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Item A phase II study of buparlisib in relapsed or refractory thymomas(Frontiers, 2022-10-17) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer Sr., Patrick J.; Department of Medicine, School of MedicinePurpose To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23–74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2–33). At a median follow up of 16.6m (2.4–31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 – 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7–31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted. (clinicaltrials.gov ID: NCT02220855). Clinical trial registration clinicaltrials.gov, identifier (NCT02220855)Item A phase II study of buparlisib in relapsed or refractory thymomas(Frontiers Media, 2022-10-18) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer, Patrick J.; Medicine, School of MedicinePurpose: To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods: This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results: Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23-74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2-33). At a median follow up of 16.6m (2.4-31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 - 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7-31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion: Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted.Item Applications of Time to Event Analysis in Clinical Data(2021-12) Xu, Chenjia; Gao, Sujuan; Liu, Hao; Zang, Yong; Zhang, Jianjun; Zhao, YiSurvival analysis has broad applications in diverse research areas. In this dissertation, we consider an innovative application of survival analysis approach to phase I dose-finding design and the modeling of multivariate survival data. In the first part of the dissertation, we apply time to event analysis in an innovative dose-finding design. To account for the unique feature of a new class of oncology drugs, T-cell engagers, we propose a phase I dose-finding method incorporating systematic intra-subject dose escalation. We utilize survival analysis approach to analyze intra-subject dose-escalation data and to identify the maximum tolerated dose. We evaluate the operating characteristics of the proposed design through simulation studies and compare it to existing methodologies. The second part of the dissertation focuses on multivariate survival data with semi-competing risks. Time-to-event data from the same subject are often correlated. In addition, semi-competing risks are sometimes present with correlated events when a terminal event can censor other non-terminal events but not vice versa. We use a semiparametric frailty model to account for the dependence between correlated survival events and semi-competing risks and adopt penalized partial likelihood (PPL) approach for parameter estimation. In addition, we investigate methods for variable selection in semi-parametric frailty models and propose a double penalized partial likelihood (DPPL) procedure for variable selection of fixed effects in frailty models. We consider two penalty functions, least absolute shrinkage and selection operator (LASSO) and smoothly clipped absolute deviation (SCAD) penalty. The proposed methods are evaluated in simulation studies and illustrated using data from Indianapolis-Ibadan Dementia Project.Item Bayesian Adaptive Dose-Finding Clinical Trial Designs with Late-Onset Outcomes(2021-07) Zhang, Yifei; Zhang, Yong; Song, Yiqing; Liu, Hao; Bakoyannis, GiorgosThe late-onset outcome issue is common in early phase dose- nding clinical trials. This problem becomes more intractable in phase I/II clinical trials because both toxicity and e cacy responses are subject to the late-onset outcome issue. The existing methods applying for the phase I trials cannot be used directly for the phase I/II trial due to a lack of capability to model the joint toxicity{e cacy distribution. We propose a conditional weighted likelihood (CWL) method to circumvent this issue. The key idea of the CWL method is to decompose the joint probability into the product of marginal and conditional probabilities and then weight each probability based on each patient's actual follow-up time. We further extend the proposed method to handle more complex situations where the late-onset outcomes are competing risks or semicompeting risks outcomes. We treat the late-onset competing risks/semi-competing risks outcomes as missing data and develop a series of Bayesian data-augmentation methods to e ciently impute the missing data and draw the posterior samples of the parameters of interest. We also propose adaptive dose- nding algorithms to allocate patients and identify the optimal biological dose during the trial. Simulation studies show that the proposed methods yield desirable operating characteristics and outperform the existing methods.Item Changing Trends of Cirrhotic and Noncirrhotic Hepatocellular Carcinoma in the Era of Directly-Acting Antiviral Agents(Wolters Kluwer, 2021-11-03) Mathur, Karan; Mazhar, Areej; Patel, Milin; Dakhoul, Lara; Burney, Heather; Liu, Hao; Nephew, Lauren; Chalasani, Naga; deLemos, Andrew; Gawrieh, Samer; Medicine, School of MedicineIntroduction: The impact of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) on burden of cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) has not been examined. We assessed recent trends in liver disease etiologies of HCC and proportion of noncirrhotic HCC since DAAs introduction. Methods: Clinical characteristics including presence or absence of underlying cirrhosis were collected from 2,623 patients diagnosed with HCC between 2009 and 2019 at 2 large US centers. Logistic regression was performed to investigate the annual trends of HCC due to different liver diseases and proportions of noncirrhotic cases. Results: In the DAA era (2014-2019), annual decline in HCV-HCC (odds ratio [OR] = 0.93, 95% confidence interval [CI] 0.88-0.99, P = 0.019), without change in trends of other liver diseases-related HCC, was observed. Annual increase in noncirrhotic HCC (OR 1.13, 95% CI 1.03-1.23, P = 0.009) and decline in cirrhotic HCC (OR 0.89, 95% CI 0.81-0.97, P = 0.009) along with similar trends for HCV-HCC-increase in noncirrhotic cases (OR 1.35, 95% CI 1.08-1.69, P = 0.009) and decrease in cirrhotic cases (OR 0.92, 95% CI 0.86-0.98, P = 0.012)-were observed during the DAA era. Compared with the pre-DAA era, HCC resection rate increased (10.7% vs 14.0%, P = 0.013) whereas liver transplantation rate decreased (15.1% vs 12.0%, P = 0.023) in the DAA era. Discussion: Since introduction of DAAs, proportions of cirrhotic HCC have decreased, whereas proportions of noncirrhotic HCC have increased. These new trends were associated with change in utilization of liver resection and transplantation for HCC. The impact of changing patterns of DAA use on these trends will require further study.Item Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: A United States multicentre study(Wiley, 2019-10) Gawrieh, Samer; Dakhoul, Lara; Miller, Ethan; Scanga, Andrew; deLemos, Andrew; Kettler, Carla; Burney, Heather; Liu, Hao; Abu-Sbeih, Hamzah; Chalasani, Naga; Wattacheril, Julia; Medicine, School of MedicineBackground Limited data exist on the burden and features of non‐cirrhotic hepatocellular carcinoma (HCC) in the United States. Aim To evaluate characteristics, aetiologies, trends and outcomes of non‐cirrhotic HCC from 2000 to 2014 at five large US centres Methods Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. Results Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non‐cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non‐cirrhotic patients, non‐alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non‐cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non‐cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). Conclusions Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non‐cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non‐cirrhotic patients presented with more advanced HCC, their survival was better.Item Distinctive Features and Outcomes of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Disease: A US Multicenter Study(Wolters Kluwer Health, 2020-03) deLemos, Andrew; Patel, Milin; Gawrieh, Samer; Burney, Heather; Dakhoul, Lara; Miller, Ethan; Scanga, Andrew; Kettler, Carla; Liu, Hao; Roche, Patrick; Wattacheril, Julia; Chalasani, Naga; Medicine, School of MedicineIntroduction: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. Methods: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. Results: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). Discussion: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.Item Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells(Wiley, 2021) Cao, Felicia; Nguyen, Phuong; Hong, Bangxing; DeRenzo, Christopher; Rainusso, Nino C.; Rodriguez Cruz, Tania; Wu, Meng-Fen; Liu, Hao; Song, Xiao-Tong; Suzuki, Masataka; Wang, Lisa L.; Yustein, Jason T.; Gottschalk, Stephen; Biostatistics and Health Data Science, School of MedicineOncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.Item ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist(American Association for the Advancement of Science, 2020-10-07) Adom, Djamilatou; Dillon, Stacey R.; Yang, Jinfeng; Liu, Hao; Ramadan, Abdulraouf; Kushekhar, Kushi; Hund, Samantha; Albright, Amanda; Kirksey, Maykala; Adeniyan, Titilayo; Lewis, Katherine E.; Evans, Lawrence; Wu, Rebecca; Levin, Steven D.; Mudri, Sherri; Yang, Jing; Rickel, Erika; Seaberg, Michelle; Henderson, Katherine; Gudgeon, Chelsea J.; Wolfson, Martin F.; Swanson, Ryan M.; Swiderek, Kristine M.; Peng, Stanford L.; Hippen, Keli L.; Blazar, Bruce R.; Paczesny, Sophie; Pediatrics, School of MedicineAcute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.Item Innovative Bayesian Designs for Clinical Trials(2022-10) He, Tian; Zang, Yong; Liu, Hao; Bakoyannis, Giorgos; Zhao, Yi; Hasan, MohammadTraditional clinical trial designs are generally based on the doctrine of studying one drug for one disease at a time, which may be slow and inefficient. With a high failure rate in drug development, there is a great need to speed up the process of drug development and minimize the cost. Novel trial designs have been proposed, such as the master protocol approach, which has expanded the trial design horizon to umbrella, basket, and platform trials. Compared to traditional clinical protocols, the master protocol enables investigators to evaluate multiple drugs and diverse disease populations simultaneously in a single protocol with the capacity to modify the protocol based on the observed trial data and new drugs. While many statistical methods for trial designs have been proposed for umbrella, basket, and platform trials in the literature, most of the designs are based on a binary or continuous endpoint. However, in the context of oncology trials, there is a great need to develop novel methods for survival endpoints. In this dissertation, we propose three novel Bayesian statistical methods for three distinctive trial design problems, respectively: 1) an optimal Bayesian design for platform trials with multiple endpoints; 2) a novel Bayesian design for basket trials with survival outcomes; 3) an adaptive Bayesian design for seamless phase II/III platform trials with survival endpoints. Extensive simulation studies are performed to evaluate the operating characteristics of the proposed designs under various scenarios.
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