Minding the gaps: assessing and addressing clinical research core competencies across a network of Canadian cancer centres.

The Canadian Cancer Clinical Trials Network (3CTN, the Network), established in 2014 to address the decline in academic cancer clinical trials' (ACCT) activity, has successfully achieved incremental year-over-year accrual targets as well as implemented recognized performance measures and supports for improving efficiency and quality of trial activities at member sites across Canada. As part of efforts to address ongoing challenges of staff recruitment, retention, and turnover in academic institutions that have been more recently exacerbated by the pandemic, the Network's Performance Strategy Sub-Committee (PSC) oversaw surveys of site clinical research professionals intended to capture workforce development status and identify knowledge gaps using the Joint Task Force Core Competency Framework (JTF CCF) as the standard basis for assessment. Accountable to the 3CTN Management Committee, the PSC consists of clinical research operations experts across Canada responsible for overseeing implementation and monitoring progress of this initiative. Staff at 3CTN's adult sites evaluated and reported trial personnel core competencies and gaps according to each domain/leveled competency statement of the framework. The most frequently noted competency gaps were in the domains of: Investigational Product Development and Regulation (28%); Scientific Concepts and Research Design (16%); and Study and Site Management (14%). Reported data was compiled and represented in the 3CTN Core Competency Report, developed as a web-based, interactive tool enabling members and stakeholders to filter data to enumerate and quantify workforce competency gaps at their site, within their node of affiliated sites, or across the national Network. Concurrently, an environmental scan and review of education resources was conducted and reviewed by the PSC. Embedded links to curated learning and development resources were incorporated into the report and associated with each domain/leveled competency statement to provide ready access to high-quality learning and development resources where needed. In the remaining years of its current strategic plan, 3CTN will continue to monitor, develop collaborative initiatives to target prioritized clinical research competency gaps and create opportunities for ongoing assessment and reporting by sites to capture changes in workforce core competencies over time.

ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .

Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy.

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m2 (49 patients) or 75 mg/m2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated with docetaxel 75 mg/m2. Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m2, the benefits of docetaxel therapy outweigh the risks.

Addressing the Barriers to Clinical Trials Accrual in Community Cancer Centres Using a National Clinical Trials Navigator:A Cross-Sectional Analysis.

INTRODUCTION: Clinical trials, although academically accepted as the most effective treatment available for cancer patients, poor accrual to clinical trials remains a significant problem. A clinical trials navigator (CTN) program was piloted where patients and/or their healthcare professionals could request a search and provide a list of potential cancer clinical trials in which a patient may be eligible based on their current status and disease. OBJECTIVES: This study examined the outcomes of a pilot program to try to improve clinical trials accrual with a focus on patients at medium to small sized cancer programs. Outcomes examined included patient disposition (referral to and accrual to interventional trials), patient survival, sites of referral to the CTN program. METHODS: One 0.5 FTE navigator was retained. Stakeholders referred to the CTN through the Canadian Cancer Clinical Trials Network. Demographic and outcomes data were recorded. RESULTS: Between March 2019 and February 2020, 118 patients from across Canada used the program. Seven per cent of patients referred were enrolled onto treatment clinical trials. No available trial excluded 39% patients, and 28% had a decline in their health and died before they could be referred or enrolled onto a clinical trial. The median time from referral to death was 109 days in those that passed. CONCLUSION: This novel navigator pilot has the potential to increase patient accrual to clinical trials. The CTN program services the gap in the clinical trials system, helping patients in medium and small sized cancer centres identify potential clinical trials at larger centres.

The Impact of COVID-19 on Academic Cancer Clinical Trials in Canada and the Initial Response from Cancer Centers.

The COVID-19 pandemic resulted in temporary holds placed on new trial startups, patient recruitment and follow up visits for trials which contributed to major disruptions in cancer center trial unit operations. To assess the impact, the Canadian Cancer Clinical Trials Network (3CTN) members participated in regional meetings and a survey to understand the impact of the pandemic to academic cancer clinical trials (ACCT) activity, cancer trial unit operations and supports needed for post-pandemic recovery. Trial performance and recruitment data collected from 1 April 2020-31 March 2021 was compared to the same period in previous years. From 1 April-30 June 2020, patient recruitment decreased by 67.5% and trial site activations decreased by 81% compared to the same period in 2019. Recovery to reopening and recruitment of ACCTs began after three months, which was faster than initially projected. However, ongoing COVID-19 impacts on trial unit staffing and operations continue to contribute to delayed trial activations, lower patient recruitment and may further strain centers' capacity for participation in academic-sponsored trials.

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

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.

Advancing Academic Cancer Clinical Trials Recruitment in Canada.

The Canadian Cancer Clinical Trials Network (3CTN) was established in 2014 to address the decline in academic cancer clinical trials (ACCT) activity. Funding was provided to cancer centres to conduct a Portfolio of ACCTs. Larger centres received core funding and were paired with smaller centres to enable support and sharing of resources. All centres were eligible for incentive-based funding for recruitment above pre-3CTN baseline. Established performance measures were collected and tracked. The overall recruitment target was 50% above pre-3CTN baseline by Year 4. An analysis was completed to identify predictive success factors and descriptive statistics were used to summarize site characteristics and outcomes. From 2014-2018, a total of 11,275 patients were recruited to 559 Portfolio trials, an overall increase of 59.6% above pre-3CTN baseline was observed in Year 4. Twenty-five (51%) adult centres met the Year 4 recruitment target and the overall recruitment target was met within three years. Three factors that correlated with sites' achieving recruitment targets were: time period, region and number of baseline trials. 3CTN was successful in meeting its objectives and will continue to support ACCTs and member cancer centres, monitor performance over time and seek continued funding to ensure success, better trial access and outcomes for patients.

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02.

BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

RECIST 1.1 for Response Evaluation Apply Not Only to Chemotherapy-Treated Patients But Also to Targeted Cancer Agents: A Pooled Database Analysis.

PURPOSE: The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS: We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS: Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION: This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.

Conducting clinical trials-costs, impacts, and the value of clinical trials networks: A scoping review.

BACKGROUND: A significant barrier to conducting clinical trials is their high cost, which is driven primarily by the time and resources required to activate trials and reach accrual targets. The high cost of running trials has a substantial impact on their long-term feasibility and the type of clinical research undertaken. METHODS: A scoping review of the empirical literature on the costs associated with conducting clinical trials was undertaken for the years 2001-2015. Five reference databases were consulted to elicit how trials costs are presented in the literature. A review instrument was developed to extract the content of in-scope papers. Findings were characterized by date and place of publication, clinical disease area, and network/cooperative group designation, when specified. Costs were captured and grouped by patient accrual and management, infrastructure, and the opportunity costs associated with industry funding for trials research. Cost impacts on translational research and health systems were also captured, as were recommendations to reduce trial expenditures. Since articles often cited multiple costs, multiple cost coding was used during data extraction to capture the range and frequency of costs. RESULTS: A total of 288 empirical articles were included. The distribution of reported costs was: patient management and accrual costs (132 articles), infrastructure costs (118 articles) and the opportunity costs of industry sponsorship (72 articles). 221 articles reported on the impact of undertaking costly trials on translational research and health systems; of these, the most frequently reported consequences were to research integrity (52% of articles), research capacity (36% of articles) and running low-value trials (34% of articles). 254 articles provided recommendations to reduce trial costs; of these, the most frequently reported recommendations related to improvements in: operational efficiencies (33% of articles); patient accrual (24% of articles); funding for trials and transparency in trials reporting (18% of articles, each). CONCLUSION: Key findings from the review are: 1) delayed trial activation has costs to budgets and research; 2) poor accrual leads to low-value trials and wasted resources; 3) the pharmaceutical industry can be a pragmatic, if problematic, partner in clinical research; 4) organizational know-how and successful research collaboration are benefits of network/cooperative groups; and 5) there are spillover benefits of clinical trials to healthcare systems, including better health outcomes, enhanced research capacity, and drug cost avoidance. There is a need for more economic evaluations of the benefits of clinical research, such as health system use (or avoidance) and health outcomes in cities and health authorities with institutions that conduct clinical research, to demonstrate the affordability of clinical trials, despite their high cost.

Current Activities of the Coalition of Cancer Cooperative Groups.

The Coalition of Cancer Cooperative Groups is an organization representing the interests of patients and researchers who conduct research through the National Cancer Institute-supported National Clinical Trials Network (NCTN). The NCTN provides a crucial mechanism for executing practice-changing cancer clinical research to achieve both cancer control and development of new therapeutic agents or modality approaches. Public funding, largely through the National Cancer Institute, ensures that the work of the NCTN achieves important research that would not otherwise be accomplished in the private sector. In fall 2017, the Coalition of Cancer Cooperative Groups convened a Scientific Leadership Council to review the current state of the network with regard to research capabilities and to develop a list of research questions to be prioritized by the network. This report presents the results of this meeting, detailing a roadmap for future work by the NCTN.

Quality of life as a prognostic indicator of survival: A pooled analysis of individual patient data from canadian cancer trials group clinical trials.

BACKGROUND: The aims of this study were to externally validate an established association between baseline health-related quality of life (HRQOL) scores and survival and to assess the added prognostic value of HRQOL with respect to demographic and clinical indicators. METHODS: Pooled data were analyzed from 17 randomized controlled trials opened by the Canadian Cancer Trials Group between 1991 and 2004; they included survival and baseline HRQOL data from 3606 patients with 8 different cancer sites. The models included sex, age (≤60 vs >60 years), World Health Organization performance status (0 or 1 vs 2-4), distant metastases (no vs yes), and 15 European Organization for Research and Treatment of Cancer (EORTC) Core Quality-of-Life Questionnaire (QLQ-C30) scales. Analyses were conducted with multivariate Cox proportional hazards models and were stratified by cancer site. Harrell's discrimination C-index was used to calculate the predictive accuracy of the model when HRQOL parameters were added to clinical and demographic variables. The added value of adding HRQOL scales to clinical and demographic variables was illustrated with Kaplan-Meier curves. RESULTS: In the stratified, multivariate model, HRQOL parameters-global health status (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-1.00; P < . 0001), dyspnea (HR, 1.04; 95% CI, 1.02-1.06; P < . 0002), and appetite loss (HR, 1.06; 95% CI, 1.04-1.08; P < . 0001)-were independent prognostic factors in addition to the demographic and clinical variables (all P values < .05). Adding these HRQOL variables to the clinical variables resulted in an added relative prognostic value for survival of 5%. CONCLUSIONS: These results confirm previous findings showing that baseline HRQOL scores on the EORTC QLQ-C30 provide prognostic information in addition to information from clinical measures. However, the impact of specific domains may differ across studies. Cancer 2018. © 2018 American Cancer Society.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.

RECIST 1.1-Update and clarification: From the RECIST committee.

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.

RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group.

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.