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A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS).

ABSTRACT: Standard drug development conducts phase I dose finding and phase II dose expansion sequentially and separately. Information between the two phases is rarely shared. Administratively, such a sequential process is time-consuming and burdensome.We propose seamless dose escalation/expansion with adaptive randomization scheme (SEARS), a seamless design that combines phase I dose escalation based on toxicity with phase II dose expansion and dose comparison based on efficacy. SEARS allows extension from phase I to phase II under one design with no gap in between and employs a dynamic and parallel procedure involving simultaneous dose escalation, dose graduation, and adaptive randomization.SEARS integrates three components into a seamless scheme. Specifically, in phase I, SEARS applies the modified toxicity probability interval (mTPI) method to monitor dose escalation based on toxicity outcome. Doses that show promising efficacy and safety are immediately graduated from phase I and placed to a phase II stage in which patients are adaptively randomized based on efficacy outcome. Phase I dose escalation, dose graduation, and phase II adaptive randomization proceed simultaneously throughout the entire trial.Examples are given comparing SEARS with two other designs, in which superior performance of SEARS is demonstrated. An important and promising finding is that SEARS reduces sample sizes without losing power. R program and demo slides of SEARS can be obtained at http://health.bsd.uchicago.edu/yji/soft.htmlWe assume that the binary efficacy and toxicity response can be measured in the same time frame. This is often achievable with surrogate efficacy markers in practice.

SUBMITTER: Pan H

PROVIDER: S-EPMC4281526 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS).

Pan Haitao H Xie Fang F Liu Ping P Xia Jielai J Ji Yuan Y

Clinical trials (London, England) 20131017 1

<h4>Background</h4>Standard drug development conducts phase I dose finding and phase II dose expansion sequentially and separately. Information between the two phases is rarely shared. Administratively, such a sequential process is time-consuming and burdensome.<h4>Purpose</h4>We propose seamless dose escalation/expansion with adaptive randomization scheme (SEARS), a seamless design that combines phase I dose escalation based on toxicity with phase II dose expansion and dose comparison based on ...[more]

PMID: 24137041

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Project description:An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (<or=5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20-25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.

Project description:BackgroundNovel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population.MethodsThis was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 μg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235.FindingsBetween Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 μg/kg and 45 μg/kg for patients with classical Hodgkin lymphoma and 80 μg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81).InterpretationThese results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma.FundingADC Therapeutics.

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A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS).

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A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS).

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