Early Oncology Clinical Trials Research Articles

Assessing clinical response in early oncology development with a predictive biomarker

ABSTRACT In early oncology clinical trials there is often limited data for biomarkers and their association with response to treatment. Thus, it is challenging to decide whether a biomarker should be used for patient selection and enrollment. Most evidence about any potential predictive biomarker comes from preclinical research and, sometimes, clinical observations. How to translate the preclinical predictive biomarker data to clinical study remains an active field of research. Here, we propose a method to incorporate existing knowledge about a predictive biomarker – its prevalence, association with response and the performance of the assay used to measure the biomarker – to estimate the response rate in a clinical study designed with or without using the predictive biomarker. Importantly, we quantify the uncertainty associated with the biomarker and its predictability in a probabilistic model. This model estimates the distribution of the clinical response when a predictive biomarker is used to select patients and compares it to unselected cohort. We applied this method to two real world cases of approved biomarker-guided therapies to demonstrate its utility and potential value. This approach helps to make a data-driven decision whether to select patients with a predictive biomarker in early oncology clinical development.

Diarrhea in Placebo Arms of Cancer Studies.

Diarrhea is among the most common adverse events in early oncology clinical trials, and drug causality may be difficult to determine. This is a systematic literature review of placebo arms of randomized cancer trials. Anemia was reported in 95 of 127 placebo monotherapy cohorts. Publications involving healthy volunteers and cancer prevention studies reported lower frequencies than those with cancer patients. The average reported frequency of diarrhea grade 1 or higher among studies in cancer patients was 15%. The maximal reported frequencies for grades 1, 2, 3, 4, 5 were 56, 24, 6, 2, and 0%, respectively. When higher diarrhea frequencies than those are observed in treatment arms of clinical trials, then drug causality is likely.

Hematopoietic Cell Transplant (HCT) in the Elderly: Myths, Controversies and Unknowns.

The incidence of most hematological malignancies increases with age. Despite the higher incidence of hematological malignancies in the elderly, the geriatric population is poorly represented in the early oncology clinical trials that established the current standards of care. Hematopoietic cell transplant (HCT), either upfront or at relapse, provides a potentially life-prolonging, often curative option for many patients with hematological malignancies and is considered the standard of care, at least for younger patients. Historically, the concern that older adults undergoing HCT may experience higher morbidity and transplant-related complications has limited the use of this potentially curative option to younger adults, particularly in allogeneic (allo-) HCT. There is growing evidence to support the feasibility, tolerability, and relatively similar effectiveness of both autologous and allo-HCT in the geriatric population. In the allo-HCT setting, nonmyeloablative/reduced-intensity conditioning (NMA/RIC) has expanded the spectrum of patients that can be considered for this approach. Overall survival is largely affected by disease stage, performance status, and comorbidities rather than by chronological age per se. Comprehensive geriatric assessment (CGA) is a promising tool that can uncover frequently undocumented vulnerabilities in an elderly transplant-eligible patient. Serial study of CGA throughout the peri-HCT period may help predict the short- and long-term impact of HCT on an older adult's functional status and quality of life. Further research is needed to evaluate whether early intervention to improve such vulnerabilities can improve survival and quality of life of these older patients.

Abstract 3597: Experiences and lessons from innovative dose escalation designs in early-phase oncology

Abstract Introduction: Since 2010, Roche-sponsored early development trials in oncology have successfully implemented innovative dose escalation (D/E) strategies including modified continual reassessment methods (CRM) and other Bayesian adaptive designs. Compared to standard 3+3 designs, these methods allow for flexibility to address a variety of clinical questions and to estimate more accurately a molecule’s maximum tolerated dose (MTD). However, CRM designs are sometimes considered as complex and difficult to implement and are not easily understood by clinicians (Le Tourneau et al., 2009, Iasonos et al. 2014). Here, we share our experiences and learnings from the initial exploration, introduction, and wide-spread implementation of CRM in early oncology clinical trials. Methods: We conducted a thorough internal review of the current statistical methods and clinical strategies used in CRM designs. In addition, we systematically collected feedback on the internal experience through surveys and interviews of participating biostatisticians, pharmacologists, clinicians and operations managers. Results: CRMs using two parameter logistic regression models and escalation with overdose control (Neuenschwander et al., 2008) are the most commonly used CRM designs in Roche-sponsored oncology D/E trials. Compared to trials in which 3+3 designs are used, we experienced significant advantages with CRM designs including: flexibility in cohort sizes; formal integration of relevant prior pre-clinical/clinical knowledge of the dose-toxicity relationship; and contribution of all dose limiting toxicities (DLTs) to an MTD determination. On the other hand, we learned about some limitations. The CRM designs modeled binary DLT events where the grade of an event was not considered. Thus, in a cohort where severe DLT event(s) were observed, clinical judgment typically superseded the CRM recommendation towards a lower dose; this decision rule was a priori defined in the protocol. In certain situations, inconsistent prior-information in the dose-toxicity relationship was observed. Therefore, prior assumptions had to be carefully assessed through simulations using multiple dose-toxicity scenarios. Conclusions: Overall, utilization of CRM designs was considered beneficial to Roche early development trials. Based on our experience, CRM designs are flexible and can be tailored to address a variety of clinical research questions. Trial simulation analyses were critical for us to understand the performance of CRM designs, including the accuracy of estimated MTD, trial duration/sample size, and sensitivity to prior assumptions. Furthermore, the introduction and implementation of CRM designs required and promoted strong multidisciplinary collaborations, especially during the design and study protocol set-up phases and the D/E recommendation phase. Citation Format: Jiawen Zhu, Ulrich Beyer, Somnath Sarkar, Gwen Nichols, William Pao, Daniel Sabanés Bové. Experiences and lessons from innovative dose escalation designs in early-phase oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2017-3597

An Escalation for Bivariate Binary Endpoints Controlling the Risk of Overtoxicity (EBE-CRO): Managing Efficacy and Toxicity in Early Oncology Clinical Trials

ABSTRACTFor about a decade, early clinical development in oncology is facing new challenges. This is due to two main reasons. The first one is linked to the developed molecular targeted agents (MTA) themselves for which the maximum tolerated dose (MTD) is no longer the only dose of interest. The second reason is related to the fact that costs and attrition rates are huge. When selecting a dose, evidence of early activity signal becomes required for future engagements. This implies the need to handle both toxicity and activity endpoints in the analysis and also in the dose escalation design of early-phase trials. We propose a model-based design taking into account both safety and activity for dose escalation. The proposed model involves a bivariate Gaussian latent variable depending on a monotonic toxicity curve and a quadratic activity curve. This model is fitted under the Bayesian framework that allows the incorporation of prior information. The predictive distributions of dose-response curves are used to lead the dose recommendation. Uncertainty in the dose–response relationship is taken into account to calculate the probability of being an over-toxic or a target dose. The proposed design is compared to two other widely used methods.

125IN - How Can Pharmaceutical Companies Facilitate Global Collaboration in Phase 1 Cancer Drug Development in Asia?

ABSTRACT Modern oncology drug development is a worldwide enterprise, and large Phase 3 registration trials are commonly conducted around the globe. However, in many pharmaceutical companies, early oncology clinical trials designed to establish proof of concept have been slower to adopt a global footprint. Historically, many western companies focused their early development efforts in specialized Phase 1 centers concentrated in western countries. Only after POC was established were programs expanded into other parts of the world such as the Asia-Pacific region. In countries such as Japan, this contributed to a delay in approval times compared with western countries; a disparity referred to as the drug lag (Ueno et al Clin Pharm Therap 2014). With the ever accelerating pace of oncology therapeutics, this lag is no longer acceptable, and efforts are underway to close this gap. Many companies are looking to initiate Asia-Pacific pre-POC clinical trials at an earlier stage, especially when there is strong therapeutic promise in areas of high unmet medical need in the region, such as liver, gastric, lung, and esophageal cancers. However, this presents many new challenges, including the requirement for close communication and coordination of early development programs globally when the drug's safety and efficacy profiles are still not defined. Furthermore, all new targeted therapy programs have companion diagnostic strategies integral to their success, and in early development many of these predictive biomarkers are still exploratory. Success also requires regional expertise in early trials and translational research on the part of the company's R&D staff and their collaborating investigators. Asian patient populations and their concomitant diseases may differ from their western counterparts. For example, the frequency of EGFR mutations in Asian patients with adenocarcinoma of the lung is vastly different than in the west. Finally, additional challenges can arise in Asia during regulatory review of early studies, and when clinical specimens must be shipped to specialized centers for predictive biomarker analysis. Nonetheless, the marked advantage of accelerating global early development oncology programs makes it essential that these obstacles be overcome. Disclosure: C.H. Takimoto: I am an employee and stock holder of Johnson & Johnson.

Clinical Pharmacogenomics and Transcriptional Profiling in Early Phase Oncology Clinical Trials

Microarray-based expression profiling studies in the field of oncology have demonstrated encouraging correlations between tumor transcriptional profiles and eventual patient outcomes. These findings have fueled great interest in the application of transcriptional profiling to samples available from real-time clinical trials, and clinical pharmacogenomic objectives utilizing transcriptional profiling strategies are becoming increasingly incorporated into clinical trial study designs. Over the last few years several retrospective studies based on the profiling of archival tumor tissues suggest that transcriptional analysis of oncology samples may provide general prognosis measures, and in some cases may even predict response to specific therapies. Recently the FDA released a voluntary genomic data guidance meant to assist both regulatory agencies and pharmaceutical companies alike in evaluating the potential benefit of implementing expression profiling studies during the preclinical and clinical phases of drug development. Despite the great promise afforded by this technology, the ultimate benefit of applying transcriptional profiling in prospective clinical trials has yet to be realized because a number of practical impediments to this process exist. The multi-fold purpose of the current review is to highlight the increasing evidence from studies that have identified transcriptional signatures in archived tumors prognostic of patient outcome, to describe some of the drivers for the implementation of transcriptional profiling strategies in real-time drug development, to discuss the use of transcriptional profiling in the context of increasingly complex translational medicine strategies, and to highlight the practical issues and potential approaches involved in the successful application of clinical pharmacogenomic objectives during real-time clinical trials. Strategic implementation of transcriptional profiling in early oncology clinical trials can provide an opportunity to identify predictive markers of clinical response and eventually provide a substantial step forward towards the era of personalized medicine.