Dataset Information

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

ABSTRACT: We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.

SUBMITTER: Ueshima K

PROVIDER: S-EPMC4698605 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

Ueshima Kazuomi K Kudo Masatoshi M Tanaka Masatoshi M Kumada Takashi T Chung Hobyung H Hagiwara Satoru S Inoue Tatsuo T Yada Norihisa N Kitai Satoshi S

Liver cancer 20151021 4

We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of s ...[more]

PMID: 26734580

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Project description:ImportanceSorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study.ObjectiveTo investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion.Design, setting, and participantsThis randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months.InterventionsRandomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks).Main outcomes and measuresThe primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.ResultsFor 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]).Conclusions and relevanceSorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion.Trial registrationClinicalTrials.gov identifier: NCT02774187.

Project description:BackgroundAlthough 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis.MethodsThis is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate.DiscussionThis is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate.Trial registrationClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.

Dataset Information

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

Publications

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

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