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Ji, Yuan, and Meizi Liu. "The i3+3 design for phase I clinical trials." Journal of Clinical Oncology 37, no. 15_suppl (2019): 3066. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3066.
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3066 Background: Other than the 3+3 design, new model-based statistical designs like the mTPI design (Ji and Wang, 2013, JCO) are alternative choices for oncology dose-finding trials, including immune oncology dose-finding trials (Atkins et al., 2018, Lancet Oncology). One major criticism of the 3+3 design is that it is based on simple rules, does not depend on statistical models for inference, and leads to unsafe and unreliable operating characteristics. However, the rule-based nature allows 3+3 to be easily understood and implemented in practice, making it practically attractive and friendly. Can friendly rule-based designs achieve great performance seen in model-based designs? For four decades, the answer has been NO. Methods: We propose a new rule-based design called i3+3, where the letter "i" represents the word "interval". The i3+3 design is based on simple but more clever rules that account for the variabilities in the observed data. In short, the i3+3 design simply asks clinicians to compare observed toxicity rates with a prespecified toxicity interval, and make dose escalation decisions according to three simple rules. No sophisticated modeling is needed and the entire design is transparent to clinicians. Results: We compare the operating characteristics for the proposed i3+3 design with other popular phase I designs by simulation. The i3+3 design is far superior than the 3+3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3+3 also demonstrates comparable performances. In other words, the i3+3 design possesses both simplicity and transparency of the rule-based approaches, and the superior operating characteristics seen in model-based approaches. An online R Shiny tool is provided to illustrate the i3+3 design, although in practice it requires no software to design or conduct a dose-finding trial using the design. Conclusions: The i3+3 design could be a practice-altering method for the clinical community. It may increase the safety and efficiency of dose finding trials.
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Shimomura, A., T. Ebata, T. Koyama, et al. "Comparison of model-based dose escalation design with rule-based design of phase I oncology trials." Annals of Oncology 29 (March 2018): iii26—iii27. http://dx.doi.org/10.1093/annonc/mdy047.067.
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Lin, Ruitao, Yanhong Zhou, Fangrong Yan, Daniel Li, and Ying Yuan. "BOIN12: Bayesian Optimal Interval Phase I/II Trial Design for Utility-Based Dose Finding in Immunotherapy and Targeted Therapies." JCO Precision Oncology, no. 4 (November 2020): 1393–402. http://dx.doi.org/10.1200/po.20.00257.
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PURPOSE For immunotherapy, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, where the efficacy does not necessarily increase with the dose, the maximum tolerated dose may not be the optimal dose for treating patients. For these novel therapies, the objective of dose-finding trials is to identify the optimal biologic dose (OBD) that optimizes patients’ risk-benefit trade-off. METHODS We propose a simple and flexible Bayesian optimal interval phase I/II (BOIN12) trial design to find the OBD that optimizes the risk-benefit trade-off. The BOIN12 design makes the decision of dose escalation and de-escalation by simultaneously taking account of efficacy and toxicity and adaptively allocates patients to the dose that optimizes the toxicity-efficacy trade-off. We performed simulation studies to evaluate the performance of the BOIN12 design. RESULTS Compared with existing phase I/II dose-finding designs, the BOIN12 design is simpler to implement, has higher accuracy to identify the OBD, and allocates more patients to the OBD. One of the most appealing features of the BOIN12 design is that its adaptation rule can be pretabulated and included in the protocol. During the trial conduct, clinicians can simply look up the decision table to allocate patients to a dose without complicated computation. CONCLUSION The BOIN12 design is simple to implement and yields desirable operating characteristics. It overcomes the computational and implementation complexity that plagues existing Bayesian phase I/II dose-finding designs and provides a useful design to optimize the dose of immunotherapy and targeted therapy. User-friendly software is freely available to facilitate the application of the BOIN12 design.
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Fried, Jessica G., Michael Joseph Lariviere, Ravi Bharat Parikh, et al. "Design and implementation of outpatient-based rapid MRI protocols to rule out metastatic spinal cord compression and brain metastases." Journal of Clinical Oncology 37, no. 15_suppl (2019): e18307-e18307. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18307.
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e18307 Background: Metastatic spinal cord compression (MSCC) and symptomatic brain metastases (mets) are potential emergencies that demand coordinated multidisciplinary management. Patients (pts) with concerning symptoms are often referred to the Emergency Department (ED) for expedited imaging, but most do not require subsequent ED or inpatient management. Unnecessary ED visits incur substantial cost to the health system and patients, and cause psychosocial stress for patients often near the end-of-life. To improve access to expedited outpatient imaging for high-risk pts and reduce unnecessary ED visits, we developed outpatient rapid MRI protocols and pathways to rule out MSCC and brain mets. Methods: Tailored abbreviated MRI protocols were developed to allow rapid acquisition of brain ( < 13 minutes) and full spine ( < 25 minutes) exams. Dedicated appointments were reserved on the daily MRI schedule. Exams were immediately interpreted and reported by Radiology to the ordering clinician. This pathway was piloted within the Thoracic Oncology group beginning in 10/2018. Results: Referring specialties included Radiation Oncology (50%), Medical Oncology (36%), Pulmonology (7%), and Surgery (7%). For 6 pts who had outpatient rapid brain imaging, median time from order to exam start was 4.3 h (1.8-31) and order to final report 6.8 h (3.2-34.1). Brain mets were found in 4/6 patients. Only 1/4 positive studies required subsequent ED management. For 8 pts referred for rapid spine imaging, median time from order to exam start was 14.4 h (2.2-72.5) and order to final report 16.7 h (4.0-74.4). Only 1 patient was found to have cord compression and required ED/inpatient management. Overall, 86% of patients did not require ED or inpatient admission. 3 pts (all with negative imaging) died a median 13.4 d (1.4-28.3) after order placement. Conclusions: Outpatient rapid MRI protocols facilitate same-day imaging, interpretation, and management, improving care for thoracic oncology pts with new concerning neurologic symptoms and reducing unnecessary ED visits. Future work will expand access beyond Thoracic Oncology and further quantify improvements in cost savings and patient quality of life.
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Skolnik, J., B. Jayaraman, D. Patel, E. O'Connor, J. S. Barrett, and P. C. Adamson. "A clinical trial simulation study of a new pediatric phase I trial methodology: The rolling six design." Journal of Clinical Oncology 25, no. 18_suppl (2007): 9564. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.9564.
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9564 Background: Phase I cancer trials have traditionally used the 3+3 study design in which cohorts of three patients at a time are enrolled. The study is suspended to accrual with every 3rd patient, and again suspended to replace inevaluable patients. As the pediatric phase I starting dose is based on adult phase I safety data, we hypothesized that pediatric study timelines could be shortened without increasing risk using a novel rolling six design, in which up to 6 patients are concurrently enrolled per dose level. Methods: A trial simulation approach comparing the standard 3+3 design to the rolling six design was performed. Discrete time events (accrual/enrollment, evaluation and/or time to dose limiting toxicity (DLT) or inevaluability) with outcome probabilities (DLT/inevaluability) assigned to each subject based on historical data from phase I pediatric oncology trials. The probability of DLT was a function of dose level and varied distributions were used to assign discrete time elements. Metrics for study efficiency (time to complete study, total number of patients required) were determined for each design. Simulated trials and decision rule logic were coded using PC/Windows SAS v9.1. Results: The rolling six design outperformed the 3+3 design for the most relevant metrics. Average (±SD) time to study completion was 373±90 days vs. 431±98 days and the total number of patients required was 20±5 vs. 17±4 for the rolling six vs. 3+3 designs, respectively. There was no difference in the number of DLTs per study (3±1) between designs. Conclusions: The rolling six design is predicted to shorten pediatric phase 1 study timelines and will be tested prospectively in upcoming COG phase I trials. No significant financial relationships to disclose.
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Melloni, Giorgio E. M., Alessandro Guida, Giuseppe Curigliano, et al. "Precision Trial Drawer, a Computational Tool to Assist Planning of Genomics-Driven Trials in Oncology." JCO Precision Oncology, no. 2 (November 2018): 1–16. http://dx.doi.org/10.1200/po.18.00015.
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Purpose Trials that accrue participants on the basis of genetic biomarkers are a powerful means of testing targeted drugs, but they are often complicated by the rarity of the biomarker-positive population. Umbrella trials circumvent this by testing multiple hypotheses to maximize accrual. However, bigger trials have higher chances of conflicting treatment allocations because of the coexistence of multiple actionable alterations; allocation strategies greatly affect the efficiency of enrollment and should be carefully planned on the basis of relative mutation frequencies, leveraging information from large sequencing projects. Methods We developed software named Precision Trial Drawer (PTD) to estimate parameters that are useful for designing precision trials, most importantly, the number of patients needed to molecularly screen (NNMS) and the allocation rule that maximizes patient accrual on the basis of mutation frequency, systematically assigning patients with conflicting allocations to the drug associated with the rarer mutation. We used data from The Cancer Genome Atlas to show their potential in a 10-arm imaginary trial of multiple cancers on the basis of genetic alterations suggested by the past Molecular Analysis for Personalised Therapy (MAP) conference. We validated PTD predictions versus real data from the SHIVA (A Randomized Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer) trial. Results In the MAP imaginary trial, PTD-optimized allocation reduces number of patients needed to molecularly screen by up to 71.8% (3.5 times) compared with nonoptimal trial designs. In the SHIVA trial, PTD correctly predicted the fraction of patients with actionable alterations (33.51% [95% CI, 29.4% to 37.6%] in imaginary v 32.92% [95% CI, 28.2% to 37.6%] expected) and allocation to specific treatment groups (RAS/MEK, PI3K/mTOR, or both). Conclusion PTD correctly predicts crucial parameters for the design of multiarm genetic biomarker-driven trials. PTD is available as a package in the R programming language and as an open-access Web-based app. It represents a useful resource for the community of precision oncology trialists. The Web-based app is available at https://gmelloni.github.io/ptd/shinyapp.html .
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Ji, Yuan. "The joint i3+3 (Ji3+3) design for phase I / II adoptive cell therapy clinical trials." Journal of Clinical Oncology 38, no. 15_suppl (2020): e14083-e14083. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14083.
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e14083 Background: Adoptive cell therapy (ACT), such as chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects. However, it has been shown by previous studies that dose-response of ACTs may be complex and non-monotonic. For example, a ten-fold increase in dose level may not necessarily lead to higher anti-cancer response. This creates a new challenge for dose-finding trials with ACTs since higher dose may not lead to higher probability of efficacy. Methods: We propose a novel statistical design called the joint i3+3 design (Ji3+3) which extends our previous work of the i3+3 design (ASCO 2019 abstract 268979) and addresses the dose-finding challenge for ACT trials. In particular, Ji3+3 is a rule-based method that can be easily understood, visualized, and implemented by clinicians. It uses a set of smart rules based on observed efficacy and toxicity outcomes, and conducts up-and-down dose escalation decisions based on dose-response intervals. The entire dose-finding algorithm and decision rules can be presented as a precalculated table, which can be examined, discussed, modified, and approved as part of trial design. Results: Motivated by a CAR T trial (NCT03971799) we demonstrate the superiority of the Ji3+3 design through extensive computer simulations. Compared with the 3+3 design and i3+3 design, we show that Ji3+3 has a much higher chance finding the BOD and allocates more patients to desirable doses. The impact of these results will be to help investigators and drug developers identify a dose that is efficacious and safe, thereby increasing the probability of success to market the ACT and improving patient care. Conclusions: The Ji3+3 design is a novel, simple, and effective method that can potentially significantly improve the dose finding for ACT clinical trials.
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Hernando-Calvo, Alberto, Abdulazeez Salawu, Marc Oliva Bernal, et al. "A risk stratification model for toxicities in phase 1 immuno-oncology (P1-IO) trials." Journal of Clinical Oncology 39, no. 15_suppl (2021): 2648. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2648.
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2648 Background: Despite an exponential increase in the number of potential targets in the immuno-oncology (IO) field, lack of risk models to predict toxicities remains a challenge in early drug development. We proposed a risk stratification strategy and investigated whether different IO classes may be associated with incremental risk of toxicities. Methods: A systematic search for IO studies from 01/2014 to 10/2020 was conducted. Among the 12053 abstracts screened, 254 reporting phase I-IO trials were selected. Type of IO treatment (IO monotherapy [mono] vs IO combination [comb]), therapeutic class (e.g. IO, molecularly targeted agents [MTA]), and dose escalation method (rule-based, model-based and model-assisted) were collected. A risk scoring model was developed after expert consensus: treatment-related deaths (1:yes, 0:no), incidence of G3/G4 treatment related adverse events (TRAE) or treatment emergent adverse events (TEAE) (0 if 1-29%,1 if ≥30-49%, 2 if ≥50%), incidence of ≥G2 cytokine release syndrome (1:yes, 0:no), incidence of ≥G2 encephalopathy (1:yes 0:no) and incidence of dose-limiting toxicity (DLT) (0:no, 1:lab, 2:clinical). Risk categories were defined by summing all points (0 = low, 1-2 = intermediate, 3+ = high) and were correlated with type of IO treatment, therapeutic class and dose escalation method. Results: Of 254 P1-IO trials reviewed, 228 (90%) were scorable, 26 were not (25 due to lack of AE data). Up to 10/26 (38%) of non-scorable studies were cell therapies. Among the 228 scorable studies, 120 (53%) scored 0, 65 (28%) scored 1-2, 43 (19%) scored 3+; 24 (11%) and 125 (55%) did not provide no. of pts with G3/G4 TRAEs or TEAEs respectively. A significant association was observed between risk categories and therapeutic class (p<0.001) (see table). Additionally, IO-MTA and IO-IO were both associated with an increased risk of toxicity as compared to IO-mono (OR=3.91 (95%CI 1.7-9.2), p=0.002) and (OR=2.79 (95%CI 1.2-6.5), p=0.02) respectively. There was no association between dose escalation method and risk of toxicity (p=0.95), but 182 (92%) used rule-based methods. Conclusions: Our results suggest that different IO classes are associated with different risks of toxicity. This risk classification strategy may guide future clinical trial design. Additionally, standards for reporting toxicities in P1-IO trials are urgently needed.[Table: see text]
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Pizzichetta, Maria Antonietta, Renato Talamini, Domenico Piccolo, et al. "Interobserver Agreement of the Dermoscopic Diagnosis of 129 Small Melanocytic Skin Lesions." Tumori Journal 88, no. 3 (2002): 234–38. http://dx.doi.org/10.1177/030089160208800309.
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Aim and background Dermoscopic diagnosis of pigmented skin lesions is based on the evaluation of dermoscopic criteria (classical pattern analysis) and on alternative diagnostic methods, such as the ABCD (A, asymmetry; B, border; C, color; D, differential structures) rule based on the total dermatoscopic score. The aim of the study was to investigate the interobserver agreement of standard dermoscopic criteria between two observers and the diagnostic validity of dermoscopic diagnosis by pattern analysis and by the ABCD rule. Study design The study included a total of 129 small (≤5 mm) melanocytic skin lesions selected from all lesions observed in consecutive patients between April 1996 and September 1998. Before surgery, each lesion was photographed with a Dermaphot. Dermoscopic images were examined independently by two observers to evaluate the presence or absence of standard dermoscopic criteria and to establish the dermoscopic diagnosis by pattern analysis and by the ABCD rule. Results Interobserver agreement for dermoscopic criteria varied from moderately good to good, with the highest agreement for radial streaks (k = 0.96) and the lowest for pseudopods (k = 0.49). Interobserver agreement was moderately good in dermoscopic diagnosis by pattern analysis (k = 0.48) and by the total dermatoscopic score (k = 0.44). The sensitivity and specificity of dermoscopic diagnosis by pattern analysis were 40% and 99%, respectively, for both observers. As regards the total dermatoscopic score (a cutoff score of ≤5.45 vs >5.45), sensitivity ranged from 80% to 100% and specificity from 48% to 59%. Conclusions The study showed that the pattern analyses as well as the ABCD rule give a poor discrimination between benign and malignant lesions and do not add relevant information for management decision in small melanocytic lesions. However, close follow-up examinations of small equivocal melanocytic lesions using digital equipment allow evaluation of their dermoscopic features during progression and whether their rather commonly found atypical dermoscopic features are lost during their natural course of growth.
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Frank, Xavier. "Is Watson for Oncology per se Unreasonably Dangerous?: Making A Case for How to Prove Products Liability Based on a Flawed Artificial Intelligence Design." American Journal of Law & Medicine 45, no. 2-3 (2019): 273–94. http://dx.doi.org/10.1177/0098858819871109.
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Artificial intelligence (AI) machines hold the world's curiosity captive. Futuristic television shows like West World are set in desert lands against pink sunsets where sleek, autonomous AI fulfill every human need, desire, and kink. But I, Robot, a movie where robots turn against the humans they serve, reminds us that AI is precarious. Academicians who study how AI interacts with tort law, such as Jessica Allain, David Vladeck, and Sjur Dyrkoltbotn, claim that the current legal regime is incapable of addressing the liability issues AI present. Both Allain and Vladeck focus their research on whether tort law can accommodate claims against fully autonomous AI machines, while Dyrkoltbotn explores how AI can be leveraged to help plaintiffs identify the genesis of their injuries. The solution this article presents is not exclusively tailored to fully autonomous AI and does not identify how technology can be used in tort claims. It instead demonstrates that the current tort law regime can provide relief to plaintiffs who are injured by AI machines. In particular, this article argues that the manner in which Watson for Oncology is designed presents a new context in which courts should adopt a per se rule of liability that favors plaintiffs who bring damage claims against AI machines by expanding the definition of what it means for a device to be unreasonably dangerous.
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Zee, Benny C. Y., Xin Lai, Ann Sing Lee, et al. "Multistage phase II design for mixed tumor response and time-to-event endpoints: An application for screening new drugs in hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 30, no. 15_suppl (2012): e14706-e14706. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14706.
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e14706 Background: Phase II trials aim to assess the anti-tumor activity of investigational therapies, and consider if they warrant further study. In some instances such as a study treatment added to standard therapy in HCC, tumor response alone may not provide a clear picture on its effectiveness (e.g. biologics and targeted therarpy). Other endpoints such as progression-free survival (PFS) in addition to conventional tumor response would increase the chance of detecting useful treatment and also be able to terminate a study earlier if the treatment was deemed ineffective. Methods: Following a similar rationale for multinomial endpoints in phase II trials by Zee (1999), we have developed a multi-stage phase II stopping rule for "mixed tumor response and time-to-event endpoints". We used a study entitled, “Randomized Phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced HCC” as an illustration. We applied this multi-stage stopping rule for mixed endpoints in a randomized phase II setting, where the control arm was being used here as a way to set up the null hypothesis. We defined the null hypothesis by a mixture of response rate of 5% and PFS of 2.6 months versus an alternative hypothesis of response rate of 20% and PFS of 5.2 months. Results: The stopping rule was such that the null hypothesis would be rejected at a correlation of 0.5 for the mixed endpoints and conclude that the treatment is effective if we have 0-1 responders and a PFS>=4.0 months, or 2 responders and PFS>=3.8 months, or 3 responders and a PFS>=3.6 months, or 4 responders and a PFS>=3.0 months, or 5 responders with any PFS. Conclusions: In the AEG35156 study, we had 3 responders (based on Choi’s criteria), and 1 responder even if we used RECIST criteria. A PFS of 4.0 months. Therefore, we concluded that the study treatment in combination with sorafenib has a positive effect and warrants further investigation. This methodology would greatly improve the efficiency for phase II screening especially on new biologics on top of a standard or for diseases where tumor response alone does not reflect the full effectiveness of the new treatment.
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Wang, Chunhao, Xiaofeng Zhu, Julian C. Hong, and Dandan Zheng. "Artificial Intelligence in Radiotherapy Treatment Planning: Present and Future." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381987392. http://dx.doi.org/10.1177/1533033819873922.
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Treatment planning is an essential step of the radiotherapy workflow. It has become more sophisticated over the past couple of decades with the help of computer science, enabling planners to design highly complex radiotherapy plans to minimize the normal tissue damage while persevering sufficient tumor control. As a result, treatment planning has become more labor intensive, requiring hours or even days of planner effort to optimize an individual patient case in a trial-and-error fashion. More recently, artificial intelligence has been utilized to automate and improve various aspects of medical science. For radiotherapy treatment planning, many algorithms have been developed to better support planners. These algorithms focus on automating the planning process and/or optimizing dosimetric trade-offs, and they have already made great impact on improving treatment planning efficiency and plan quality consistency. In this review, the smart planning tools in current clinical use are summarized in 3 main categories: automated rule implementation and reasoning, modeling of prior knowledge in clinical practice, and multicriteria optimization. Novel artificial intelligence–based treatment planning applications, such as deep learning–based algorithms and emerging research directions, are also reviewed. Finally, the challenges of artificial intelligence–based treatment planning are discussed for future works.
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Evans, W. K., E. A. Eisenhauer, Y. Cormier, et al. "Phase II study of amonafide: results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer." Journal of Clinical Oncology 8, no. 3 (1990): 390–95. http://dx.doi.org/10.1200/jco.1990.8.3.390.
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Thirteen previously untreated patients with extensive small-cell lung cancer (SCLC) were treated with the investigational agent amonafide in a dose of 300 mg/m2 intravenously (IV) over 1 hour daily for 5 consecutive days. No responses were seen in 12 eligible patients. Myelosuppression was only occasionally seen. Other toxicities included diaphoresis, chest pain, local irritation at the injection site, arthralgias, nausea and vomiting, and neuromuscular problems. There were two early deaths, both attributable to tumor progression with resultant obstruction of a vital structure. Ten patients crossed over to alternate active therapy (etoposide [VP-16]-cisplatin) and five responded. The median survival time (MST) of the whole group of treated patients was 31 weeks. In future trials of investigational new drugs in previously untreated SCLC, we recommend that patients with the following characteristics be excluded: Eastern Cooperative Oncology Group (ECOG) performance status 2, 3, and 4; superior vena cava (SVC) obstruction; any major paraneoplastic syndrome; serious comorbid illness; and extensive hepatic involvement by tumor. The trial design should include prompt crossover to active alternative therapy, such as VP-16 and cisplatin, for disease progression or for failure to respond after two treatment cycles. Also, the trial design should use an early stopping rule based on interest in identifying only very active agents with a minimum response rate of 30%.
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Tannock, I. F. "Treatment of cancer with radiation and drugs." Journal of Clinical Oncology 14, no. 12 (1996): 3156–74. http://dx.doi.org/10.1200/jco.1996.14.12.3156.
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PURPOSE To review the current status and future prospects of combined treatment of cancer with radiation and drugs. DESIGN A review of (1) mechanisms whereby combined use of radiation and drugs might lead to improved therapeutic benefit for the treatment of cancer; (2) problems related to the design and analysis of clinical trials that evaluate combined modality treatment; and (3) clinical results of larger randomized trials that have compared combined versus single modality treatment for various types of cancer. RESULTS Improvement in the therapeutic index depends on exploitation of the biologic properties that differ between tumors and normal tissues; such properties may include mechanisms of resistance to radiation and drugs, tissue microenvironment, and cell proliferation or repopulation during radiotherapy. To detect or rule out the small but clinically important differences in outcome that might occur will require the performance of large, randomized, controlled trials or patient-based meta-analyses; single-arm studies, small randomized trials, and subgroup analyses of larger trials can generate hypotheses. Clinical gains from combined treatment have been demonstrated in a few sites, with disappointing results in others. In general, more promising results have accrued from concurrent treatment, despite greater toxicity, than from sequential use of drugs and radiation. CONCLUSION Clinical gains from combined treatment with radiation and drugs have been small. New, mechanistically based approaches to combined treatment are required.
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Eastman, C., Jae-min Lee, Yeon-suk Jeong, and Jin-kook Lee. "Automatic rule-based checking of building designs." Automation in Construction 18, no. 8 (2009): 1011–33. http://dx.doi.org/10.1016/j.autcon.2009.07.002.
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Li, Yi-Na, Kang Zhang, and Dong-Jin Li. "Rule-Based Automatic Generation of Logo Designs." Leonardo 50, no. 2 (2017): 177–81. http://dx.doi.org/10.1162/leon_a_00961.
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This article proposes the application of shape grammar to the automatic generation of logo designs based on artists’ logo creation knowledge and visual structures of logos. The authors propose a set of rules to encode the design knowledge and enable automatic generation. They then present an experiment that was conducted to validate the feasibility of the proposed approach.
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Pilie, Patrick Glen, Surena F. Matin, Ashley Henriksen Woodson, et al. "Pilot study of dovitinib in patients with VHL disease." Journal of Clinical Oncology 34, no. 2_suppl (2016): 587. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.587.
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587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differentially increased FGFR3 levels in HBs compared to RCC. In this pilot trial, we investigated the safety and efficacy profile of TKI 258 (dovitinib), a tyrosine kinase inhibitor of VEGF and FGF receptors, in VHL related lesions, focusing on HBs. Methods: A MDACC IRB-approved protocol planned to enroll 25 subjects who had genetically confirmed VHL disease or clinical diagnosis of VHL, and measurable HBs with no immediate risk of needing intervention. Dovitinib 500mg/day was given in a 4 week cycle on 5 day on/2 day off schedule. In the absence of adverse events (AE), treatment lasted 6 cycles or until disease progression. Evaluation of response to treatment was done every 8 weeks including imaging, laboratory, and clinical evaluation. The trial design used a continuous Bayesian stopping rule based on toxicities that resulted in discontinuation of dovitinib and another for lack of efficacy. Signed informed consent completed on all patients enrolled. Results: Trial stopped after six patients enrolled due to toxicity stopping rule. Patients’ ages ranged 18-61 with 5/6 being male. With regards to safety, 6/6 subjects had at least one AE with the most common AEs being rash, diarrhea, and fatigue including a grade 3 AE (severe rash) in one patient. 1/6 was stopped due to noncompliance, 1/6 stopped due to progression, 3/6 stopped due to side effects despite dose reduction, and 1/6 completed full six cycles at full dose. Best response in 6/6 subjects was stable disease (SD) in HBs. Conclusions: This pilot study of dovitinib in patients with VHL disease with measureable HBs did not show a favorable safety or efficacy profile for this dose and schedule. Half of the patients discontinued the drug due to AEs before study completion, and the best achieved response was SD. Further investigation into alternative scheduling and other FGFR inhibitors in the treatment of HBs is warranted given the strong pre-clinical data. Clinical trial information: NCT01266070.
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Tosi, Diego, Yassine Laghzali, Marie Vinches, et al. "Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies." Journal of Clinical Oncology 33, no. 19 (2015): 2158–65. http://dx.doi.org/10.1200/jco.2014.58.1082.
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Purpose We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. Methods We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. Results A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. Conclusion This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
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Harrell, F. E., T. Rodell, and D. Apelian. "Case study of a flexible bayesian design in a phase II study in patients with resected pancreas cancer." Journal of Clinical Oncology 27, no. 15_suppl (2009): e15651-e15651. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15651.
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e15651 Background: This presentation will describe a Bayesian flexible design for an ongoing randomized, placebo controlled phase II trial in newly diagnosed, resected pancreas cancer comparing gemcitabine plus therapeutic vaccine (GI-4000) vs. gemcitabine alone. The design allows for infinitely many looks at the data, possible study expansion, and conversion to adaptive allocation. Unlike frequentist approaches, the Bayesian procedure does not require penalizing the final analysis for earlier analyses nor does it require down-weighting of data collected before the decision to expand the study. The same analysis procedure is used for final and interim analyses, whereas there is no consensus in the frequentist approach for how to analyze an expanded study. Methods: Our primary analysis is based on a Bayesian Cox proportional hazards model using a skeptical prior distribution. The endpoint is time to recurrence or death. Evidence for efficacy is taken to be a posterior probability of efficacy ≥ 0.95 at any analysis time, where ‘efficacy’ means a true hazard ratio < 1.0. The planned rule for expanding the study is a probability of efficacy ≥ 0.7 prior to the last pre-planned analysis. Results: This ongoing study remains blinded. Results will include statistical methods (including simulations to assess study properties of the design) and experience in collaborating on the design with the FDA. Conclusions: In the frequentist approach, computing the probability of getting a result as or more impressive than that observed if there is truly no treatment effect (the P-value) requires contemplating experiments that were never carried out and analyses that were never done. The Bayesian approach offers the advantage of computing only ‘forward’ probabilities (Bayesian posterior probabilities) and conditioning only on what has been observed up to the time of analysis. There is no requirement to assume unknowable information such as the true population treatment effect. The adaptability afforded by Bayesian trial design can greatly enhance the likelihood of gaining useful clinical data from phase II trials. [Table: see text]
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Stein, Rob, Andreas Makris, Luke Hughes-Davies, et al. "OPTIMA prelim: Optimal personalized treatment of early breast cancer using multiparameter tests." Journal of Clinical Oncology 31, no. 15_suppl (2013): TPS656. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps656.
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TPS656 Background: Chemotherapy may have little effect on some subtypes of early breast cancer, identified as being hormonally responsive tumours without HER2 gene amplification and with a low or intermediate grade. Multi-parameter genomic tests such as Oncotype DX are increasingly used to identify patients for whom the addition of chemotherapy may confer little additional benefit. OPTIMA has an adaptive design seeking to advance development of personalised medicine in breast cancer by assessing the value of multi-parameter tests in a UK population of intermediate risk. Methods: OPTIMA prelim, the feasibility phase, has 3 objectives: (1) To evaluate performance and health-economics of multi-parameter tests to determine which test(s) will be used in the main trial; (2) To establish efficient and timely sample collection and analysis essential to deliver multi-parameter test driven treatment; (3) To establish the acceptability to patients and clinicians of randomisation to test-directed treatment assignment. OPTIMA prelim aims to recruit 300 patients with ER+ve HER2-ve tumours with involved nodes (pN1-2). Patients are randomized to the standard arm of chemotherapy with endocrine therapy, or to the “test-directed treatment” arm assigned to either the same chemotherapy with endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. The decision to continue to a main trial will be determined by concordance, cost and willingness of patients to be randomized to test guided treatment. Cost-effectiveness models will be based on the model developed in preparation for the OPTIMA trial, updated with contemporary evidence from the feasibility study and appropriate external data, e.g. the Ontario prospective cohort study. Results: Optima opened in Sept 2012 with 25 centres involved. To date 22 patients are registered, of which 17 have been randomised. Patient focus groups show the trial design is acceptable and has potential to reduce need for chemotherapy. TSC and DMEC agree that this is an important trial testing the feasibility within this patient population. Decision rules are challenging for this study but employment of adaptive designs gives the flexibility needed for the main trial. Clinical trial information: ISRCTN42400492.
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Twardowski, P., W. M. Stadler, P. Frankel, et al. "Phase II study of aflibercept (VEGF-Trap) in patients (pts) with recurrent or metastatic transitional cell carcinoma (TCC) of the urothelium: A California Cancer Consortium trial." Journal of Clinical Oncology 27, no. 15_suppl (2009): e16030-e16030. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e16030.
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e16030 Background: The role and efficacy of subsequent systemic therapies for advanced TCC following failure of frontline platinum-based chemotherapy is unclear. There is evidence that vascular endothelial growth factor (VEGF) is important in the pathophysiology of TCC. Aflibercept is a recombinant fusion protein that binds and neutralizes multiple VEGF isoforms. Methods: Pts with measurable, metastatic or locally advanced urothelial TCC previously treated with one platinum-containing regimen were entered. Aflibercept was given at 4 mg/kg IV q 2 weeks. Response rate (RR) and progression free survival (PFS) were assessed in a 2-stage accrual design (22+18). A maximum of 40 pts were to be accrued to rule out a null hypothesized RR of 4% and PFS of 3 months versus alternative of 15% RR and 5.4 months PFS with α=0.12 and β=0.19. Results: 22 pts were accrued between 11/06–2/08. Pt characteristics: M/F 15/7; Median age 67 years (45–79); 18 had bladder primary. One partial response (4.5% RR) was seen in a pt with nodal metastasis. Median PFS was 3.5 months (95% CI: 1.8–4.1). Attributable grade 3 toxicities included: hypertension (2), proteinuria (1), pulmonary hemorrhage (1), back pain (1), upper GI bleed (1), hyponatremia (1), anorexia (1) and fatigue (1). There were no attributable grade 4+ toxicities Conclusions: Aflibercept was well tolerated with toxicities similar to those seen with other VEGF pathway inhibitors, however it has limited single agent activity in platinum-pretreated TCC pts. [Table: see text]
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Calais, Jeremie, Francesco Ceci, Matthias Eiber, et al. "Prospective head-to-head comparative phase 3 study between 18F-fluciclovine and 68Ga-PSMA-11 PET/CT in patients with early biochemical recurrence of prostate cancer." Journal of Clinical Oncology 37, no. 15_suppl (2019): 5014. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5014.
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5014 Background: This is a prospective single-center, single-arm, head-to-head phase 3 study of paired 18F-fluciclovine (FACBC) and 68Ga-PSMA-11 (PSMA) PET/CT scans for localizing early biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) (NCT02940262). Methods: Fifty consecutive patients with BCR and prostate specific antigen (PSA) levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were included. All patients underwent FACBC and PSMA PET/CT scans within ≤15 days. PET/CT scans were each interpreted by 3 independent blinded expert readers not involved in study design and data acquisition. Region consensus interpretation (T,N,M1a,M1b,M1c) was generated based on majority rule in cases of reader disagreement (2 vs 1). PET/CT scans were considered as positive if any region was rated as positive. Detection rates per-patient and per-region served as primary study endpoint. Results: Median time interval between the 2 scans was 6 days (range 1-15). Median PSA level at the time of imaging was 0.50 ng/ml (mean 0.63; range 0.2-2.0 ng/ml). The detection rates were significantly lower with FACBC than with PSMA PET/CT per-patient (26% vs 56%; p = 0.003) and per-region for pelvic nodes (N) (8% vs 30%; p = 0.003) or any extra-pelvic lesions (M) (0% vs 16%; p = 0.008). Reader agreement for PSMA PET/CT image interpretations was significantly higher than for FACBC PET/CT (0.67 vs 0.20; p = 0.015). Conclusions: In patients with BCR and low serum PSA levels after RP, PSMA PET/CT demonstrates higher detection rates and superior reader agreement when compared with FACBC PET/CT. Therefore, PSMA PET/CT should be the imaging modality of choice in patients with early BCR. Clinical trial information: NCT03515577.
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Kossler, Thibaud, Buchs Nicolas, Valérie Dutoit, et al. "A phase II study to evaluate safety and efficacy of neoadjuvant pembrolizumab and radiotherapy in localized MSS rectal cancer." Journal of Clinical Oncology 38, no. 4_suppl (2020): TPS272. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.tps272.
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TPS272 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitors use. This prospective phase II trial will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PD-1 agent Pembrolizumab. Methods: This monocentric phase II trial, will enroll patients (pts) with rectal cancer who are undergoing neoadjuvant short course RT (scRT) (25 Gy in 5 fractions). according to the standard of care. Eligible includes pts with MSS stage II-III rectal cancer with adequate organ function and availability of pre-treatment tumor, who are undergoing scRT with intention to proceed to surgical resection. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes 4 doses of Pembrolizumab (200mg IV, once every 3 wks), the first dose being given before the first scRT fraction. Surgery will be performed within 12-16 weeks of the final scRT dose. Primary endpoint is tumor regression grade (TRG) using the Mandard regression grade score targeting a 30% pathological complete response (pCR) compared to 10% in historical controls. Secondary endpoints include OS, DFS, toxicity, local and distant relapse-free survival, negative surgical margins, QoL, quality of surgery and exploratory assessments of tumor infiltrating lymphocytes, profiling of circulating immune cell populations, and molecular predictors of response. A safety stopping rule is planned based on Wald’s sequential probability ratio test for the occurrence of the safety outcome. Enrollment target is 25 pts. Support: MSD. Clinical trial information: NCT04109755 .
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Blaszkowsky, L. S., D. P. Ryan, C. Earle, et al. "A phase II study of docetaxel in combination with ZD1839 (gefitinib) in previously treated patients with metastatic pancreatic cancer." Journal of Clinical Oncology 25, no. 18_suppl (2007): 15080. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15080.
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15080 Background: The reported activity of docetaxel in pancreatic cancer and high level of EGFR expression in pancreatic carcinomas led us to examine the efficacy of combination docetaxel and gefitinib in patients with metastatic pancreatic cancer. Methods: Eligibility criteria included PS = 1, failed prior adjuvant ot metastatic gemcitabine-containing regimen, = 1 prior regimen for metastatic disease, no prior taxane or EGFR inhibitor, and adequate organ function. Patients received docetaxel 40 mg/m2 intravenously weekly for 2 of every 3 weeks and daily oral gefitinib 250 mg. The primary endpoint was CA19–9 response (>50% decrease in tumor marker CA19–9 levels). Additional endpoints included radiologic response, toxicity, and survival. Results: Fifteen patients received docetaxel and gefitinib between 11/2/04 and 11/26/05. The median age of patients was 60 (46–76), and included 7 women and 8 men. The regimen was generally well tolerated, and there were no unanticipated toxicities. Grade 3 or 4 toxicities included lymphopenia (6 pts), hyperglycemia (3 pts), leucopenia (3 pts), infection (2 pts), fatigue (2 pts), elevated transaminases (2 pts), neutropenia (2 pts), pleural effusion (2 pts), irregular menses (1 pt), anorexia (1 pt), dysphagia/esophagitis (1 pt), diarrhea (1 pt), alkaline phosphatase (1 pt), and sensory neuropathy (1 pt). No treatment-related deaths occurred. No patient experienced a biochemical (CA 19–9) response to treatment. All 15 patients were evaluable for radiologic response, of which 9 experienced stable disease and 6 progressive disease as their best response to therapy. The trial was stopped due to lack of efficacy, in accordance with an early stopping rule incorporated into the trial design. Conclusions: In the doses and schedule used in this trial, the combination of docetaxel and gefitinib does not appear to be active in patients with pancreatic cancer who have failed prior gemcitabine-based chemotherapy. No significant financial relationships to disclose.
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Rugo, Hope S., Roy S. Herbst, Glenn Liu, et al. "Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results." Journal of Clinical Oncology 23, no. 24 (2005): 5474–83. http://dx.doi.org/10.1200/jco.2005.04.192.
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Purpose We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. Patients and Methods Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. Results Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. Conclusion In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.
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Schwabacher, Mark, and Andrew Gelsey. "Intelligent gradient-based search of incompletely defined design spaces." Artificial Intelligence for Engineering Design, Analysis and Manufacturing 11, no. 3 (1997): 199–210. http://dx.doi.org/10.1017/s0890060400003127.
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AbstractGradient-based numerical optimization of complex engineering designs offers the promise of rapidly producing better designs. However, such methods generally assume that the objective function and constraint functions are continuous, smooth, and defined everywhere. Unfortunately, realistic simulators tend to violate these assumptions. We present a rule-based technique for intelligently computing gradients in the presence of such pathologies in the simulators, and show how this gradient computation method can be used as part of a gradient-based numerical optimization system. We tested the resulting system in the domain of conceptual design of supersonic transport aircraft, and found that using rule-based gradients can decrease the cost of design space search by one or more orders of magnitude.
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Bhattacharya, Saveri, Cindy Yun, Katja Schulze, et al. "Phase II clinical trial of atezolizumab (A) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with PD1-directed therapy." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS9105. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps9105.
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TPS9105 Background: While inhibition of the PD1 axis is associated with improved response rates vs cytotoxic therapy in pts with previously treated NSCLC, the majority of pts will not benefit from objective response. Anti-PD1 and PD-L1 antibodies block distinct inhibitory pathways, possibly resulting in different clinical outcomes. While anti-PD1 antibodies block PD1 binding to PD-L1 and PD-L2, they do not affect the inhibitory signal of the PD-L1/B7.1 interaction. This trial is critical to establishing the clinical activity of sequencing PD-L1 inhibition in pts previously treated with PD1 directed and identifying candidate biomarkers of response and resistance to PD1/PD-L1 directed therapies. Methods: In this phase II clinical trial, pts with advanced NSCLC with stable or progressive disease on anti-PD1 therapy (nivolumab or pembrolizumab) will be treated with A1200 mg day 1 of a 21-day cycle until disease progression, unacceptable toxicity or death. The kinetics of response to anti-PD1 therapy can be variable and in some cases characterized by pseudo-progression. In order to account for variable response kinetics to PD1 therapy, pts will be enrolled in 3 parallel cohorts based on best overall response (BOR) to PD1 therapy (stable disease; progressive disease; complete or partial response followed by progressive disease). The primary objective is BOR to A. Secondary endpoints include duration of response, progression free survival, overall survival, and safety. 37 pts will be enrolled per cohort. A Simon 2-stage design will be employed with a stopping rule for futility if 0 of the first 11 evaluable patients within a cohort have a confirmed objective response in Stage 1. A promising result would be if ≥3 responses are seen at the conclusion of stage 2. This design has 80% power to detect a true response rate of 15% in each cohort (null rate 2%; alpha 0.05). Mandatory biopsies at time of enrollment, archival tumor pre-PD1 directed therapy, and optional biopsy at the time of progression on A will be collected for exploratory studies of immune biomarkers of response and resistance. Clinical trial information: NCT03014648.
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Mai, Yun, Kyeryoung Lee, Zongzhi Liu, et al. "Phenotyping of clinical trial eligibility text from cancer studies into computable criteria in electronic health records." Journal of Clinical Oncology 39, no. 15_suppl (2021): 6592. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6592.
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6592 Background: Clinical trial phenotyping is the process of extracting clinical features and patient characteristics from eligibility criteria. Phenotyping is a crucial step that precedes automated cohort identification from patient electronic health records (EHRs) against trial criteria. We establish a clinical trial phenotyping pipeline to transform clinical trial eligibility criteria into computable criteria and enable high throughput cohort selection in EHRs. Methods: Formalized clinical trial criteria attributes were acquired from a natural-language processing (NLP)-assisted approach. We implemented a clinical trial phenotyping pipeline that included three components: First, a rule-based knowledge engineering component was introduced to annotate the trial attributes into a computable and customizable granularity from EHRs. The second component involved normalizing annotated attributes using standard terminologies and pre-defined reference tables. Third, a knowledge base of computable criteria attributes was built to match patients to clinical trials. We evaluated the pipeline performance by independent manual review. The inter-rater agreement of the annotation was measured on a random sample of the knowledge base. The accuracy of the pipeline was evaluated on a subset of randomly selected matched patients for a subset of randomly selected attributes. Results: Our pipeline phenotyped 2954 clinical trials from five cancer types including Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Prostate Cancer, Breast Cancer, and Multiple Myeloma. We built a knowledge base of 256 computable attributes that included comorbidities, comorbidity-related treatment, previous lines of therapy, laboratory tests, and performance such as ECOG and Karnofsky score. Among 256 attributes, 132 attributes were encoded using standard terminologies and 124 attributes were normalized to customized concepts. The inter-rater agreement of the annotation measured by Cohen’s Kappa coefficient was 0.83. We applied the knowledge base to our EHRs and efficiently identified 33258 potential subjects for cancer clinical trials. Our evaluation on the patient matching indicated the F1 score was 0.94. Conclusions: We established a clinical trial phenotyping pipeline and built a knowledge base of computable criteria attributes that enabled efficient screening of EHRs for patients meeting clinical trial eligibility criteria, providing an automated way to efficiently and accurately identify clinical trial cohorts. The application of this knowledge base to patient matching from EHR data across different institutes demonstrates its generalization capability. Taken together, this knowledge base will be particularly valuable in computer-assisted clinical trial subject selection and clinical trial protocol design in cancer studies based on real-world evidence.
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Buyse, Marc, and Stefan Michiels. "Omics-based clinical trial designs." Current Opinion in Oncology 25, no. 3 (2013): 289–95. http://dx.doi.org/10.1097/cco.0b013e32835ff2fe.
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Komaki, Fumiyasu, and Atanu Biswas. "Bayesian optimal response-adaptive design for binary responses using stopping rule." Statistical Methods in Medical Research 27, no. 3 (2016): 891–904. http://dx.doi.org/10.1177/0962280216647210.
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Response-adaptive designs are used in phase III clinical trials to allocate a larger number of patients to the better treatment arm. Optimal designs are explored in the recent years in the context of response-adaptive designs, in the frequentist view point only. In the present paper, we propose some response-adaptive designs for two treatments based on Bayesian prediction for phase III clinical trials. Some properties are studied and numerically compared with some existing competitors. A real data set is used to illustrate the applicability of the proposed methodology where we redesign the experiment using parameters derived from the data set.
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Chen, Tom Wei-Wu, Ruey-Long Hong, Chueh-Chuan Yen, et al. "The phase Ib result of the safety and efficacy of lenvatinib (lenv) plus eribulin (eri) in advanced adipocytic sarcoma (LPS) and leiomyosarcoma (LMS): LEADER study (NCT03526679)." Journal of Clinical Oncology 37, no. 15_suppl (2019): e22524-e22524. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e22524.
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e22524 Background: Eri, although approved for advanced LPS, has limited activity in terms of tumor shrinkage. Anti-angiogenic agents have shown to increase tumor response in certain cancer types. This study aims to understand the safety, optimal dose, and efficacy of the combination of lenv, a multi-kinase anti-angiogenic inhibitor, and eri in LMS and LPS. Methods: Advanced LMS and LPS with no more than 2 lines of systemic chemotherapy were eligible. The starting dose was lenv 18mg/day daily and eri 1.1mg/m2 D1, D8 in a 21-day cycle. The primary endpoint of the phase Ib part was to assess the dose-limiting toxicity (DLT) in the first 21 days and to determine the recommended phase II dose (RP2D). A rule-based (≤ 33% DLT in first 6 pts) design was implemented in the phase Ib part. Results: From 2018 Jul 24 to 2019 Jan 8, a total of 6 pts (4 LMS, 1 dedifferentiated LPS, 1 myxoid LPS) were enrolled. The median age was 56 (range 30-70), female: male 3:3. Only 1 pt had a DLT, which was < 75% of the planned dosage. Within all (27) cycles, common grade (gr) 3 or higher adverse events (AE) included hypertension (HTN, n = 4), hand-foot syndrome (HFS, n = 3), and neutropenia (n = 4). However, 4 pts had late-onset gr3 or multiple coexisting gr2 AEs that necessitated dose reduction(s) (dr) for lenv (7 dr) or eri (2 dr) after the DLT assessment period (see table). The median time to 14 mg/day, 10mg/day of lenv, and eri 0.7mg/m2 was 22, 28 (after starting lenv 14mg/day), and 69 days, respectively. In terms of preliminary anti-tumor activity, 5 (83%) pts had target lesion shrinkage and 2 (33%) reached PR (1 confirmed) as best response according to RECIST 1.1. Conclusions: Late-onset AEs after cycle 1 leading to dose reduction was notable for lenv + eri and the RP2D was thus determined at a lower starting dose of lenv 14mg/day and eri 1.1mg/m2. The preliminary tumor response was also promising. Efficacy and safety of lenv + eri for LMS and LPS will continue to be explored in phase II study. Clinical trial information: NCT03526679. [Table: see text]
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Chanda, Souptick, Kaushik Mukherjee, Sanjay Gupta, and Dilip Kumar Pratihar. "A comparative assessment of two designs of hip stem using rule-based simulation of combined osseointegration and remodelling." Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine 234, no. 1 (2019): 118–28. http://dx.doi.org/10.1177/0954411919890998.
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The stem–bone interface of cementless total hip arthroplasty undergoes an adaptive process of bone ingrowth until the two parts become osseointegrated. Another important phenomenon associated with aseptic loosening of hip stem is stress-shielding induced adverse bone remodelling. The objective of this study was to preclinically assess the relative performances of two distinct designs of hip stems by addressing the combined effect of bone remodelling and osseointegration, based on certain rule-based criteria obtained from the literature. Premised upon non-linear finite element analyses of patient-specific implanted femur models, the study attempts to ascertain in silico outcome of the hip stem designs based on an evolutionary interfacial condition, and to further comment on the efficacy of the rule-based technique on the prediction of peri-prosthetic osseointegration. One of the two hip stem models was a trade-off design obtained from an earlier shape optimization study, and the other was based on TriLock stem (DePuy). Both designs predicted similar long-term osseointegration (∼89% surface), although trade-off stem predicted higher post-operative osseointegration. Proximal bone resorption was found higher for TriLock (by ∼110%) as compared to trade-off model. The rule-based technique predicted clinically coherent osseointegration around both stems and appears to be an alternative to expensive mechanobiology-based schemes.
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Drusbosky, Leylah, Taher Abbasi, Shireen Vali, et al. "A Genomic Signature Predicting Venetoclax Treatment Response in AML Identified By Protein Network Mapping and Validated By Ex Vivo Drug Sensitivity Testing: A Beat AML Project Study." Blood 128, no. 22 (2016): 1713. http://dx.doi.org/10.1182/blood.v128.22.1713.1713.
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Abstract Background: Data from a small clinical trial of venetoclax in acute myeloid leukemia (AML) recently supported FDA breakthrough therapy designation for use in combination with hypomethylating agents in treatment-naïve patients who are ineligible for high-dose induction chemotherapy. Approval of this BCL-2 inhibitor raises the question of mechanism of action in AML and patient selection for treatment. Unfortunately, no biomarkers or methods exist to predict venetoclax response in AML, making treatment selection challenging. Aim: To define a novel genomic signature rule to predict AML response to venetoclax therapy and to validate the rule with ex vivo drug sensitivity testing. Methods: The Beat AML project (supported by the Leukemia & Lymphoma Society) collects clinical data and bone marrow specimens from AML patients. Bone marrow samples are analyzed by conventional cytogenetics, whole-exome sequencing, RNA-seq, and an ex vivo drug sensitivity assay. For 19 of these randomly chosen patients, every available genomic abnormality was inputted into a computational biology program (Cellworks Group) that uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated protein pathways. Digital drug simulations with venetoclax were conducted by quantitatively measuring drug effect on a composite AML disease inhibition score (i.e., cell proliferation, viability, and apoptosis). Computational predictions of drug response were compared to venetoclax IC50 values from the Beat AML ex vivo testing. Results: Ten of the 19 AML patients were predicted by computer simulation to respond to venetoclax, and 9 of those 10 patients had the lowest IC50 values to venetoclax. Nine of the 19 patients were predicted to not respond to venetoclax, and 8 of those 9 patients had the highest IC50 values to venetoclax. Ex vivo venetoclax responses were correctly matched to their computer simulation prediction in 17 of 19 cases, and incorrectly matched in 2 cases. The positive predictive value of the computational method was 90%, negative predictive value was 89%, sensitivity was 90%, specificity was 89%, and accuracy was 89%. Amplification of the genes RB1CC1 and/or RB1was predicted by computational modeling to increase MCL1, which made venetoclax less responsive in the digital drug simulation. This genomic rule was validated with 3 AML patients: one who received venetoclax as treatment and showed refractory disease, and 2 patients who achieved complete remission after venetoclax treatment. Conclusion: We identified a new genomic signature, confirmed by functional testing, that predicts AML response to venetoclax treatment. This unique computer-based approach is intended to inform the design of phase 2 and 3 clinical trials of venetoclax in AML patients for a forthcoming precision enrollment clinical trial. Disclosures Abbasi: Cellworks: Employment. Vali:Cellworks Group: Employment. Radhakrishnan:Cellworks: Employment. Kumar Singh:Cellworks: Employment. Usmani:Cellworks: Employment. Parashar:Cellworks: Employment. Vidva:Cellworks: Employment. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.
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Jackson, Erica, Elizabeth Claire Dees, John S. Kauh, et al. "A phase I study of indoximod in combination with docetaxel in metastatic solid tumors." Journal of Clinical Oncology 31, no. 15_suppl (2013): 3026. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3026.
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3026 Background: The indoleamine-2, 3-dioxygenase (IDO) pathway catabolizes tryptophan to create a state of immunosuppression. Indoximod (1-methyl-(D)-tryptophan, D-1MT) is an IDO pathway modulator. Preclinical studies in MMTV-neu mouse models have shown indoximod combined with chemotherapy was more effective in causing tumor regression than either agent alone. Based on this data, a phase IB trial was designed to study the safety of the combination of docetaxel (Doc) and indoximod. The primary goal of this trial was to determine the MTD for the combination of Doc and oral indoximod. Secondary endpoints were PK data and efficacy for indoximod/Doc. Methods: This phase IB study consisted of 5 dose levels (DL). Doc was dosed IV q 3 wks at 60 mg/m2 in DL 1-4 and 75 mg/m2 at DL 5. Indoximod was dosed at 300, 600, 1,000, 2,000, and 1,200 mg PO BID continuously in DL 1-5 respectively. MTD was determined using a 3+3 design. The DLT rule was 1st cycle ≥G3 non-heme AEs or ≥G4 heme AEs despite supportive care or that delay therapy >14d. The PK of indoximod and Doc was analyzed using a HPLC assay. PK was measured on C1D1 and 8. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilumimab. Treatment was continued until disease progression, intolerance, or unacceptable side effects. Results: Total # of patients treated at DL1-5 were 7, 6, 6, 2, and 6 respectively, with 22 total patients evaluable for response. DLTs included: G3 dehydration (at 300 mg), G5 neutropenic colitis (at 600 mg), G3 hypotension (at 2,000 mg) and G3 mucositis (at 2,000 mg). DL 5 was well tolerated and is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 PRs (2 breast, 1 NSCLC, 1 thymic), 9 SD, and 9 PD. There were no drug-drug interactions, and PK was similar to Doc and indoximod single-agent studies. Conclusions: The Doc+ indoximod combination was well tolerated with no increase in expected toxicities or unexpected PK interactions. It was active in a pretreated population of patients with metastatic solid tumors. The RP2D is 75 mg/m2 of Doc with 1,200 mg of indoximod BID for the current phase II metastatic breast cancer trial. NCT01191216 Clinical trial information: NCT01191216.
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Knox, Jennifer J., Rui Qin, Jonathan R. Strosberg, et al. "A phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients with advanced hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 30, no. 15_suppl (2012): 4099. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4099.
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4099 Background: There is strong rationale to combine an m-TOR inhibitor (TEM) with a VEGF inhibitor (BEV) as a potentially active and well tolerated treatment for HCC. Both agents have shown modest single agent activity in HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage Simon design planned 25 or 50 patients (pts) to test the null hypothesis that true tumor response rate is at most 10% andtrue 6-mo progression-free survival rate (PFS) (by RECIST) is at most 65%, or no better than single agent BEV (6 mo PR >2 pts or PFS 6 mo >18 out of 25.) Toxicity, TTP, PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with disease unresectable or amenable to other localised therapies, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR class of agents. TEM was administered at starting dose 25 mg IV d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% male, PS 0/1: 35/65, 58% metastatic, >85% BCLC stage C. With med 6 cycles (range 1-14) delivered, most pts (88%) experienced a grade 3+ adverse event (a/e.) Common grade 3 a/es related to treatment included thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue (8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% each). There was one possible treatment related death. Per protocol dose reductions/discontinuation for TEM-related a/es were most common. There were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt developed a late PR at cycle 13. Median TTP on study was 6 mos, median PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. Accrual closed at end of stage 1 as neither the number of responses nor the PFS at 6 mos passed the futility stopping rule set for this combination. Conclusions: This multicenter study is the first HCC trial evaluating the BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did not surpass assumptions based on single agent BEV in HCC. Further study of BEV/TEM combination in this advanced HCC population is not recommended.
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Gadgeel, Shirish M., Jieling Miao, Jonathan W. Riess, et al. "S1507: Phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 37, no. 15_suppl (2019): 9021. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9021.
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9021 Background: KRAS+ NSCLC remains the most common genetically defined subset of NSCLC. Despite promising pre-clinical data, MEK inhibitors have failed to provide meaningful clinical benefit both as single agents and in combination with chemotherapy in KRAS+ NSCLC patients. Pre-clinical data suggest that efficacy of MEK inhibitors in KRAS+ NSCLC differs based on specific KRAS mutations such as G12C and by status of p53 or LKB1 mutations. We conducted a phase II study to assess the efficacy of docetaxel plus trametinib in KRAS+ NSCLC patients and in specific genetic subsets. Methods: KRAS+ NSCLC patients who had progressive cancer following 1 or 2 prior regimens were eligible. Docetaxel was given at 75 mg/m2 every 3 weeks and trametinib orally at 2 mg daily. The study was 2-stage design to rule out a response rate (RR) of 17% at the 3% level with 90% power if the true rate were 37%. The study required 45 pts with a futility analysis at 30 pts; 13/45 responses would indicate a success. RR was also assessed in G12C and non-G12C cohorts and will be assessed according to presence of co-mutations in p53 and LKB1. Progression free survival (PFS) and overall survival (OS) were secondary endpoints. Multivariate analysis including age, sex, number of prior treatments, prior immunotherapy (IO) and G12C status was conducted. Results: The study enrolled 54 evaluable pts (19 G12C, 9 G12D, 9 G12A); median age 65 years; female 57%; never smokers 7%; adenocarcinoma 89%; liver metastases 31%; 2 prior regimens 70%; prior IO 57%. Outcomes are summarized in Table. Median duration of therapy was 2.2 months and most common toxicities were fatigue (78%), diarrhea (68%), nausea (57%) and vomiting (28%). One patient died of treatment related respiratory failure. There was a trend for worse PFS (HR- 1.86, p = 0.06) and survival (HR- 1.80, p = 0.14) in G12C patients. Analysis of efficacy data according to co-mutations in p53 or LKB1 is ongoing. Conclusions: Docetaxel plus trametinib met the primary endpoint of the study, with a RR of 33% and median survival of 11.1 months in patients with KRAS+ NSCLC, 70% of whom had received 2 prior regimens. Although, there was no statistical difference between KRAS+ subtypes, these data suggest that outcomes may differ between G12C and non-G12C patients. Clinical trial information: NCT02642042. [Table: see text]
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Luoni, Marco, Paolo Declich, Alberto De Paoli, et al. "Bone Marrow Biopsy for the Staging of Non-Hodgkin's Lymphoma: Bilateral or Unilateral Trephine Biopsy?" Tumori Journal 81, no. 6 (1995): 410–13. http://dx.doi.org/10.1177/030089169508100604.
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Aim The occurrence of unilateral involvement in bilateral bone marrow trephine biopsies in non-Hodgkin's lymphomas (NHL) at disease onset (10-20% of cases) has been reported since the early 70s. Therefore, although these studies were based on small series, the use of bilateral bone marrow biopsies has become the rule. However, the clinical value of this procedure has never been clearly established. The aim of the present study was to ascertain the true value of bilateral bone marrow biopsy in the staging of NHL. Study Design We examined 368 cases of NHL (A-H according to the Working Formulation) (WF), without leukemic involvement of the peripheral blood, in order to evaluate: 1) the incidence of unilateral bone marrow involvement; 2) the percentage of patients who, as a result of unilateral bone marrow involvement, changed from stages I-II to stage IV; 3) assessment of response to therapy for patients with both bilateral or unilateral bone marrow involvement. Results In the A-C NHL groups of WF there was a unilateral bone marrow involvement of 8.8%. Overall, bone marrow involvement induced a change from clinical stages I-II to stage IV in 5.6% of cases, a figure which would correspond to a false negative rate of 2.8%, if unilateral bone marrow biopsy was performed. In the D-F and G, H groups of WF, unilateral involvement was 10.1% and 8.5% respectively; the change in stage from I-II to IV by unilateral bone marrow involvement respectively amounted to 1.4% and 2.8%, which correspond to respective false negative rates of 0.7% and 1.4%. Conclusions On the basis of these results and of the present therapeutic strategies, we propose: bilateral bone marrow biopsy for clinical stages I-II of all NHL; no bone marrow biopsy at disease onset for clinical stages III and IV of A to H histologic subtypes of the WF; unilateral bone marrow biopsy (A-C subtypes of the WF) or bilateral (D-H of the WF), after the regression of extramedullary localizations.
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Shiva, Sajjan G., and Judit U. Jones. "A VHDL Based Expert System for Hardware Synthesis." VLSI Design 1, no. 2 (1994): 113–26. http://dx.doi.org/10.1155/1994/93168.
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This paper describes an expert system for Hardware Synthesis. Details of the target digital system are input to the expert system using Very High Speed Integrated Circuit Hardware Description Language (VHDL). The VHDL representation is first translated to a knowledge representation scheme known as a ‘hologram’ which is a combination of rule, frame and semantic network representation schemes. The hologram representation of the target system is then input to the inference engine, which matches the target system to the Knowledge Base components and selects an appropriate set for implementation, and connects them creating a digital circuit. Some design examples are described. The expert system approach results in designs very close to designs from a human designer. In its present form, the system does not perform a design space exploration for alternate designs, but expects the designer to alter the VHDL representation, after observing the results from previous design cycles.
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Oza, Jay, Shing Mirn Lee, Mia C. Weiss, et al. "A phase 2 study of belinostat and SGI-110 (guadecitabine) for the treatment of unresectable and metastatic conventional chondrosarcoma." Journal of Clinical Oncology 39, no. 15_suppl (2021): TPS11578. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps11578.
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TPS11578 Background: Conventional chondrosarcoma (cCS) accounts for ̃25% of primary bone cancers and is the second most common primary bone tumor after osteosarcoma. Surgical resection is the primary treatment for localized disease. No FDA approved therapy exists for advanced disease and chemotherapy has marginal efficacy with ORR < 12%. IDH1/2 mutation is seen in 50% of cases. Epigenetic dysregulation is central to oncogenesis in both IDH1/2 mutant and wild-type CS. Pre-clinical studies from our group show that combination treatment with HDAC and DNMT inhibitors is significantly more effective at suppressing the growth of CS models in vitro and in vivo compared to either therapy alone. The combination regimen mediates anti-tumor effects on CS by induction of apoptosis, induction of tumor suppressor genes (eg. E-cadherin), the induction of interferon responsive genes (eg. IRF7, OASL, ISG15, DDX58) and reversal of global hypomethylated state. Based on these findings we have designed a phase 2 clinical trial with an HDAC inhibitor (belinostat) and a DNMT inhibitor (guadecitabine) in patients with advanced cCS. Methods: NCI # 10330 is a single-arm, multi-center, Simon 2-stage, phase 2 clinical trial evaluating belinostat and guadecitabine in patients with advanced cCS. Eligible patients will have biopsy proven cCS which is measurable by RECIST v1.1 and amenable to biopsy, ECOG PS ≤ 2, any number of prior treatments (including none). Patients will receive guadecitabine 45 mg/m2 SC followed by belinostat 1000 mg/m2 IV once daily on days 1-5 of a 28-day cycle. A safety lead-in and continuous toxicity monitoring rule will be applied. The primary endpoint will be ORR. Since chemotherapy is associated with an ORR of 8-12% and targeted agents have shown an ORR of 0% in cCS, we will consider an ORR of 8% as inactive while an ORR of 28% will suggest promising activity. A Simon 2-stage design is employed. The design calls for 26 patients. If ≥ 2 responses are observed among 13 patients in stage I, the study will proceed to full accrual. If ≥ 5 responses are seen among 26 patients, the study treatment is considered promising. This design has 85% power with α of 0.054 to test for a response rate of 8% vs 28%. Secondary objectives include safety, tolerability and PFS. All patients will undergo pre-treatment and on-treatment tumor biopsies. Paired tissue will be used for correlative analysis including: 1) whole exome sequencing/RNAseq to evaluate changes in gene expression in response to treatment, 2) multiplex IHC to interrogate the effect of combination therapy on tumor immune microenvironment and 3) a global DNA methylation assay to better understand the changes in epigenetic landscape in response to treatment. This study is open throughout the ETCTN (NCT04340843). Six of the planned 26 patients in the safety lead-in have been enrolled without DLT. Further accrual is on hold pending completion of the safety lead-in. Clinical trial information: 04340843.
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Gamrot, Wojciech. "A Stopping Rule for Simulation‑Based Estimation of Inclusion Probabilities." Acta Universitatis Lodziensis. Folia Oeconomica 4, no. 349 (2020): 67–80. http://dx.doi.org/10.18778/0208-6018.349.04.
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Design‑based estimation of finite population parameters such as totals usually relies on the knowledge of inclusion probabilities characterising the sampling design. They are directly incorporated into sampling weights and estimators. However, for some useful sampling designs, these probabilities may remain unknown. In such a case, they may often be estimated in a simulation experiment which is carried out by repeatedly generating samples using the same sampling scheme and counting occurrences of individual units. By replacing unknown inclusion probabilities with such estimates, design‑based population total estimates may be computed. The calculation of required sample replication numbers remains an important challenge in such an approach. In this paper, a new procedure is proposed that might lead to the reduction in computational complexity of simulations.
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Uozumi, Ryuji, and Chikuma Hamada. "Utility-Based Interim Decision Rule Planning in Adaptive Population Selection Designs With Survival Endpoints." Statistics in Biopharmaceutical Research 12, no. 3 (2019): 360–68. http://dx.doi.org/10.1080/19466315.2019.1689844.
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Kline, Ronald M., L. Daniel Muldoon, Heidi K. Schumacher, et al. "Design Challenges of an Episode-Based Payment Model in Oncology: The Centers for Medicare & Medicaid Services Oncology Care Model." Journal of Oncology Practice 13, no. 7 (2017): e632-e645. http://dx.doi.org/10.1200/jop.2016.015834.
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The Centers for Medicare & Medicaid Services developed the Oncology Care Model as an episode-based payment model to encourage participating practitioners to provide higher-quality, better-coordinated care at a lower cost to the nearly three-quarter million fee-for-service Medicare beneficiaries with cancer who receive chemotherapy each year. Episode payment models can be complex. They combine into a single benchmark price all payments for services during an episode of illness, many of which may be delivered at different times by different providers in different locations. Policy and technical decisions include the definition of the episode, including its initiation, duration, and included services; the identification of beneficiaries included in the model; and beneficiary attribution to practitioners with overall responsibility for managing their care. In addition, the calculation and risk adjustment of benchmark episode prices for the bundle of services must reflect geographic cost variations and diverse patient populations, including varying disease subtypes, medical comorbidities, changes in standards of care over time, the adoption of expensive new drugs (especially in oncology), as well as diverse practice patterns. Other steps include timely monitoring and intervention as needed to avoid shifting the attribution of beneficiaries on the basis of their expected episode expenditures as well as to ensure the provision of necessary medical services and the development of a meaningful link to quality measurement and improvement through the episode-based payment methodology. The complex and diverse nature of oncology business relationships and the specific rules and requirements of Medicare payment systems for different types of providers intensify these issues. The Centers for Medicare & Medicaid Services believes that by sharing its approach to addressing these decisions and challenges, it may facilitate greater understanding of the model within the oncology community and provide insight to others considering the development of episode-based payment models in the commercial or government sectors.
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Watson, James A., and William M. Hayden. "Overview of Coast Guard Plan Review for High-Tech Ship Design." Marine Technology and SNAME News 27, no. 01 (1990): 47–55. http://dx.doi.org/10.5957/mt1.1990.27.1.47.
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The competitive nature of the marine industry has compelled ship and drill rig owners to expect vessel designs which operate more efficiently and are less expensive to build. Designers have abandoned the "old reliable" rule based designs of the 1960's and 1970's in favor of state-of-the-art, high-tech approaches to reduce design unknowns. Analysis techniques include six-degree-of-freedom motion simulation, finite-element structural analysis, fatigue and fracture mechanics techniques, structural and component reliabilities, and electronic on-board monitoring systems. At the Coast Guard Marine Safety Center, where construction plans are reviewed and approved, evaluating the safety of these designs is not an easy task! Unlike the rule-based designs, there are no "cookbook" formulas for double-checking the designer's calculations. An acceptable level of safety must be established and the design approach must be proven for its application to be accepted. Unfortunately, the level of safety that is built into "the rules" is not completely clear, so "acceptable" becomes difficult to establish. This paper discusses the requirements and capabilities of the Coast Guard commercial vessel plan review program and proposes an alternative plan submittal procedure for nonstandard designs.
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Love, Sharon B., Sarah Brown, Christopher J. Weir, et al. "Embracing model-based designs for dose-finding trials." British Journal of Cancer 117, no. 3 (2017): 332–39. http://dx.doi.org/10.1038/bjc.2017.186.
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Cabrera, Juan R., Jennie W. Taylor, and Annette M. Molinaro. "Phase I cancer clinical trials†." Neuro-Oncology Practice 4, no. 1 (2016): 67–72. http://dx.doi.org/10.1093/nop/npw014.
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Abstract An efficient phase I trial is a crucial step in developing a new drug in a safe and timely manner. The main objective of a phase I trial is to determine the maximum tolerated dose in order to recommend the dose for a phase II trial. There are many designs that are implemented in phase I trials. Rule-based designs such as the traditional 3 + 3 method and rolling six design are easy to implement and assess for safety using a conservative approach. Model-based designs such as the continual reassessment method and the time-to-event continual reassessment method use mathematical models to increase the precision of dose estimation. The advantages and shortcomings of these designs, along with other designs, are reviewed.
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Qin, Rui, and Manish Kohli. "Pharmacogenetics- and pharmacogenomics-based rational clinical trial designs in oncology." Personalized Medicine 10, no. 8 (2013): 859–69. http://dx.doi.org/10.2217/pme.13.78.
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Baldi Antognini, Alessandro, and Simone Giannerini. "Generalized Pólya urn Designs with Null Balance." Journal of Applied Probability 44, no. 03 (2007): 661–69. http://dx.doi.org/10.1017/s002190020000334x.
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In this paper we propose a class of sequential urn designs based on generalized Pólya urn (GPU) models for balancing the allocations of two treatments in sequential clinical trials. In particular, we consider a GPU model characterized by a 2 x 2 random addition matrix with null balance (i.e. null row sums) and replacement rule depending upon the urn composition. Under this scheme, the urn process has a Markovian structure and can be regarded as a random extension of the classical Ehrenfest model. We establish almost sure convergence and asymptotic normality for the frequency of treatment allocations and show that in some peculiar cases the asymptotic variance of the design admits a natural representation based on the set of orthogonal polynomials associated with the corresponding Markov process.
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Baldi Antognini, Alessandro, and Simone Giannerini. "Generalized Pólya urn Designs with Null Balance." Journal of Applied Probability 44, no. 3 (2007): 661–69. http://dx.doi.org/10.1239/jap/1189717536.
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In this paper we propose a class of sequential urn designs based on generalized Pólya urn (GPU) models for balancing the allocations of two treatments in sequential clinical trials. In particular, we consider a GPU model characterized by a 2 x 2 random addition matrix with null balance (i.e. null row sums) and replacement rule depending upon the urn composition. Under this scheme, the urn process has a Markovian structure and can be regarded as a random extension of the classical Ehrenfest model. We establish almost sure convergence and asymptotic normality for the frequency of treatment allocations and show that in some peculiar cases the asymptotic variance of the design admits a natural representation based on the set of orthogonal polynomials associated with the corresponding Markov process.
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Zhang, Wei Guo, Yi Chu, Ming Yu Zhao, and Fu Bin Hong. "Electric Vehicles Online Monitoring System Design Based on the Hybrid Reasoning." Applied Mechanics and Materials 278-280 (January 2013): 878–83. http://dx.doi.org/10.4028/www.scientific.net/amm.278-280.878.
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This paper designs a set of electric vehicles online monitoring system with SOA framework, which includes acquisition layer, network layer, support platform, knowledge base layer and presentation layer, and knowledge layer includes a knowledge base management system, reasoning system and man-machine interface system. Also, this paper constructs a knowledge expert system with hybrid rule-based reasoning method of CBR and RBR, finally, electric automobile remote intelligent fault diagnosis is illustrated with the expert systems.
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Zhu, Jing, Chen Xi Wang, Cheng Jun Zhang, and Shi Kai Zhang. "New Evidence Combination Method Based on Redistribution of Global Conflict." Applied Mechanics and Materials 303-306 (February 2013): 930–37. http://dx.doi.org/10.4028/www.scientific.net/amm.303-306.930.
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The combination of high conflict evidence is a research focus in belief function theory, this paper analyzes two major solving strategy of the modifying rule and the modifying evidence body, and proposes a new evidence synthesis method by modifying rule. In allusion to the combination of high conflict evidence and focusing downwards problem, the method constructs new global conflict measurement under the framework of conjunction combination, which can solve the illogicality of of Shafer conflict measurement. Then the paper designs the solution of local redistribution of global conflict, through choosing the reasonable proportion coefficient, which can overcome focusing downwards and synthesis convergence problem together. Compared with other methods, the new method is more effective to solve the combination problem of high conflict evidence, and meet the quasi-association, and has the higher value of application.