Two‐sample binary phase 2 trials with low type I error and low sample size

Litwin, Samuel; Basickes, Stanley; Ross, Eric A.

doi:10.1002/sim.7226

Cited by 5 publications

(4 citation statements)

References 3 publications

(43 reference statements)

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“…A trial that has been used previously as an example in comparing two-arm binary outcome trial designs is CALGB 50502, a randomised phase II trial for the treatment of Hodgkin Lymphoma. 20 , 22 , 33 The design parameters of the trial are ( α , β , p 0 , p 1 ) = (0.15,0.20,0.70,0.85). Optimal designs for this set of design parameters were sought for the designs of Jung, Carsten and Chen, Chen et al and the block designs, using the same methods as for the main comparisons.…”

Section: Resultsmentioning

confidence: 99%

“…The designs were also compared using a real-life example, used previously to compare two-arm designs. 10,22,33 When minimising expected sample size under either p C = p T = p 0 or p C = p 0 , p T = p 1 , the reduction in expected sample size for the proposed block designs was considerable compared to existing designs. When minimising maximum sample size, the proposed block designs had comparable maximum sample size and smaller expected sample size compared to existing designs, again with monitoring frequency reduced considerably when using blocks of size eight.…”

Section: Discussionmentioning

confidence: 97%

“…We note that other two-arm approaches have been proposed. 17 , 18 , 19 , 20 , 21 , 22 However, it is impractical to compare all randomised two-arm designs, and so our approach will be compared only to Jung’s design, as this is the two-arm analogue to the popular Simon design, and Carsten and Chen and Chen et al’s designs, as these designs use curtailment and as such are similar to our approach. 10 , 11 , 12 Table 1 shows the main differences between the designs to be compared.…”

Section: Introductionmentioning

confidence: 99%

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A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

Law

Grayling

Mander

2020

Pharmaceutical Statistics

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Summary Randomised controlled trials are considered the gold standard in trial design. However, phase II oncology trials with a binary outcome are often single‐arm. Although a number of reasons exist for choosing a single‐arm trial, the primary reason is that single‐arm designs require fewer participants than their randomised equivalents. Therefore, the development of novel methodology that makes randomised designs more efficient is of value to the trials community. This article introduces a randomised two‐arm binary outcome trial design that includes stochastic curtailment (SC), allowing for the possibility of stopping a trial before the final conclusions are known with certainty. In addition to SC, the proposed design involves the use of a randomised block design, which allows investigators to control the number of interim analyses. This approach is compared with existing designs that also use early stopping, through the use of a loss function comprised of a weighted sum of design characteristics. Comparisons are also made using an example from a real trial. The comparisons show that for many possible loss functions, the proposed design is superior to existing designs. Further, the proposed design may be more practical, by allowing a flexible number of interim analyses. One existing design produces superior design realisations when the anticipated response rate is low. However, when using this design, the probability of rejecting the null hypothesis is sensitive to misspecification of the null response rate. Therefore, when considering randomised designs in phase II, we recommend the proposed approach be preferred over other sequential designs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

Law

Grayling

Mander

2020

Pharmaceutical Statistics

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“…Prespecified statistical assumptions estimated that 20% of patients in Arm A would have undetectable PSA at 32 weeks versus 40% of patients in Arm B. To detect a difference between 20% and 40% with 80% power and type I error < 5%, a cohort of 39 patients was initially planned and, if the study continued, a second cohort of 27 patients was planned to be randomized 1:2 to arms A and B respectively, with a planned final sample size of 66 patients [ 15 ]. Analyses were performed on an intention-to-treat basis.…”

Section: Methodsmentioning

confidence: 99%

A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1)

Bilušić

Toney

Donahue

et al. 2022

Prostate Cancer Prostatic Dis

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Background: Metformin may have anticancer effects that are independent of its hypoglycemic effects. Retrospective studies have shown that metformin use is associated with decreased incidence of prostate cancer and prostate cancer-specific mortality. Preclinical studies suggesting additive anticancer effects of combining metformin and bicalutamide prompted this clinical trial ( NCT02614859 ). Methods: This open-label, randomized, phase 2 trial enrolled non-diabetic patients with biochemically recurrent prostate cancer, a PSADT of 3–9 months, BMI > 25 and normal testosterone. Patients were randomized 1:2 to observation for an initial 8 weeks (Arm A) or metformin 1000 mg twice daily (Arm B). Bicalutamide 50 mg/day was added after 8 weeks to both arms. The primary objective was to evaluate the number of patients with undetectable PSA (< 0.2 ng/mL) at the end of 32 weeks. Immune correlatives were assessed as exploratory endpoints. Results: 29 patients were enrolled from March 2015 to January 2020. No difference was seen between the 2 arms in the proportion of patients with undetectable PSA. Modest PSA decrease ranging from 4 to 24% were seen in 40.0% (95% CI: 19.1% - 64.0%) of patients with metformin monotherapy, compared to 11.1% (95% CI: 0.3% - 48.3%) in the observation arm. Metformin monotherapy reduced PD-1 + NK cells, and increased NKG2D + NK cells. The combination of metformin and bicalutamide led to greater reductions in PD-1 expressing NK, CD4 + T, and CD8 + T-cell subsets compared to bicalutamide alone. The trial was stopped early due to predicted inability to achieve its primary endpoint. Conclusions: Although metformin plus bicalutamide was well tolerated, there was no improvement in rates of achieving undetectable PSA at 32 weeks. Metformin monotherapy induced modest PSA declines in 40% of patients after 8 weeks. Metformin, given alone and in combination with bicalutamide, displayed immune modifying effects, primarily within NK and T cells subsets.

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Practical and robust test for comparing binomial proportions in the randomized phase II setting

Attwood

Park

Hutson

2021

Pharmaceutical Statistics

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The one-arm, non-randomized, one/two-stage phase II designs have been a mainstay in oncology trials for evaluating response rates or similar variants (i.e., tests about single proportions). With the goal of screening new therapies that have the potential to move into a randomized phase III trial or a subsequent randomized phase II trial, all while maintaining a logistically feasible sample size. However, since the implementation of the Food and Drug Administration's Fast Track Designation, there has been a trend toward randomized phase II clinical trials as a source of stronger evidence for those seeking fasttrack approvals. While there are many single-and multi-stage randomized designs for evaluating proportions in this phase II setting, there still exist limitations in terms of sample size (which directly impacts cost and study duration) or operating characteristics (ex. maintained type I error). In this article, we propose a new test for comparing two binomial proportions, which is a modification across existing methods (the standard z-test and Jung's test). This approach is contrasted with existing methods via numeric evaluation and further contrasted using a real-world oncology trial. The proposed method demonstrates improvements in efficiency and robustness against deviations from design assumptions. When applied to the existing trial, significant savings with respect to cost and time are illustrated. Our proposed test for comparing binomial proportions provides an efficient and robust alternative in the randomized phase II oncology setting, especially when the control arm has a high rate.

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Two‐sample binary phase 2 trials with low type I error and low sample size

Cited by 5 publications

References 3 publications

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1)

Practical and robust test for comparing binomial proportions in the randomized phase II setting

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