scholarly journals Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment

2009 ◽  
Vol 27 (33) ◽  
pp. 5660-5669 ◽  
Author(s):  
Philip A. Philip ◽  
Margaret Mooney ◽  
Deborah Jaffe ◽  
Gail Eckhardt ◽  
Malcolm Moore ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Predictive Biomarkers ◽  
Steering Committee ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Ii Studies ◽  
Planning Meeting

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

Cetuximab in the Treatment of Locally Advanced Head and Neck Cancer

2011 ◽  
Vol 07 (01) ◽  
pp. 16
Author(s):  
Rainald Knecht ◽  
Keyword(s):  
Quality Of Life ◽  
Clinical Trials ◽  
Head And Neck ◽  
Phase Ii ◽  
Locally Advanced ◽  
Phase Iii ◽  
Significant Advance ◽  
Life Questionnaire ◽  
Large Phase

Locally advanced squamous cell cancer of the head and neck (LA SCCHN) includes various cancers of the oral cavity, pharynx and larynx that have spread from the primary site but have not metastasised. Due to poor public awareness of SCCHN and its symptoms, about 50–70% of cases are diagnosed only when the disease has become locally advanced; prognosis by this time is poorer than during earlier stages. Combinations of chemotherapy with radiotherapy have produced greater efficacy in treating LA SCCHN over radiotherapy alone in various clinical trials, but this approach increases the incidence of toxicities. An alternative therapeutic approach is to use the monoclonal antibody cetuximab (Erbitux®). Cetuximab targets epidermal growth factor receptor (EGFR), which is overexpressed in LA SCCHN, and this overexpression of EGFR is associated with poor prognosis. A number of recent phase II and III clinical trials have demonstrated that cetuximab is an effective and safe treatment for LA SCCHN. One large phase III clinical trial demonstrated that the addition of cetuximab to radiotherapy in patients with LA SCCHN provides substantial efficacy and quality of life benefits, including improvements in overall survival, disease-free survival, response rate and European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 parameters, without markedly affecting safety and tolerability. Other, smaller phase II studies in patient populations having either resectable or non-resectable tumours have demonstrated the benefits of adding cetuximab to other chemotherapy/radiotherapy regimens for LA SCCHN. Cetuximab is currently the only targeted biological therapy approved for use in combination with radiation therapy for LA SCCHN. In conclusion, cetuximab represents a significant advance in the treatment of LA SCCHN. Furthermore, based on the data from the large phase III trial, the most recent European Society for Medical Oncology (ESMO) guidelines recommend the use of cetuximab in combination with radiotherapy in LA SCCHN.

A phase II trial design with direct assignment option for initial marker validation.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
Sumithra J. Mandrekar ◽  
Ming-Wen An ◽  
Daniel J. Sargent
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Type I Error ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Phase Iii ◽  
Type I ◽  
Design Strategies ◽  
Number Of Patients ◽  
The Impact

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (<1.8%) and minimal increase in T1ER (<2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was <1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.

scholarly journals Comparison between phase III randomized clinical trials and their preceeding phase II studies

2019 ◽  
Vol 30 ◽  
pp. v674
Author(s):  
I. Lyra-Gonzalez ◽  
O. Espin-Garcia ◽  
M.K. Krzyzanowska ◽  
R W-J Jang ◽  
E. Elimova
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
Phase Ii Studies

Characteristics of a phase II study that predict for a positive phase III trial—A study of 383 clinical trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6604-6604
Author(s):  
S. M. Ueda ◽  
V. E. Sugiyama ◽  
C. Stave ◽  
J. Y. Shin ◽  
B. J. Monk ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Predictive Factors ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Iii Trial ◽  
Phase Iii Clinical Trials ◽  
Phase Ii Studies ◽  
Phase Iii Trials

6604 Background: To identify the characteristics of a phase II study that predict for a subsequent positive phase III trial. Methods: All phase II studies and subsequent phase III clinical trials on biologics in advanced cancers published from 1985 to 2005 were extracted. Chi-square test and logistic regression models were used for analyses. Results: 383 phase III clinical trials and their preceding phase II studies were identified. 183 (47.8%) phase III trials were “positive” and 200 (52.2%) were negative. 220 trials (57.4%) used biologics alone and 162 (42.3%) used a combination of biologics and chemotherapy. Over the study periods 1985–1990, 1991–1995, 1996–2000, 2001–2005, the percentage of phase II studies that led to positive phase III trials increased from 37.7% to 33.3% to 56.0% to 76.8% (p<0.001). The interval between the publication of phase II and III studies, 0.5–5, 6–10, 11–15, and 16–20 years were also associated with the success of phase III trial, 55.6%, 42.2%, 32.6%, and 10.0%, respectively (p<0.001). Phase II studies from multiple rather than single institutions were more likely to have a successful trial (60.4% vs. 39.4%; p<0.001). The percent of successful trials from pharmaceutical companies was significantly higher compared to academic, cooperative groups, and research institutes (89.5% vs. 44.2%, 45.2%, 46.3%; p=0.002). The publication of the phase II studies in journals with an impact factor of 8 or greater compared to those less than 8 was also predictive (44.1% vs. 58.0%; p=0.024). Phase II studies with a lower attrition rate were also associated with a positive phase III trial (61.1% vs. 41.8%; p=0.025). On multivariable analysis, all factors, except for journal impact factor, were independent predictive factors for a positive phase III trial. Conclusions: In phase II biologic studies, characteristics such as larger number of patients, more recent year of study, multiple vs. single institution participation, shorter time period between publication of phase II to phase III trial, and lower rate of attrition were predictive factors of success in a phase III trial. Investigators need to be cognizant of these phase II study characteristics before designing phase III trials. No significant financial relationships to disclose.

scholarly journals Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2186
Author(s):  
Rupesh Kotecha ◽  
Raees Tonse ◽  
Muni Rubens ◽  
Haley Appel ◽  
Federico Albrecht ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Systemic Chemotherapy ◽  
Meta Analysis ◽  
Performance Status ◽  
Locally Advanced ◽  
Phase Iii ◽  
Pleural Mesothelioma ◽  
Prognostic Variables ◽  
Phase Ii Studies

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

624 A PHASE III STUDY ON NEOADJUVANT TORIPALIMAB PLUS CHEMOTHERAPY VERSUS NEOADJUVANT CHEMOTHERAPY FOR LOCALLY RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Yan Zheng ◽  
Jiangong Zhang ◽  
Wenqun Xing
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
R0 Resection ◽  
Phase Iii Trial ◽  
Free Survival

Abstract   In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in our Hospital. Methods A two-arm phase III trial was launched in April 2020 in our Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future. Results Until Dec. 2021, one hundred and twenty ESCC patients recruited in the trial. The trial is ongoing. Conclusion This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

scholarly journals Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jiali Du ◽  
Jichun Gu ◽  
Ji Li
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Solid Tumours ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Iii Trials ◽  
Exploitation And Exploration ◽  
Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

Measuring the Incremental Cost of Clinical Cancer Research

2001 ◽  
Vol 19 (1) ◽  
pp. 105-110 ◽  
Author(s):  
Dana P. Goldman ◽  
Michael L. Schoenbaum ◽  
Arnold L. Potosky ◽  
Jane C. Weeks ◽  
Sandra H. Berry ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Treatment ◽  
Incremental Cost ◽  
Cancer Patients ◽  
Phase Ii ◽  
The United States ◽  
Phase Iii ◽  
Ongoing Effort ◽  
Cancer Trials ◽  
The Cost

PURPOSE: To summarize evidence on the costs of treating patients in clinical trials and to describe the Cost of Cancer Treatment Study, an ongoing effort to produce generalizable estimates of the incremental costs of government-sponsored cancer trials. METHODS: A retrospective study of costs will be conducted with 1,500 cancer patients recruited from a randomly selected sample of institutions in the United States. Patients accrued to either phase II or phase III National Cancer Institute–sponsored clinical trials during a 15-month period will be asked to participate in a study of their health care utilization (n = 750). Costs will be measured approximately 1 year after their trial enrollment from a combination of billing records, medical records, and an in-person survey questionnaire. Similar data will be collected for a comparable group of cancer patients not in trials (n = 750) to provide an estimate of the incremental cost. RESULTS: Evidence suggests insurers limit access to trials because of cost concerns. Public and private efforts are underway to change these policies, but their permanent status is unclear. Previous studies found that treatment costs in clinical trials are similar to costs of standard therapy. However, it is difficult to generalize from these studies because of the unique practice settings, insufficient sample sizes, and the exclusion of potentially important costs. CONCLUSION: Denials of coverage for treatment in a clinical trial limit patient access to trials and could impede clinical research. Preliminary estimates suggest changes to these policies would not be expensive, but these results are not generalizable. The Cost of Cancer Treatment Study is an ongoing effort to provide generalizable estimates of the incremental treatment cost of phase II and phase III cancer trials. The results should be of great interest to insurers and the research community as they consider permanent ways to finance cancer trials.

Sign in / Sign up

Export Citation Format

Share Document