9 research outputs found
assessment of disease burden in the phase iii celestial trial of cabozantinib c versus placebo p in advanced hepatocellular carcinoma hcc
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Supplementary Material for: Phase I Trial of Sorafenib Following Liver Transplantation in Patients with High-Risk Hepatocellular Carcinoma
Liver transplantation offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who fall within established criteria. For those outside such criteria, or with high-risk pathologic features in the explant, HCC recurrence rates are higher. We conducted a multicenter phase I trial of sorafenib in liver transplantation patients with high-risk HCC. Subjects had HCC outside the Milan criteria (pre- or post-transplant), poorly differentiated tumors, or vascular invasion. We used a standard 3+3 phase I design with a planned duration of treatment of 24 weeks. Correlative studies included the number of circulating endothelial cells (CECs), plasma biomarkers, and tumor expression of p-Erk, p-Akt, and c-Met in tissue micro-arrays. We enrolled 14 patients with a median age of 63 years. Of these, 93% were men and 71% had underlying hepatitis C virus (HCV) and 21% had HBV. The maximum tolerated dose of sorafenib was 200 mg BID. Grade 3-4 toxicities seen in >10% of subjects included leukopenia (21%), elevated gamma-glutamyl transferase (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, one patient died and four recurred. The mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean soluble vascular endothelial growth factor receptor-2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression to correlate with increased risk of recurrence. Post-transplant sorafenib was found to be feasible and tolerable at 200 mg PO BID. The effect of post-transplant sorafenib on recurrence-free survival is potentially promising but needs further validation in a larger study
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1919MO Efficacy and safety of botensilimab (BOT) plus balstilimab (BAL) in patients (pts) with refractory metastatic sarcoma
Efficacy and Safety of Nivolumab plus Ipilimumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib: The CheckMate 040 Randomized Clinical Trial
Importance: Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. Objective: To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. Design, Setting, and Participants: CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). Interventions: Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). Main Outcomes and Measures: Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). Results: Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). Conclusions and Relevance: In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. Trial Registration: ClinicalTrials.gov Identifier: NCT01658878
Supplementary Material for: A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma
<b><i>Objectives:</i></b> To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> A total of 90 patients with advanced HCC, Child-Pugh class AâB7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (<i>n</i> = 47) (B+E) or 400 mg S orally twice daily (<i>n</i> = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. <b><i>Results:</i></b> The median OS was 8.55 months (95% CI: 7.00â13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69â12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57â1.47). The median EFS was 4.37 months (95% CI: 2.99â7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84â4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42â1.07; <i>p</i> = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5â15.7) for patients treated with B+E (<i>n</i> = 39) and 10.26 months (95% CI: 5.9â13.0) for patients treated with S (<i>n</i> = 38) (HR = 0.88; 95% CI: 0.53â1.46). <b><i>Conclusions:</i></b> There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis