Stopping rules for phase I clinical trials with dose expansion cohorts

Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample size of these designs. However, even with a small sample size, this paper shows that easily implementable stopping rules can terminate dose-escalation early with minimal loss to the accuracy of maximum tolerated dose estimation. These stopping rules are developed when the goal is to identify one or two dose levels, as the maximum tolerated dose and co-maximum tolerated dose. In oncology, this latter goal is frequently considered when the study includes dose-expansion cohorts, which are used to further estimate and compare the safety and efficacy of one or two dose levels. As study protocols do not typically halt accrual between escalation and expansion, early termination is of clinical importance as it either allows for additional patients to be treated as part of the dose expansion cohort to obtain more precise estimates of the study endpoints or allows for an overall reduction in the total sample size.

Finding a Home: Stopping Theory and Its Application to Home Range Establishment in a Novel Environment

Familiarity with the landscape increases foraging efficiency and safety. Thus, when animals are confronted with a novel environment, either by natural dispersal or translocation, establishing a home range becomes a priority. While the search for a home range carries a cost of functioning in an unfamiliar environment, ceasing the search carries a cost of missed opportunities. Thus, when to establish a home range is essentially a weighted sum of a two-criteria cost-minimization problem. The process is predominantly heuristic, where the animal must decide how to study the environment and, consequently, when to stop searching and establish a home range in a manner that will reduce the cost and maximize or at least satisfice its fitness. These issues fall within the framework of optimal stopping theory. In this paper we review stopping theory and three stopping rules relevant to home range establishment: the best-of-n rule, the threshold rule, and the comparative Bayes rule. We then describe how these rules can be distinguished from movement data, hypothesize when each rule should be practiced, and speculate what and how environmental factors and animal attributes affect the stopping time. We provide a set of stopping-theory-related predictions that are testable within the context of translocation projects and discuss some management implications.

Importance and role of independent data monitoring committees (IDMCs) in oncology clinical trials

The role and use of independent data monitoring committees (IDMCs) has evolved over the past decades. The Food and Drug Administration and European Medicines Agency have issued guidelines on the role and functioning of such committees. In general, data monitoring committees are recommended for large, often randomised clinical trials involving life-threatening diseases, studies performed in vulnerable populations or where the experimental intervention can potentially harm the trial participant. Such committees play an important role in trials evaluating treatments with the potential to prolong life or reduce the risk of major adverse health outcomes.Typically, oncology clinical trials fall within these recommendations, as they are often large, randomised, multicentric protocols aiming at improving survival outcomes by exploring the use of study treatments that may be associated with a significant risk of serious, even life-threatening adverse events. IDMCs are required for National Cancer Institute phase III randomised trials, European Organisation for Research and Treatment of Cancer phase II/III trials with formal interim analyses, early-stopping rules or adaptive studies. The primary role of an IDMC of ensuring the safety of study participants and maintaining clinical trial integrity is particularly important in oncology trials, due to the nature of the disease, the potential for treatment toxicity and for instilling confidence that the clinical trial data are reliable. A clear understanding by IDMC members of the natural course of the disease, treatment landscape, importance and relevance of certain adverse events in trial participants, clinical trial methodology in general and stopping rules for oncology trials in particular, is crucial for the functioning of an IDMC.It is recommended that IDMC members should be experienced trialists, have a track record of strong clinical, statistical and/or methodological expertise and the required level of independence, as they play a highly important role in the protection of study participants, and in commercially and strategically important go/no decisions. Ideally, IDMC members should have relevant experience or have some training, mentorship or guidelines.

P07.03 ‘myTcell’: a smartphone applicationguides logisticsand management of CAR T-cell & BiTE related toxicities

BackgroundBispecific T-cell engagers (BiTE) and CD19-specific Chimeric Antigen Receptor (CAR) T-cell products are approved for relapsed and refractory B-cell neoplasms. However, rapid disease progression and the pre-treatment workflow during manufacturing challenges several specialities of health care professionals and involves a well educated team in the in-patient and out-patient setting. In addition, CARs and BiTEs are accompanied by a new spectrum of immune related toxicities. Currently, clinical trials investigate the safety of outpatient CAR T-cell administration, requiring high-level care during the early post-infusion period. To support the optimal management of these patients, we developed the interactive smartphone application ‘myTcell’, which guides and educates physicians in the pre-treatment logistics of CARs and BiTEs and management of related toxicities.Materials and MethodsWe initiated a multi step content development process with an extensive literature research of toxicity guidelines consented by the ASTCT, SITC, NCCN and EBMT as well as of officially released drug information. Findings were translated into an information platform with diagnostic and therapeutic recommendations as well as algorithms for interactive toxicity grading tools. A prototype has been validated at five Geman treatment centers through a questionnaire, which measures the advantage over common guideline practice. ‘myTcell’ will become available as medicinal product class I for iOS, Android and desktop in Europe on 15th of July. App development has been funded through educational grants by Celgene, Gilead Sciences, Janssen and Novartis.Results‘myTcell’ guides disease and product specific in a step by step process through the clinical workflow of cell therapy. This includes recommendations for patient screening, safety assessment and stopping rules prior to leukapheresis and CAR T-cell transfusion. Upon entering relevant clinical data for grading of CRS, ICANS and HLH interactive tools display toxicity grade or likelihood of toxicity as well as grade-specific management. Further, ‘myTcell’ assists with the diagnosis and treatment of pancytopenia and infections. A map visualizes the availability of CAR T-cell therapy in Germany and links in-patient and out-patient care. Besides, ‘myTcell’ includes an overview of important publications and refers directly to respective PubMed abstracts.Conclusions‘myTcell’ has the potential to become a highly usable smartphone app supporting the application of T-cell recruiting immunotherapies as well as the assessment and treatment of novel immunotoxicities. In addition, it facilitates outreach and connects treatment centers and referrig physicians. Thus, ‘myTcell’ can translate into increased guideline adherence, accelerated broader and safer application of CARs and BiTEs and improved patient outcomes.Disclosure InformationV. Blumenberg: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Novartis, Gilead Sciences, Janssen, BMS/Celgene. L. Siegmund: None. L. Fröhlich: None. M. Bergwelt: None. V. Bücklein: None. M. Subklewe: None.

Monitored Tomographic Reconstruction—An Advanced Tool to Study the 3D Morphology of Nanomaterials

Detailed and accurate three-dimensional (3D) information about the morphology of hierarchically structured materials is derived from multi-scale X-ray computed tomography (XCT) and subsequent 3D data reconstruction. High-resolution X-ray microscopy and nano-XCT are suitable techniques to nondestructively study nanomaterials, including porous or skeleton materials. However, laboratory nano-XCT studies are very time-consuming. To reduce the time-to-data by more than an order of magnitude, we propose taking advantage of a monitored tomographic reconstruction. The benefit of this new protocol for 3D imaging is that the data acquisition for each projection is interspersed by image reconstruction. We demonstrate this new approach for nano-XCT data of a novel transition-metal-based materials system: MoNi4 electrocatalysts anchored on MoO2 cuboids aligned on Ni foam (MoNi4/MoO2@Ni). Quantitative data that describe the 3D morphology of this hierarchically structured system with an advanced electrocatalytically active nanomaterial are needed to tailor performance and durability of the electrocatalyst system. We present the framework for monitored tomographic reconstruction, construct three stopping rules for various reconstruction quality metrics and provide their experimental evaluation.

Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II

PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, HEC30654, in Healthy Chinese Subjects

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer’s disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects.Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples.Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4–12 h), t1/2 of 10–60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (&lt;10%), and HEC30654 was mainly eliminated unchanged through feces.Conclusion: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated. Based on preclinical efficacy in various models of cognition, HEC30654 may represent a therapeutic option for symptomatic treatment of cognitive disorders.

Unified exact design with early stopping rules for single arm clinical trials with multiple endpoints

Adaptive designs are gaining popularity in early phase clinical trials because they enable investigators to change the course of a study in response to accumulating data. We propose a novel design to simultaneously monitor several endpoints. These include efficacy, futility, toxicity and other outcomes in early phase, single-arm studies. We construct a recursive relationship to compute the exact probabilities of stopping for any combination of endpoints without the need for simulation, given pre-specified decision rules. The proposed design is flexible in the number and timing of interim analyses. A R Shiny app with user-friendly web interface has been created to facilitate the implementation of the proposed design.

EMBR-17. DE-INTENSIFICATION OF RADIOTHERAPY IN RIGOROUSLY DEFINED LOW-RISK WNT-SUBGROUP MEDULLOBLASTOMA IS ASSOCIATED WITH UNACCEPTABLY HIGH RISK OF NEURAXIAL FAILURE: RESULTS FROM THE PROSPECTIVE FOR-WNT STUDY

Background Medulloblastoma is a heterogenous disease comprising four molecular subgroups (WNT, SHH, Group 3, and Group 4) with varying outcomes. Excellent long-term survival (&gt;90%) has prompted de-intensification of therapy in WNT-subgroup medulloblastoma globally. FOR-WNT is one such prospective study (CTRI/2017/12/010767) testing the hypothesis that focal conformal radiotherapy (RT) (54Gy/30 fractions/6-weeks) with avoidance of upfront craniospinal irradiation (CSI) followed by standard adjuvant chemotherapy significantly reduces RT-related late toxicity without unduly compromising survival in low-risk WNT-subgroup medulloblastoma (residual tumor &lt;1.5cm2 with no evidence of metastases in children aged between 3–16 years). Methods Patients with low-risk WNT-subgroup medulloblastoma were enrolled after written informed consent/assent. To ensure patient safety, stopping rules were devised according to group-sequential method. Results Between July 2017 till Feb 2019, seven children of WNT-pathway medulloblastoma were treated with focal conformal RT followed by 6-cycles of adjuvant chemotherapy (cisplatin, cyclophosphamide, and vincristine). One child succumbed to acute renal failure during chemotherapy, while the other 6 patients completed all 6-cycles as planned. Three children were detected with neuraxial failure (supratentorial brain and/or spine) without synchronous local recurrence in the treated tumor-bed on surveillance neuro-imaging between 1.5–2 years from index diagnosis following which the study was terminated prematurely. All 3 children with relapse were treated with salvage CSI (35Gy/21 fractions) with (conformal avoidance of previously treated tumor-bed) plus boost irradiation (10.8-18Gy/6–10 fractions) of metastatic deposits resulting in complete/near complete response and are alive with controlled disease. The other 3 children have not shown any evidence of relapse for over 2-years from index diagnosis and remain on active clinico-radiological surveillance. Conclusion In rigorously defined low-risk WNT-subgroup medulloblastoma, avoidance of upfront CSI is associated with unacceptably high risk of neuraxial failure. A successor study (FOR-WNT 2) incorporating low-dose CSI (18Gy/10 fractions) with similar tumor-bed dose and adjuvant systemic chemotherapy is currently underway.