scholarly journals Comparison of Error Rates in Single-Arm Versus Randomized Phase II Cancer Clinical Trials

2010 ◽  
Vol 28 (11) ◽  
pp. 1936-1941 ◽  
Author(s):  
Hui Tang ◽  
Nathan R. Foster ◽  
Axel Grothey ◽  
Stephen M. Ansell ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Phase Ii ◽  
Patient Selection ◽  
Statistical Models ◽  
False Positive ◽  
Error Rates ◽  
Phase Iii ◽  
Selection Effects ◽  
Randomized Phase Ii

PurposeTo improve the understanding of the appropriate design of phase II oncology clinical trials, we compared error rates in single-arm, historically controlled and randomized, concurrently controlled designs.Patients and MethodsWe simulated error rates of both designs separately from individual patient data from a large colorectal cancer phase III trials and statistical models, which take into account random and systematic variation in historical control data.ResultsIn single-arm trials, false-positive error rates (type I error) were 2 to 4 times those projected when modest drift or patient selection effects (eg, 5% absolute shift in control response rate) were included in statistical models. The power of single-arm designs simulated using actual data was highly sensitive to the fraction of patients from treatment centers with high versus low patient volumes, the presence of patient selection effects or temporal drift in response rates, and random small-sample variation in historical controls. Increasing sample size did not correct the over optimism of single-arm studies. Randomized two-arm design conformed to planned error rates.ConclusionVariability in historical control success rates, outcome drifts in patient populations over time, and/or patient selection effects can result in inaccurate false-positive and false-negative error rates in single-arm designs, but leave performance of the randomized two-arm design largely unaffected at the cost of 2 to 4 times the sample size compared with single-arm designs. Given a large enough patient pool, the randomized phase II designs provide a more accurate decision for screening agents before phase III testing.

Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

2005 ◽  
Vol 23 (28) ◽  
pp. 7199-7206 ◽  
Author(s):  
Lawrence V. Rubinstein ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
Sally Hunsberger ◽  
S. Percy Ivy ◽  
...  
Keyword(s):  
Phase Ii ◽  
False Positive ◽  
Standard Treatment ◽  
False Negative ◽  
Error Rates ◽  
Targeted Treatment ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Treatment Control ◽  
Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4036-4036 ◽  
Author(s):  
Daniel M. Halperin ◽  
J. Jack Lee ◽  
James C. Yao
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Predictive Value ◽  
Error Rates ◽  
Phase Iii ◽  
Type I ◽  
Type Ii ◽  
Type Ii Error ◽  
Phase Ii Trials ◽  
Fda Approval

4036 Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ≥0.1 in 8 studies, 0.05 in 6 studies and <0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used >0.1, 10 used 0.1, and 4 used <0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. [Table: see text]

Randomized phase II/III trial comparing gemcitabine/carboplatin (GC) and methotrexate/carboplatin/vinblastine (M-CAVI) in patients (pts) with advanced urothelial cancer (UC) unfit for cisplatin-based chemotherapy (CHT): Phase III results of EORTC study 30986.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA4519-LBA4519 ◽  
Author(s):  
M. De Santis ◽  
J. Bellmunt ◽  
G. Mead ◽  
J. M. Kerst ◽  
M. G. Leahy ◽  
...  
Keyword(s):  
Renal Function ◽  
Phase Ii ◽  
Impaired Renal Function ◽  
Performance Status ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Logrank Test ◽  
Randomized Phase Ii ◽  
Grade 3

LBA4519 Background: About 50% of pts with advanced UC are not eligible for cisplatin based CHT (“unfit”) due to impaired renal function, performance status (PS) or comorbidity. This is the first randomized phase II/III trial comparing two chemotherapy regimens in this pts group. Methods: The primary objective of the phase III part of this study was to compare the overall survival (OS) of CHT naïve pts with measurable disease and an impaired renal function (GFR<60 but >30 ml/min) and/or PS 2 who were randomized to receive either GC (G 1000 mg/m2 d1 and 8 and C AUC 4.5) q21 days or M-CAVI (M 30 mg/m2 d1 and 15 and 22, C AUC 4.5 d1 and VI 3 mg/m2 d1 and 15 and 22) q28 days. In order to detect an increase of 50% in median survival on GC compared to M-CAVI (13.5 versus 9 months) based on a two sided logrank test at error rates alpha=0.05 and beta=0.20, 225 pts were required. Secondary endpoints were overall response rate (ORR) and progression free survival (PFS). Results: 238 pts, 119 in each arm, were randomized between January 2001 and March 2008 by 29 institutions. The median follow-up is 4.5 years. Two pts were ineligible and two other pts never started treatment. Best ORRs (CR + PR) were 41.2% (36.1% confirmed response) on GC versus 30.3% (21.0% confirmed response) on M-CAVI (p = 0.08). Median OS was 9.3 months on GC and 8.1 months on M-CAVI (p = 0.64). There was no difference in PFS between the two arms (p = 0.78). OS, PFS and ORR were similar in each of the risk groups (reason unfit for cisplatin and Bajorin risk group). Severe acute toxicity (SAT) (death, grade 4 thrombocytopenia with bleeding, or grade 3/4 renal toxicity, neutropenic fever or mucositis) was observed in 9.3% of pts on GC (2 toxic deaths) and 21.2% on M-CAVI (4 toxic deaths). The most common grade 3/4 toxicities were leucopenia (44.9%, 46.6%), neutropenia (52.5%, 63.5%), febrile neutropenia (4.2%, 14.4%), thrombocytopenia (48.3%, 19.4%), and infection (11.8%, 12.7%) on GC and M-CAVI, respectively. Conclusions: There were no significant differences in efficacy between the two treatment groups. The incidence of SATs was slightly higher on M-CAVI. [Table: see text]

scholarly journals Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

2012 ◽  
Vol 30 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Maria De Santis ◽  
Joaquim Bellmunt ◽  
Graham Mead ◽  
J. Martijn Kerst ◽  
Michael Leahy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.

Randomized Phase II Designs in Cancer Clinical Trials: Current Status and Future Directions

2005 ◽  
Vol 23 (19) ◽  
pp. 4450-4457 ◽  
Author(s):  
J. Jack Lee ◽  
Lei Feng
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Statistical Design ◽  
Stopping Rules ◽  
Phase Iii ◽  
Current Status ◽  
Cancer Clinical Trials ◽  
Future Directions ◽  
Randomized Phase Ii ◽  
Accrual Rate

Purpose Randomized phase II (RPh2) designs are popular in cancer clinical trials because of the smaller sample size requirements when multiple treatments are being evaluated. We reviewed the use of RPh2 designs and give comments on future directions. Design The trial design, statistical properties, conduct, data analysis, results, and reporting were examined in RPh2 trials reported from 1986 to 2002. Results A statistical design was reported in only 46% of the 266 cancer trials, and approximately half of those provided inadequate information. Most studies applied randomization to achieve patient comparability, while embedding a one-sample phase II design within each treatment arm. Seventy-five percent of the trials’ accruals were within ± 10% of their targets. The average accrual rate was 3.3 patients per month. Planned interim analyses were reported in 27% of the trials, and 56% of the trials were stopped early; 69%, 13%, 13%, and 4% of the trial discontinuations were because of lack of efficacy, efficacy, toxicity, and slow accrual, respectively. Thirty-nine trials (14%) recommended or started phase III evaluations, with four positive reports in six phase III studies identified. Conclusion There is a trend of increasing use of RPh2 designs in cancer research. Continued improvement in study design, conduct, analysis, and reporting is required to enhance the quality of RPh2 designs. The accrual rate and success rate of the trials remain low, and therefore, futility stopping rules to terminate ineffective treatment arm(s) should be implemented more frequently. More innovative, flexible RPh2 designs are needed to facilitate the development of effective cancer treatments.

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.

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

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