed as of July 2018. Precision medicine trial designs fuel new hopes for identifying best treatments, but there is also the potential for hype. The benefits and challenges associated with their use will need continued monitoring.     

Quality evaluation of investigator‐initiated trials using post‐approval cancer drugs in Japan

Investigator‐initiated trials (IIT) are important aspects of medical research and have contributed substantially to modern oncology. IIT using post‐approval drugs have been conducted by domestic institutions in Japan. Data from the present study were obtained by all IIT registered clinical trials for five cancers (lung, colorectal cancer, gastric cancer, liver cancer, and breast cancer) using drugs approved from 1999 to 2009 in Japan. Kaplan–Meier method, analysis of variance (anova ), and Kruskal–Wallis test were used to estimate time to enrolment completion (TTEC) and time to enrolment per patient (TTEP). Of 1222 trials eligible for analysis, 465 trials (38%) completed enrolment to the studies, and 203 trials (17%) published results. In the distribution according to trial phase, 98 (8%) were phase I, 1058 (87%) were phase I/II + II, and 66 (5%) were phase II/III + III. Accrual achievement and publication rates were higher in late‐phase than in early‐phase trials. Median TTEC was 1387 days (95% confidence interval [CI], 1302–1472). Median TTEP was 38.5 days (95% CI, 34.5–42.5). The median TTEC and TTEP were significantly different in each trial phase (P < 0.01), funding source (P < 0.01), and publication status (median TTEC published trials versus unpublished trial; 720 days vs 1672 days, median TTEP; 16 days vs 55.8 days; P < 0.001). Many IIT using approved cancer drugs have been conducted; however, the quality of the clinical trials was low in terms of accrual achievement, publication rate, and time to publication of trial results.     

Contract research organizations in oncology clinical research: Challenges and opportunities

Contract research organizations (CROs) represent a multibillion dollar industry that is firmly embedded in the contemporary clinical trial process. Over the past 30 years, and especially within the last decade, the reach of CROs has extended to service all phases of drug trials in an increasingly global research environment. The presence of CROs is particularly noticeable in medical oncology because of the large number of investigational compounds developed to treat cancer that are currently undergoing testing in human subjects. Although limited data are available with which to objectively define the effects that CROs have had on the clinical trial process, with the expansion of these organizations, several reports have called into question whether ethical and professional standards in research conduct are at times secondary to economic considerations. CROs can add considerable value to the clinical trial process, but difficulty communicating with CRO representatives and time spent answering trivial data queries generated by CROs are current obstacles for study site personnel interacting with CROs. Further study of the effect of the CRO industry on the clinical trial process is needed to ensure efficient data collection and patient safety while collaboratively developing novel therapies in an expedited fashion. Cancer 2016;122:1476–82 . © 2016 American Cancer Society.     

Melanoma trials that defined surgical management

Treatment of regional lymph nodes in melanoma has been controversial for more than a century. A series of clinical trials evaluating elective lymph node dissection and then sentinel lymph node biopsy have helped define the current standard of care. These trials resulted in increasingly selective application of surgical intervention for regional lymph nodes in melanoma. First by focusing on optimal candidates for elective lymph node dissection and then by identifying patients through sentinel lymph node biopsy. The current standard of sentinel lymph node biopsy for appropriately selected patients and nodal observation for many patients, even with involved sentinel nodes is both more accurate in staging and much less morbid than what came before.     

Clinical trial design: Past,present, and future in the context of big data and precision medicine

Clinical trials are fundamental for advances in cancer treatment. The traditional framework of phase 1 to 3 trials is designed for incremental advances between regimens. However, our ability to understand and treat cancer has evolved with the increase in drugs targeting an expanding array of therapeutic targets, the development of progressively comprehensive data sets, and emerging computational analytics, all of which are reshaping our treatment strategies. A more robust linkage between drugs and underlying cancer biology is blurring historical lines that define trials on the basis of cancer type. The complexity of the molecular basis of cancer, coupled with manifold variations in clinical status, is driving the individually tailored use of combinations of precision targeted drugs. This approach is spawning a new era of clinical trial types. Although most care is delivered in a community setting, large centers support real-time multi-omic analytics and their integrated interpretation by using machine learning in the context of real-world data sets. Coupling the analytic capabilities of large centers to the tailored delivery of therapy in the community is forging a paradigm that is optimizing service for patients. Understanding the importance of these evolving trends across the health care spectrum will affect our treatment of cancer in the future and is the focus of this review.     

A randomised controlled trial of nurse-managed trial conclusion following early phase cancer trial participation

The effect of a nurse-managed intervention, for early phase cancer trial participants at trial conclusion, on psychosocial outcomes was evaluated at two cancer centres in the Midlands, England using a randomised controlled trial. It involved 117 patients who were participating in an early phase cancer clinical trial. It was a nurse-managed trial exit, which included a trial exit interview, trial feedback information leaflet and telephone follow-up compared with standard care at trial conclusion. Psychological distress at 1 week and 4-6 weeks post-trial conclusion, patient's knowledge and understanding and patient's satisfaction were assessed. The results showed there was no significant difference between the two groups regarding scores for anxiety and depression at time one and time two. There is some suggestion that the intervention reduced anxiety from trial conclusion to follow-up (P=0.27). Patients in both groups felt they had contributed to cancer research through trial participation. However, intervention patients were more likely to feel that they knew how the trial was going (P<0.001), knew how other people in the trial were doing (P=0.001), had all the feedback they needed about the trial they took part in (P<0.01) and knew how they would be followed up (P=0.02). Patient satisfaction with the intervention was high (median score=4.5 where 5 is greatest satisfaction). In conclusion, nurse-managed trial conclusion led to positive outcomes for patients who had recently completed a clinical trial.     

Lymphoma Study Titles on ClinicalTrials.gov Lack Details Necessary for Study Identification

BackgroundClinicalTrials.gov is used by clinicians and patients to identify clinical trials. We assessed the ease with which users could identify relevant trials related to lymphoma using the short and official titles. We hypothesized that lymphoma titles frequently lack important information.Materials and MethodsWe performed 2 searches on ClinicalTrials.gov. The first search was performed before June 2017, when ClinicalTrials.gov underwent updates to improve usability. The second was performed after 2017. We assessed whether the short and official titles of each trial provided information on the study phase, eligible disease status, lymphoma histologic subtype, study intervention, primary objective, and the presence of randomization and placebo control.ResultsOf the pre-overhaul lymphoma trials, the official versus short titles included information regarding study intervention (99% vs. 96%), study phase (82% vs. 14%), lymphoma histologic subtype (78% vs. 72%), disease status (46% vs. 35%), randomization (13% vs. 2%), presence of placebo (6% vs. 2%), and primary objective (38% vs. 26%). Of the post-overhaul trials, the official versus short titles included information regarding study intervention (97% vs. 96%), lymphoma histologic subtype (83% vs. 78%), study phase (78% vs. 8%), disease status (64% vs. 50%), primary objective (38% vs. 23%), presence of placebo (11% vs. 0%), and randomization (18% vs. 0%).ConclusionThe official titles were more informative than were the short titles on ClinicalTrials.gov. However, the short and official titles both often lacked the basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of the format and content included in study titles.     

2006年培美曲塞研究新进展

培美曲塞是一种多靶点的抗代谢类药物,目前已经在70余个国家批准上市,用于治疗恶性胸膜间皮瘤和非小细胞肺癌。在过去的两年间,在多种肿瘤中开展了多项有关培美曲塞的临床研究,部分研究结果在今年的ASCO年会上报道,我们对这些资料进行了汇总。     

A randomized phase II selection trial in patients with advanced/recurrent gastric cancer: Trial for Advanced Stomach Cancer (TASC)

A randomized phase II clinical trial is being conducted for patients with advanced or recurrent gastric cancer, in order to select the most promising treatment for subsequent evaluation in a large-scale phase III trial. We compare four chemotherapeutic treatments, which include two sequential and two combination regimens using paclitaxel with 5-fluorouracil or S-1, an oral fluorouracil derivative. The primary endpoint is 10-month overall survival rate, while the secondary endpoints are adverse events, time to treatment failure and progression-free survival. A Bayesian method is used to provide a statistical rule for monitoring the trial. Forty patients per treatment regimen (160 in total) were randomized into one of the four regimens using a centralized dynamic method.     

Do Screening Trial Recruitment Logs Accurately Reflect the Eligibility Criteria of a Given Clinical Trial? Early Lessons from the RAVES 0803 Trial

AimsMaintaining clinical trial screening logs and reporting data from such logs are given importance due to the relevance of a trial's patient population to the generalisability of its findings. However, screening logs may not always reflect a clinical trial's true target population. The aim of the present study was to define and compare ‘apparent recruitment’ to a trial as captured in a clinical trial screening log with ‘true recruitment’, which considers all potentially eligible patients. The Trans Tasman Radiation Oncology Group (TROG) 0803 RAVES clinical trial was used to examine the above.Materials and methodsA prospective, surgical database was interrogated for the 12 month period to identify patients potentially eligible for the TROG 0803 RAVES trial. Information on whether patients were referred to a RAVES trial recruitment site and reasons for non-referral were obtained.ResultsOf 92 men undergoing radical prostatectomy, 28 met the RAVES clinical trial eligibility criteria. Fifteen of the 28 eligible men were assessed at a RAVES trial site, with five being ultimately recruited to RAVES (33% ‘apparent recruitment fraction’ as captured by the site's trial screening log). The ‘true recruitment fraction’ was 5/28 (18%).ConclusionScreening logs at a recruiting trial site may underestimate the trial's target population and overestimate recruitment. Only a subpopulation of all eligible patients may be captured in trial screening logs and subsequently reported on. This may affect the generalisability of the trial's reported findings.     

Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs.

BACKGROUND: Although the evaluation of new investigational drugs in phase I, II and III trials requires considerable time and patient resources, only a few of these drugs are ultimately established as anticancer drugs. MATERIALS AND METHODS: We collected papers of phase I trials by a Medline search using the key words 'Neoplasms/Drug Therapy in MeSH' and 'Phase I' for the period from 1976 to 1993. A drug was defined as 'effective' if a regimen including the drug produced positive results in at least one phase III trial. We analyzed the relationship between objective (complete and partial) responses in phase I trials and the effectiveness of agents in phase III trials. RESULTS: A total of 399 single-agent phase I trials of cytotoxic agents in adult patients with solid tumors were obtained. Further clinical investigation was not recommended in 36 trials (9%) because of severe toxicity. In the remaining 363 trials, 174 drugs were evaluated and the median number of trials for each drug was two (range one to nine). Objective responses were observed in 495 (4.1%) of 12 076 patients, 178 (49%) of 363 trials, and 115 (66%) of 174 drugs. Of the 174 drugs, 48 (28%) were considered to be effective. Percentages of effective drugs rose as the number of responders in phase I trials increased. Logistic regression analyses showed the number of responders to be significantly associated with drug effectiveness [odds ratio = 1.16 (1.06-1.27), P = 0.001 for 174 drugs; odds ratio = 1.16 (1.05-1.28), P = 0.0038 for 363 trials]. Although 10 active drugs failed to produce an objective response in phase I trials, seven of them produced a tumor regression of <50%, and three reportedly produced objective responses in phase I trials conducted before 1975. The numbers of responders among patients with lung, ovarian, breast or colorectal cancer, but not those among patients with lymphoma, melanoma, sarcoma or renal-cell carcinoma, were associated significantly with drug effectiveness against the respective tumors. CONCLUSIONS: Objective responses observed in phase I trials are important for determining the future development of an anticancer drug.     

Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer

Summary The primary objective of study is to evaluate cardiac safety of trastuzumab in combination with epirubicin and docetaxel. HER2-overexpressing metastatic breast cancer patients were enrolled in a two-stage, multicenter phase II trial with weekly trastuzumab (4 and then 2 mg/kg) with epirubicin and docetaxel (either 75 mg/m²) on day 1 every 3 weeks. After eight courses of chemotherapy, trastuzumab was continued as a single agent. To assess cardiotoxicity, patients were evaluated for left ventricular ejection fraction (LVEF) at baseline, every two cycles during chemotherapy and trastuzumab, and every 3 months during trastuzumab alone. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in LVEF of ≥20 units or a decline to ≤45%. In the first stage of the study, three episodes of cardiotoxicity were observed (two asymptomatic declines of LVEF and one CHF) in 29 patients, and recruitment continued. During follow-up of patients who continued trastuzumab after chemotherapy, seven further cardiologic events occurred (three asymptomatic decline of LVEF and four CHF). Therefore, recruitment was interrupted after the 45th patient. The majority of cardiac events occurred late during trastuzumab alone, half were asymptomatic and all cases of CHF were resolved using cardiac therapy. Complete and partial responses were 20 and 47%, respectively, and the median time to progression was 15.7 months (95% CI, 11.6–19.0 months). In light of the cardiotoxicity experienced during this study, we currently recommend that this combination be used only in controlled clinical trials under vigilant cardiac monitoring.