<i>p</i>-Value Calculation for Multistage Phase II Cancer Clinical Trials

Jung, Sin‐Ho; Owzar, Kouros; George, Stephen L.; Lee, Taiyeong

doi:10.1080/10543400600825645

Cited by 21 publications

(20 citation statements)

References 17 publications

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“…This two-stage design had a type I error rate of 5% if the true ORR was 45%, and 85% power if the true ORR was 65%. Accounting for the two-stage design, the ORR was estimated using the method of Jung and Kim [19], the confidence interval was calculated by the method of Jennison and Turnbull [20], and the p-value for ORR was calculated by the method of Jung et al [21]. The sample size was calculated to include a potential 10% ineligibility rate.…”

Section: Methodsmentioning

confidence: 99%

Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501)

Morrison

Jung

Johnson

et al. 2014

Leukemia & Lymphoma

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CALGB designed a phase II trial of lenalidomide+bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete and partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free- (PFS), event-free- (EFS), and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median follow-up is 46 (range, 12-67) months. Best response was CR (n=8, 15%), PR (n=13, 25%). 5/8 CR and 4/13 PR patients received maintenance therapy. Of responders, 6 CR/1 PR patients remain in remission at a median of 3.2 years. Thirty-three (62%) patients have died. One-year PFS, EFS, OS are 40%, 25%, and 68%, respectively. This combination will not be pursued further at this dose/schedule.

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Section: Methodsmentioning

confidence: 99%

Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501)

Morrison

Jung

Johnson

et al. 2014

Leukemia & Lymphoma

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“…The bias-corrected estimators have the same ordering as the MLE [23]. They thus result in exactly the same p -value.…”

Section: Methodsmentioning

confidence: 99%

What inference for two-stage phase II trials?

Porcher

Desseaux

2012

BMC Med Res Methodol

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BackgroundSimon’s two-stage designs are widely used for cancer phase II trials. These methods rely on statistical testing and thus allow controlling the type I and II error rates, while accounting for the interim analysis. Estimation after such trials is however not straightforward, and several different approaches have been proposed.MethodsDifferent approaches for point and confidence intervals estimation, as well as computation of p-values are reviewed and compared for a range of plausible trials. Cases where the actual number of patients recruited in the trial differs from the preplanned sample size are also considered.ResultsFor point estimation, the uniformly minimum variance unbiased estimator (UMVUE) and the bias corrected estimator had better performance than the others when the actual sample size was as planned. For confidence intervals, using a mid-p approach yielded coverage probabilities closer to the nominal level as compared to so-called ’exact’ confidence intervals. When the actual sample size differed from the preplanned sample size the UMVUE did not perform worse than an estimator specifically developed for such a situation. Analysis conditional on having proceeded to the second stage required adapted analysis methods, and a uniformly minimum variance conditional estimator (UMVCUE) can be used, which also performs well when the second stage sample size is slightly different from planned.ConclusionsThe use of the UMVUE may be recommended as it exhibited good properties both when the actual number of patients recruited was equal to or differed from the preplanned value. Restricting the analysis in cases where the trial did not stop early for futility may be valuable, and the UMVCUE may be recommended in that case.

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“…Using the stochastic ordering of UMVUE (3), Jung et al [25] propose a p-value method for 2-stage phase II clinical trials. Noting that a p-value is defined as the probability to observe an extreme test statistic value toward the direction of H 1 when H 0 is true, they propose to calculate the probability to observe a UMVUE value larger than that obtained from the study under H 0 .…”

Section: P-value Calculationmentioning

confidence: 99%

“…Jung et al [25] show that, if the observed sample size at each stage is identical to that specified by the design, the decision by the two-stage design exactly matches with that by the p-value compared with the α * value. As discussed in the previous section, the confidence interval by Jennison and Turnbull [16] has this property too.…”

Section: P-value Calculationmentioning

confidence: 99%

Statistical issues for design and analysis of single-arm multi-stage phase II cancer clinical trials

Jung

2015

Contemporary Clinical Trials

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Summary Phase II trials have been very widely conducted and published every year for cancer clinical research. In spite of the fast progress in design and analysis methods, single-arm two-stage design is still the most popular for phase II cancer clinical trials. Because of their small sample sizes, statistical methods based on large sample approximation are not appropriate for design and analysis of phase II trials. As a prospective clinical research, the analysis method of a phase II trial is predetermined at the design stage and it is analyzed during and at the end of the trial as planned by the design. The analysis method of a trial should be matched with the design method. For two-stage single arm phase II trials, Simon's method has been the standards for choosing an optimal design, but the resulting data have been analyzed and published ignoring the two-stage design aspect with small sample sizes. In this article, we review analysis methods that exactly get along with the exact two-stage design method. We also discuss some statistical methods to improve the existing design and analysis methods for single-arm two-stage phase II trials.

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p-Value Calculation for Multistage Phase II Cancer Clinical Trials

Cited by 21 publications

References 17 publications

Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501)

Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501)

What inference for two-stage phase II trials?

Statistical issues for design and analysis of single-arm multi-stage phase II cancer clinical trials

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