scholarly journals Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation

Hepatology ◽  
2019 ◽  
Author(s):  
John B. Kisiel ◽  
Brian A. Dukek ◽  
Reddappa V.S.R. Kanipakam ◽  
Hassan M. Ghoz ◽  
Tracy C. Yab ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Validation ◽  
Methylated Dna ◽  
Discovery Phase

1044 - Hepatocellular Carcinoma Detection by Plasma Assay of Methylated Dna Markers: Phase II Clinical Validation

2018 ◽  
Vol 154 (6) ◽  
pp. S-1113-S-1114 ◽  
Author(s):  
John B. Kisiel ◽  
Hatim T. Allawi ◽  
Maria Giakoumopoulos ◽  
William R. Taylor ◽  
Tracy C. Yab ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Dna Markers ◽  
Clinical Validation ◽  
Methylated Dna ◽  
Plasma Assay

Phase I study of SIR-sphere plus sorafenib as first-line treatment in patients with nonresectable hepatocellular carcinoma: The Asia-Pacific Hepatocellular Carcinoma Trials Group protocol 05 (AHCC05)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15538-e15538 ◽  
Author(s):  
P. K. Chow ◽  
D. Poon ◽  
S. Choo ◽  
H. Lai ◽  
A. Goh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Asia Pacific ◽  
Tumour Regression ◽  
Sorafenib Therapy ◽  
Radio Therapy ◽  
Grade 3

e15538 Background: Sorafenib has been shown to significantly prolong survival in patients with nonresectable hepatocellular carcinoma (HCC) without however significant tumour regression. The addition of radio-ablative therapy could confer additional survival benefit. This phase I trial was carried out to ascertain the toxicities and safety of this combination and was designed as a prelude to a phase II trial. Methods: Eligible patients were administered SIR-sphere (max dose 3 GBq) and subsequently given Sorafenib therapy (400mg bd) either 14 days (Cohort 1: first 3 patients) or 11 days (Cohort 2: subsequent patients) later. Assessment was carried out for 30 days after commencement of Sorafenib. Results: 10 patients were recruited into this phase I trial. The second patient became ineligible for sorafenib therapy after SIR-sphere due to pulmonary bleeding not related to radio-therapy and was excluded from assessment. The characteristics of the patients are in the Table. At the end of the study period, there was no adverse events (AE) of grade 3 or 4 for Cohort 1 and 3 for Cohort 2. The only serious adverse event (SAE) recorded was from Cohort 2. Conclusions: Starting sorafenib 14 days after SIR-sphere therapy is associated fewer AEs and SAEs. The phase II trial has commenced withsorafenib starting 14 days after SIR-sphere. [Table: see text] [Table: see text]

Resminostat and sorafenib combination therapy for advanced hepatocellular carcinoma in patients previously untreated with systemic chemotherapy.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 252-252 ◽  
Author(s):  
Masatoshi Kudo ◽  
Baek-Yeol Ryoo ◽  
Ho Yeong Lim ◽  
Do Young Kim ◽  
Takuji Okusaka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Phase I ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Histone Deacetylases ◽  
Specific Effect ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Significant Difference

252 Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count > = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788.

Phase I/II trial of BMS-986205 and nivolumab as first-line therapy in hepatocellular carcinoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS57-TPS57
Author(s):  
Justin Chen ◽  
Jingran Ji ◽  
May Thet Cho ◽  
Arta Monjazeb ◽  
Sepideh Gholami ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Phase Ii ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
First Line ◽  
Intracellular Enzyme ◽  
Tissue Biopsy ◽  
Line Therapy

TPS57 Background: Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death worldwide and incidence is rising. Sorafenib and lenvatinib are approved for first-line use in unresectable HCC; however, survival benefit remains low. Nivolumab, a human monoclonal antibody to programmed death-1 (PD1) receptor, has been approved as second-line therapy in patients with unresectable HCC refractory to sorafenib. BMS-986205 selectively inhibits human indoleamine-2,3- dioxygenase 1 (IDO1), an intracellular enzyme expressed in various malignancies that promotes immune tolerance. Thus, the combination of PD-1 antibody and IDO1 inhibitor is a promising strategy to augment immunotherapy against HCC. We aim to evaluate the combination of BMS-986205 with nivolumab 3 mg/kg every 2 weeks in unresectable and metastatic HCC. Methods: Primary objectives were to identify tolerable dosing of BMS-986205, and to evaluate safety, tolerability, and efficacy of combination therapy, the latter defined by objective response rate. Secondary objectives were to evaluate disease control rate, duration of response, progression free survival, and overall survival. Phase I (dose escalation phase) will monitor two dose levels of BMS-986205: 50mg daily with conditional escalation to 100mg daily depending on dose-limiting toxicity. Phase II (expansion phase) will begin after maximum tolerated dose is reached. The phase II cohort will be run as a Simon two-stage design to allow for early trial stoppage for futility. Estimated study duration is 36 months with a 24-month accrual period for a total of 17 patients. Patients will be followed for 100 days after the last dose of treatment or until all treatment-related clinical toxicities resolve to baseline or grade ≤ 1. Assessments prior to therapy include imaging, tissue biopsy, serum correlatives, and stool samples. Tissue biopsy will be repeated at 4 weeks. Imaging will be repeated at 8 and 16 weeks, then every 12 weeks until end of treatment. Serum correlatives will be repeated intermittently throughout. At progression, imaging, tissue biopsy, and serum correlatives will be repeated. Data will be reported using 95% confidence intervals, Kaplan-Meier estimates, and frequency tables. Clinical trial information: NCT03695250.

Stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma with Child-Pugh class B.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14683-e14683
Author(s):  
Higinia Rosa Cardenes ◽  
Foster D Lasley ◽  
Paul Kwo ◽  
Susan M. Perkins ◽  
Mary A. Maluccio
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Phase I ◽  
Phase Ii ◽  
Local Control ◽  
Stereotactic Body Radiotherapy ◽  
Interim Analysis ◽  
Liver Volume ◽  
Upper Limit ◽  
Pugh Class

e14683 Background: Stereotactic body radiotherapy (SBRT) is a promising therapeutic modality in hepatocelular carcinoma (HCC). A Phase I trial was conducted at Indiana University (IU) in patients with Child Pugh Class (CPC) A and B. Based on our results, patients with CPC-B patients with score <=7 continued enrollment in the phase II. We now present an interim analysis for this patient population. Methods: 14 patients with HCC with liver cirrhosis, CPC-B, were treated with SBRT in a Phase I-II trial at IU. All patients were scheduled to receive five fractions, 800 cGy per fraction (total dose 4000 cGy), 1-2 fractions per week. Dose was prescribed to the 80-90% isodose line covering the planning target volume (PTV). A modified RECIST criterion was used to determine local failure. Demographics, clinical variables, treatment –related toxicities within 90 days of end of treatment, and local control (LC) at 6 and 12 months were tabulated. Progression Free Survival (PFS), Time to Progression (TTP), and Overall Survival (OS) estimates were calculated using Kaplan-Meier methodology. This was an unplanned interim analysis. A formal interim analysis will take place later. Results: There were 13 males and 1 female; median age of 56.5 years (range 49-69). All patients had 1 treated lesion. Median (range) for gross tumor volume (GTV) (cc) was 40.1 (8.0-74.6); PTV volume (cc) was 120.1 (34.7-210.0); and uninvolved liver volume (cc) was 2137.9 (973.0-2796.0). There were 3 grade 4 toxicities, 1 each of hyperbilirubinemia, hypokalemia, and thrombycytopenia. Four patients underwent orthotopic liver transplant. Local control at 6 and 12 months were 90% [95% C.I. (55.5%, 99.8%)] and 87.5% [95% C.I. (47.4%, 99.7%)], respectively. Median PFS is 11.0 months (95% CI: 3.9 months, 17.4 months). Ten patients died or progressed including 4 patients who died without progressing. Median TTP is 17.4 months (95% CI: 5.3 months, upper limit not estimable). Median OS is 19.8 months (95% CI: 4.0 months, upper limit not estimable). Conclusions: in carefully selected patients with hepatocellular carcinoma in the context of CPC B liver cirrhosis, score less or equal than 7, SBRT is an effective therapy with a good toxicity profile. Phase II is ongoing.

scholarly journals Epigenetic Therapy Using Belinostat for Patients With Unresectable Hepatocellular Carcinoma: A Multicenter Phase I/II Study With Biomarker and Pharmacokinetic Analysis of Tumors From Patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group

2012 ◽  
Vol 30 (27) ◽  
pp. 3361-3367 ◽  
Author(s):  
Winnie Yeo ◽  
Hyun C. Chung ◽  
Stephen L. Chan ◽  
Ling Z. Wang ◽  
Robert Lim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Phase Ii ◽  
Group Performance ◽  
Cancer Therapeutics ◽  
Exploratory Analysis ◽  
Epigenetic Therapy ◽  
Pharmacokinetic Analysis ◽  
Potential Biomarker ◽  
Disease Stabilization

PurposeEpigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II.Patients and MethodsMajor eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2per day (level 1), 900 mg/m2per day (level 2), 1,200 mg/m2per day (level 3), and 1,400 mg/m2per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response.ResultsBelinostat pharmacokinetics were linear from 600 to 1,400 mg/m2without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036).ConclusionEpigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

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