Clinical Outcome Event Adjudication in a 10-Year Prospective Study of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B.

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.

Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.

BACKGROUND: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. METHODS: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. RESULTS: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. CONCLUSIONS: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742).

Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.

Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia.

Many traditional pharmacopeias include Aristolochia and related plants, which contain nephrotoxins and mutagens in the form of aristolochic acids and similar compounds (collectively, AA). AA is implicated in multiple cancer types, sometimes with very high mutational burdens, especially in upper tract urothelial cancers (UTUCs). AA-associated kidney failure and UTUCs are prevalent in Taiwan, but AA's role in hepatocellular carcinomas (HCCs) there remains unexplored. Therefore, we sequenced the whole exomes of 98 HCCs from two hospitals in Taiwan and found that 78% showed the distinctive mutational signature of AA exposure, accounting for most of the nonsilent mutations in known cancer driver genes. We then searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with exposure through known herbal medicines, 47% of Chinese HCCs showed the signature, albeit with lower mutation loads than in Taiwan. In addition, 29% of HCCs from Southeast Asia showed the signature. The AA signature was also detected in 13 and 2.7% of HCCs from Korea and Japan as well as in 4.8 and 1.7% of HCCs from North America and Europe, respectively, excluding one U.S. hospital where 22% of 87 "Asian" HCCs had the signature. Thus, AA exposure is geographically widespread. Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure. We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted.

Brain Metastases from Breast Cancer and Response to Treatment with Eribulin: A Case Series.

Brain metastases are common in patients with advanced breast cancer (BC), causing considerable morbidity and mortality. Eribulin is a microtubule dynamics inhibitor approved for treating certain patients with metastatic BC, previously treated with an anthracycline and a taxane. In the 301 phase 3 study in 1102 women with advanced BC, eribulin and capecitabine treatments did not differ for co-primary endpoints (overall survival [OS]: 15.9 vs 14.5 months, P = 0.056; progression-free survival [PFS]: 4.1 vs 4.2 months, P = 0.30). Here, we report outcomes for six patients (eribulin, n = 3; capecitabine, n = 3) who had received treatment for brain metastases from BC (BCBM) at baseline. All eribulin-treated patients experienced brain lesion shrinkage at some point during treatment, compared with one capecitabine-treated patient. Fewer patients in study 301 developed new BCBM with eribulin (13/544, 2.4%) compared with capecitabine (25/546, 4.6%). Eribulin does not cross the healthy blood-brain barrier (BBB), but could have the potential to do so after cranial radiation therapy. Capecitabine may cross the BBB and has demonstrated activity in BCBM. Data from these patients and previous cases suggest that further investigation of eribulin for BCBM may be warranted.

Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells.

BACKGROUND: Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines. METHODS: Growth inhibition was assessed by MTS assay. EGFR, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3 expressions were measured by western blot. Cell adhesion, migration and invasion were performed with and without dasatinib treatment. RESULTS: The IC50 of 9 cell lines ranged from 0.7 µM ~ 14.2 µM. In general the growth inhibition by dasatinib was related to total Src (t-Src) and the ratio of activated Src (p-Src) to t-Src. There was good correlation of the sensitivity to dasatinib and the inhibition level of p-Src, p-FAK576/577 and p-Akt. No inhibition was found on Stat3 and MAPK42/44 in all cell lines. The inhibition of cell adhesion, migration and invasion were correlated with p-FAK inhibition. CONCLUSION: Dasatinib inhibits the proliferation, adhesion, migration and invasion of HCC cells in vitro via inhibiting of Src tyrosine kinase and affecting SFK/FAK and PI3K/PTEN/Akt, but not Ras/Raf/MEK/ERK and JAK/Stat pathways. T-Src and p-Src/t-Src may be useful biomarkers to select HCC patients for dasatinib treatment.

In-vitro growth inhibition of chemotherapy and molecular targeted agents in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and challenging malignant disease. The prognosis is poor in patients with advanced disease. Although sorafenib prolongs survival in these patients, improvement remains modest. We used doxorubicin and sorafenib as controls and screened eight new agents including ixabepilone, gefitinib, cetuximab, brivanib, dasatinib, sunitinib, BMS-690514, and BMS-536924 against nine HCC cell lines and evaluated their interactions. We studied growth inhibition of 10 drugs against nine HCC cell lines. Single-agent activity was tested using an MTS assay. Combination studies were carried out in both resistant and sensitive cells to determine the combination index. The IC50 of each agent varied widely among nine cell lines. Ixabepilone was more potent than doxorubicin. HT-17 cells were more sensitive to gefitinib and cetuximab than the other eight cell lines. BMS-536924 showed good efficacy (IC50 ≤ 1 µmol/l) on all three α-fetoprotein (AFP)-producing cell lines (HepG2, Hep3B, Huh-7). Three cell lines showed moderate sensitivity to dasatinib (IC50 ≤ 1 µmol/l). Dasatinib showed the most frequent and strongest synergism with ixabepilone, gefitinib, brivanib, BMS-690514, or BMS-536924. Ixabepilone, sorafenib, brivanib, dasatinib, and BMS-536924 are active against HCC cell lines. The heterogeneity of the sensitivity of each cell line emphasizes the need for individualized treatment. The sensitivity to BMS-536924 is closely associated with the production of AFP. AFP may be a biomarker predicting response to the insulin-like growth factor-1 receptor inhibitor in HCC patients. Additional studies are warranted. The synergism between dasatinib and other agents also provides future research directions to understand drug resistance and improve outcome.

Bevacizumab in combination with oxaliplatin and doxorubicin or liposomal doxorubicin for hepatocellular cancer: a case series.

AIMS: Despite the emergence of sorafenib as the standard treatment for patients with advanced hepatocellular cancer (HCC), therapy remains sub-optimal and toxic. METHODS: We report on five patients with advanced HCC treated with bevacizumab, oxaliplatin and doxorubicin or liposomal doxorubicin. RESULTS: Of the five patients, four had cirrhosis; two patients had Child-Pugh A cirrhosis, while one each had Child-Pugh B and C cirrhosis. Grade 3/4 toxicity was uncommon. Four patients had a decrease of ≥50% in alpha-fetoprotein levels following therapy and one patient each had a radiographic complete response and stable disease. CONCLUSION: These data add to the growing phase II data that bevacizumab-containing regimens are active in advanced HCC patients. Further evaluation of regimens containing bevacizumab with oxaliplatin and/or doxorubicin may be warranted.

Final results of a prematurely discontinued Phase 1/2 study of eniluracil with escalating doses of 5-fluorouracil administered orally in patients with advanced hepatocellular carcinoma.

PURPOSE: Eniluracil (EU) is a potent dihydropyrimidine (DPD) inhibitor, which improves the oral bio-availability of 5-fluorouracil (5-FU) and may overcome fluoropyrimidine (FP) resistance in hepatocellular carcinoma (HCC). Based on preclinical evidence, we aimed at studying a new dosing schedule for the combination with sequential administration, a lower dose of EU and higher doses of 5-FU than previously investigated. METHODS: Patients with a diagnosis of hepatocellular carcinoma were eligible for this Phase 1/2 study. The primary endpoint for the Phase 1 was the determination of dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of oral 5-FU when given 14 h after oral EU 5 mg, weekly for 3 out of 4 weeks. The starting dose of 5-FU was 20 mg, followed by 30 mg and 80 mg. Secondary endpoints were anti-tumor activity, pharmacokinetics, and DPD activity in peripheral blood mononuclear cells. RECIST was used for assessment of efficacy and NCI CTC-AE version 3.0 for describing toxicity. RESULTS: Nine patients enrolled in the trial. Median age was 53 years. All patients were Asian (one from Hawaii, 8 from Singapore). Prior treatment was as follows: liver surgery, 2 patients; chemo-embolization, 2 patients; thalidomide, 3 patients; adriamycin, 3 patients. Patients received a median of 2 cycles (range, 1-14) of therapy. No DLTs were seen up to the 80-mg 5-FU cohort. Out of 3 patients in the 80-mg cohort, one had pancytopenia. One patient at the 20-mg cohort had stable disease that lasted for 14 months. CONCLUSION: EU, at a 5.0-mg weekly dose, was well tolerated. There was no evidence of dose-related safety effects. This trial did not define the MTD for oral 5-FU. No objective responses by RECIST were noted but one patient had stable disease and a decrease of 28% in the sum of the largest diameters of her target lesions. The study was terminated early because of CNS-related toxicities noted in the single higher dose levels in a companion study, AHX-03-104.

The role of gefitinib in the management of Asian patients with non-small cell lung cancer.

BACKGROUND: Lung cancer is the most common cause of death in cancer patients worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. The prognosis of NSCLC is still poor, albeit slow and steady improvement achieved in the past three decades by chemotherapy. Recently, the importance of epidermal growth factor receptor (EGFR) in the pathogenesis and progression in NSCLC was identified particularly in those cancer cells with EGFR mutation and/or increased gene copy number. Gefitinib was the first EGFR tyrosine kinase inhibitor approved for treating advanced NSCLC [corrected] It has become a popular choice in treating Asian patients after a higher response rate was reported in Japanese patients than in non-Japanese patients in the first Phase II trial. OBJECTIVE: To evaluate the role of gefitinib in the treatment of Asian patients with NSCLC. METHODS: A review of published papers in PubMed and Embase (2000-2007) and meeting reports of the American Society of Clinical Oncology and World Conference on Lung Cancer (2000-2007) was carried out. RESULTS/CONCLUSIONS: In general, gefitinib is well tolerated. As the second- or third-line treatment, gefitinib has proven survival benefits in Asian patients with advanced NSCLC, when compared with placebo. It has equivalent efficacy to docetaxel with less toxicity as the second-line therapy. As the first-line therapy, it yielded encouraging results but its final role is pending on the results of the ongoing randomised Phase III trial. Gefitinib should be considered as the treatment of choice for second- or third-line therapy in advanced NSCLC in Asian patients after progression from previous chemotherapy. Its role as the first-line, adjuvant or neoadjuvant therapy remains to be determined.

Phase II trial of 5-fluorouracil/leucovorin/gemcitabine/cisplatin as second-line treatment in patients with metastatic or recurrent colorectal carcinoma: a cancer therapeutics research group study.

BACKGROUND: Second-line treatment of relapsed or metastatic colorectal cancer (CRC) after failure of treatment with a fluoropyrimidine is composed of oxaliplatin in combination with a fluoropyrimidine or an irinotecan-containing regimen. Cisplatin and gemcitabine are synergistic in preclinical studies, as is 5-fluorouracil (5-FU) combined with either agent. Fixed-rate infusional gemcitabine is more effective than bolus administration in animal models. PATIENTS AND METHODS: A 2-stage phase II trial was conducted to assess the efficacy (the primary endpoint was response rate) and safety of a regimen consisting of 5-FU 400 mg/m(2) as an intravenous bolus at the middle of a 60-minute infusion of leucovorin 100 mg/m(2), followed by gemcitabine 800 mg/m(2) over 80 minutes, and cisplatin 20 mg/m(2) over 15 minutes. Treatment was repeated weekly for 3 weeks followed by a 1-week rest. Patients with advanced CRC were eligible if they had experienced treatment failure with fluoropyrimidine-based therapy. RESULTS: Nineteen patients were enrolled. The median age was 60 years; 15 patients were men and 4 were women. Twelve patients had colon cancer and 7 had rectal cancer. Sites of metastasis were as follows: liver (n = 10), lung (n = 8), skin (n = 1), and non-regional lymph nodes (n = 1). All patients had an Eastern Cooperative Oncology Group performance status of 0/1. A total of 44 cycles of chemotherapy were delivered (median, 2 cycles; range, 1-5 cycles). One patient exhibited a partial response (5%), 8 had stable disease (42%), and 5 experienced disease progression (26%); another 5 patients were nonevaluable (26%). The median time to progression was 8 weeks and median survival was 36 weeks. Grade 3/4 toxicities were as follows: diarrhea (n = 1), dyspnea (n = 1), pneumonia (n = 1), neutropenia (n = 2), and thrombocytopenia (n = 1). CONCLUSION: Despite acceptable toxicity and a reasonable overall survival, the combination of 5-FU/leucovorin/gemcitabine/cisplatin does not seem to improve current standard therapy in the second-line treatment of patients with CRC in whom a first-line fluoropyrimidine-containing regimen has failed.

Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma.

PURPOSE: To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment. PATIENTS AND METHODS: A multicenter, open-label, single-arm, phase II study in patients with epidermal growth factor receptor-expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles. RESULTS: Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab. CONCLUSION: Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.