Statistical Methods for Sequential Monitoring and Incorporating Real-World Evidence in Bayesian Clinical Trial Design

In the first part of the dissertation, we present a Bayesian framework for sequential monitoring that allows for use of external data, and that can be applied in a wide range of clinical trial applications. Monitoring priors are defined using the family of generalized normal distributions which comprise a flexible class of priors, naturally allowing one to construct a prior that is peaked or flat about the parameter values thought to be most likely. External data are incorporated into the monitoring process though mixing an a priori skeptical prior with an enthusiastic prior using a weight that can be fixed or adaptively estimated. We introduce an adaptive monitoring prior for efficacy evaluation which dynamically weights skeptical and enthusiastic prior components based on the degree to which observed data are consistent with an enthusiastic perspective. We illustrate the method for both single-arm and two-arm randomized controlled trials (RCTs). Preposterior analyses of each trial are discussed. In the second part of the dissertation, we develop a design for hybrid analyses that uses external controls from real world data (RWD) to augment internal control arms in RCTs where the degree of borrowing is evaluated based on similarity between RCT and RWD patients to account for systematic differences. We develop the case weighted adaptive power prior, an extension of the power prior where the discounting weight is computed separately for each external control subject based on compatibility with the randomized control data. This method is applied in an example using a proportional hazards model with piecewise constant baseline hazard. In the third part of the dissertation, we extend the case weighted adaptive power prior methodology to provide robustness for both systemic bias (e.g. shift in baseline hazard) and partial contamination in a hybrid design using external controls. We develop a family of two-part transformation functions for the case weights: a scaling function for the individual case weights and a cohort-level penalty function acting uniformly on each case weight. We also develop an individually-weighted commensurate prior and compare preposterior analyses of these designs.Doctor of Philosoph

Phase Ib/Ii Study of Lacnotuzumab in Combination With Spartalizumab in Patients With advanced Malignancies

INTRODUCTION: Blocking the colony-stimulating factor 1 (CSF-1) signal on tumor-associated macrophages can lead to an upregulation of checkpoint molecules, such as programmed cell death ligand 1 (PD-L1), thus causing resistance to this blockade. Combining spartalizumab (PDR001), a high-affinity, ligand-blocking, humanized anti-PD-1 immunoglobulin G4 antibody, with lacnotuzumab (MCS110), a high-affinity, humanized monoclonal antibody directed against human CSF-1 can potentially overcome this resistance. METHODS: This was a multicenter, phase Ib/II trial using a combination of spartalizumab with lacnotuzumab in patients with advanced cancers, including anti-PD-1/PD-L1 treatment-resistant melanoma, and anti-PD-1/PD-L1 treatment-naïve triple-negative breast cancer, pancreatic cancer, and endometrial cancer (ClinicalTrials.gov identifier: NCT02807844). The primary objective of dose escalation phase Ib was to assess safety, tolerability, and recommended phase II dose. The primary objective of the phase II expansion study was to assess the combination\u27s antitumor activity, including objective response rate and clinical benefit rate. RESULTS: A total of eight patients (five in phase Ib and three in phase II) were evaluable for adverse events (AEs) at our study site. All eight patients experienced at least grade 1 AE. The most common treatment-related AEs were increased serum aspartate aminotransferase (38%), fatigue (38%), anemia (25%), increased alkaline phosphatase (25%), hyperbilirubinemia (25%), hypocalcemia (25%), and hypoalbuminemia (25%). Most of these AEs were grade 1 or 2. None of the patients experienced grade 4 AEs and no drug-related fatal AEs were reported among the eight patients treated in the study. One (13%) patient had stable disease (SD) (captured as unknown by the study sponsor because the evaluation criteria set per protocol was not met) and three (38%) patients had progressive disease. Four (50%) patients developed clinical disease progression based on investigator evaluation. One patient with pancreatic cancer achieved immune-related SD for 26 months while on the study treatments. CONCLUSION: The study completed phase Ib dose escalation and phase II. However, gating criteria for efficacy were not met for expansion beyond 80 patients in phase II and the sponsor did not continue development of the combination of spartalizumab and lacnotuzumab for oncology indications. The potential signal of activity in pancreatic cancer should be further explored

Case Weighted Power Priors For Hybrid Control analyses With Time-To-Event Data

We develop a method for hybrid analyses that uses external controls to augment internal control arms in randomized controlled trials (RCTs) where the degree of borrowing is determined based on similarity between RCT and external control patients to account for systematic differences (e.g., unmeasured confounders). The method represents a novel extension of the power prior where discounting weights are computed separately for each external control based on compatibility with the randomized control data. The discounting weights are determined using the predictive distribution for the external controls derived via the posterior distribution for time-to-event parameters estimated from the RCT. This method is applied using a proportional hazards regression model with piecewise constant baseline hazard. A simulation study and a real-data example are presented based on a completed trial in non-small cell lung cancer. It is shown that the case weighted power prior provides robust inference under various forms of incompatibility between the external controls and RCT population

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related adverse Events During Checkpoint Blockade Immunotherapy

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs

Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience

Introduction Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing, and clinicopathologic correlations are presented. Methods Mutation testing in at least one of 8 genes (EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing +/− PNA and/or sizing assays, along with ALK and/or MET FISH were performed in 6 labs on 1007 patients from 14 institutions. Results 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared to 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22, 25, 8.5, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never smoking status, and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK or MET. Conclusion Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations

Involvement of local indigenous peoples in Arctic research – expectations, needs and challenges perceived by early career researchers

Rapid changes in the natural and social environments of the Arctic region have led to increased scientific presence across the Arctic. Simultaneously, the importance of involving local indigenous peoples in research activities is increasingly recognized for several reasons, including knowledge sharing and sustainable development. This study explores Arctic early career researchersâ (ECRs) perceptions on involving local indigenous peoples in their research. The results, based on 108 online survey respondents from 22 countries, show that ECRs value the knowledge of local indigenous peoples and generally wish to extend the involvement of this group in their research. ECRs in North America and in the social sciences have more experience working with indigenous communities and value it more than researchers in the Nordic area and in the natural sciences. Respondents cited more funding, networking opportunities, and time as the main needs to increase collaborations. The results of this study are helpful for developing strategies to build good relationships between scientists and indigenous peoples and for increasing the involvement of Arctic indigenous peoples in science and engagement of their knowledge systems. The complementary views from Arctic indigenous peoples are however needed for a full understanding of how to effectively achieve this.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Case Weighted Adaptive Power Priors for Hybrid Control Analyses with Time-to-Event Data

We develop a method for hybrid analyses that uses external controls to augment internal control arms in randomized controlled trials (RCT) where the degree of borrowing is determined based on similarity between RCT and external control patients to account for systematic differences (e.g. unmeasured confounders). The method represents a novel extension of the power prior where discounting weights are computed separately for each external control based on compatibility with the randomized control data. The discounting weights are determined using the predictive distribution for the external controls derived via the posterior distribution for time-to-event parameters estimated from the RCT. This method is applied using a proportional hazards regression model with piecewise constant baseline hazard. A simulation study and a real-data example are presented based on a completed trial in non-small cell lung cancer. It is shown that the case weighted adaptive power prior provides robust inference under various forms of incompatibility between the external controls and RCT population.Comment: 27 pages, 10 figure

Voltage-sensitive rhodol with enhanced two-photon brightness

We have designed, synthesized, and applied a rhodol-based chromophore to a molecular wire-based platform for voltage sensing to achieve fast, sensitive, and bright voltage sensing using two-photon (2P) illumination. Rhodol VoltageFluor-5 (RVF5) is a voltage-sensitive dye with improved 2P cross-section for use in thick tissue or brain samples. RVF5 features a dichlororhodol core with pyrrolidyl substitution at the nitrogen center. In mammalian cells under one-photon (1P) illumination, RVF5 demonstrates high voltage sensitivity (28% ΔF/F per 100 mV) and improved photostability relative to first-generation voltage sensors. This photostability enables multisite optical recordings from neurons lacking tuberous sclerosis complex 1, Tsc1, in a mouse model of genetic epilepsy. Using RVF5, we show that Tsc1 KO neurons exhibit increased activity relative to wild-type neurons and additionally show that the proportion of active neurons in the network increases with the loss of Tsc1. The high photostability and voltage sensitivity of RVF5 is recapitulated under 2P illumination. Finally, the ability to chemically tune the 2P absorption profile through the use of rhodol scaffolds affords the unique opportunity to image neuronal voltage changes in acutely prepared mouse brain slices using 2P illumination. Stimulation of the mouse hippocampus evoked spiking activity that was readily discerned with bath-applied RVF5, demonstrating the utility of RVF5 and molecular wire-based voltage sensors with 2P-optimized fluorophores for imaging voltage in intact brain tissue