Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 262-262 ◽  
Author(s):  
Masafumi Ikeda ◽  
Shuichiro Shiina ◽  
Kohei Nakachi ◽  
Shuichi Mitsunaga ◽  
Satoshi Shimizu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Treatment Dose ◽  
Pugh Class ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Treatment Safety

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience

2017 ◽  
Vol 35 (6) ◽  
pp. 611-617 ◽  
Author(s):  
Kazuomi Ueshima ◽  
Naoshi Nishida ◽  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Sequential Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Effective Treatment Option ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Grade 3

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

scholarly journals Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kai-Lin Yang ◽  
Mau-Shin Chi ◽  
Hui-Ling Ko ◽  
Yi-Ying Huang ◽  
Su-Chen Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase I ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Normal Liver ◽  
Maximum Tolerated Dose ◽  
Outcome Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

Abstract Background To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). Methods This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS). Results Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months. Conclusions Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort. Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

Tumor c-Met expression and prognosis of advanced hepatocellular carcinoma patients treated with sorafenib.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 317-317
Author(s):  
Yu Yun Shao ◽  
Chi-Huang Hsiao ◽  
Ray Lee ◽  
Oscar Puig ◽  
Soa-Yu Chan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Score ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
First Line Therapy ◽  
Clinical Scores ◽  
Tumor Tissues ◽  
Pugh Class ◽  
Tumor Expression

317 Background: Overexpression of c-Met signaling has been associated with development and progression of hepatocellular carcinoma (HCC). We explored the prognostic role of tumor c-Met expression in patients with advanced HCC. Methods: Patients who had received sorafenib alone as first-line therapy for advanced HCC and had available archival tumor tissues were enrolled. Expression of total c-Met was determined by immunohistochemical staining using CONFIRM anti-total c-MET (SP44) rabbit monoclonal primary antibody (Ventana) on the BenchMark ULTRA staining platform. We evaluated c-Met expression by H scores and by a clinical score as defined in the table. Results: The study enrolled 62 patients, all with Child-Pugh class A status. The HCC etiology was hepatitis B in 48 patients, and hepatitis C in 12 patents; 57 had BCLC disease; 40 had extrahepatic metastasis, and 37 had macrovascular invasion. Clinical scores of c-Met were 0 in 30 (48%) patients, 1 in 31 (50%) patients, 2 in 1 (2%) patients, and 3 in 0 patients. Patients with different clinical scores of c-Met had similar PFS (p = 0.821) or OS (p = 0.533). The median membranous H score and cytoplasmic score were 32.5 and 5, respectively. Patients with higher (≥ median) and lower c-Met membranous H scores or cytoplasmic H scores also had similar PFS and OS. Conclusions: High c-Met expression was rare in this advanced HCC cohort. Tumor expression of c-Met had no obvious associations with the prognosis of advanced HCC. (This study was supported by National Science Council, Taiwan (NSC-102-2314-B-002-120, NSC-103-2314-B-002-181-MY2, NSC-103-2314-B-002-092)). [Table: see text]

Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4087-4087 ◽  
Author(s):  
Shukui Qin ◽  
Tae-You Kim ◽  
Ho Yeong Lim ◽  
Baek-Yeol Ryoo ◽  
Jürgen Scheele ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Progression Free Survival ◽  
Response Duration ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Modest Improvement ◽  
Phase Ib ◽  
Advanced Hcc ◽  
Ecog Ps

4087 Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival > 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.

Rapamycin in patients with advanced hepatocellular carcinoma progressing on prior antiangiogenic therapy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 356-356
Author(s):  
Mohamed Bouattour ◽  
Johanna Wassermann ◽  
Chantal Dreyer ◽  
Valérie Vilgrain ◽  
Valerie Paradis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stable Disease ◽  
Tumor Response ◽  
Antiangiogenic Therapy ◽  
Mtor Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Disease Stabilization ◽  
Heavily Pretreated ◽  
Grade 3

356 Background: PI3K/Akt/mTOR is a critical survival pathway in hepatocellular carcinoma (HCC) often correlated with poor prognosis. Rapamycin (sirolimus) and its analogue everolimus, are specific mTOR inhibitors that showed promising antitumor activity in preclinical models and clinical cases of HCC Aims: To evaluate the safety and efficacy of rapamycin in patients (pts) with advanced HCC after failure or intolerance to prior antiangiogenic therapy Methods: In this retrospective cohort, we analyzed consecutive patients with progressive HCC after 1 to 3 lines of treatment including at least sorafenib. All pts received oral rapamycin at 20 to 30 mg once a week. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST criteria. Results: Nine patients (F/M: 1/8) with compensated liver cirrhosis (Child A, n = 6; Child B7, n = 2) or no cirrhosis (n=1) and histologically proven HCC were included in this study. Overall, therapy with rapamycin was well tolerated. Most common toxicities were asthenia (grade 1-2: 5 pts) anaemia (all grade: 5 pts; grade 3: 2 pts ) and thrombocytopenia (grade 1-2: 2 pts). Liver function deterioration was observed in 2 pts with advanced cirrhosis (Child B7). Radiological evaluation was available in 6 pts. No objective tumor response was observed however stable disease ≥ 3 months was observed in 4 cases. Moreover, 2 pts showed stable disease at 6 months. Prolonged stabilization under rapamycin was observed in pts who were previously controlled at least for 6 months with sorafenib. Rapamycin was discontinued due to disease progression in 7/8 pts, toxicity in 1/8 pts. One pt shows ongoing long-lasting disease stabilization (8 + months). Conclusions: Rapamycin displayed an acceptable safety profile and may achieved disease stabilization in patients with heavily pretreated advanced HCC.

Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15676-e15676 ◽  
Author(s):  
Sandrine J. Faivre ◽  
Jean-Frédéric Blanc ◽  
Philippe Merle ◽  
Angelica Fasolo ◽  
Angelo Iacobellis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Tumor Size ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Phase Ib ◽  
Advanced Hcc ◽  
Peripheral Edema ◽  
Met Inhibitor ◽  
Grade 3

e15676 Background: The prognosis for patients (pts) with advanced hepatocellular carcinoma (HCC) after failure of sorafenib is poor, with few systemic therapy options. c-Met is a receptor tyrosine kinase implicated in the progression of HCC. Tepotinib, a highly selective c-Met inhibitor, has shown activity first-line in patients with c-Met+ HCC. We report final results of a phase Ib study of tepotinib in pts with advanced HCC after failure of first-line sorafenib. Methods: Eligible pts were ≥18 years with advanced HCC, Child-Pugh Class A, ECOG PS 0-1, and progression after ≥4 weeks of sorafenib. Tepotinib doses of 300 and 500 mg/day on a 21-day cycle were explored to establish the recommended phase II dose (RP2D) of tepotinib. Secondary objectives included antitumor activity by RECIST v1.1, biochemical response, and safety. Results: Seventeen pts were enrolled: 4 pts received tepotinib 300 mg/day and 13 pts 500 mg/day, confirmed as the RP2D. Fourteen pts experienced treatment-related adverse events (TRAEs), the most frequent being peripheral edema (n = 5, 2 grade 3), lipase increase (2, 1 grade 3), acute kidney injury (2, 1 grade 3), renal impairment (2, 1 grade 3), fatigue (2), nausea (2), asthenia (2). One pt with peripheral edema permanently discontinued treatment. No grade ≥4 TRAEs and no dose-limiting toxicities (DLTs) were reported. The best overall response was partial response (PR) in 2 pts and stable disease (SD) in 4 pts. The duration of the PRs was 57 and 91 weeks. In the first of these pts, tumor size decreased by 55% and serum alfa-fetoprotein (AFP) levels had decreased from 15,923 μg/L at baseline to < 3,000 μg/L by day 15 of cycle 2 and remained at this level until progression. In the second pt, tumor size decreased by > 60% from baseline. No consistent change in AFP was seen in pts with SD. Median overall survival was 7.2 months (range 0.7–22.9 months). Conclusions: The RP2D of tepotinib as second-line therapy for pts with advanced HCC who progress after sorafenib treatment is 500 mg/day. Tepotinib was well tolerated at this dose and showed signs of activity. The ongoing phase II part of this trial is investigating the efficacy and safety of tepotinib 500 mg/day in pts with c-Met+ HCC. Clinical trial information: NCT02115373.

Efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15504-e15504
Author(s):  
Wei Zhang ◽  
Zhiping Yan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Transcatheter Arterial Chemoembolization ◽  
Advanced Hepatocellular Carcinoma ◽  
Efficacy And Safety ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Treatment Safety ◽  
Unacceptable Toxicity ◽  
Arterial Chemoembolization

e15504 Background: Effective options for patients with advanced hepatocellular carcinoma (HCC) are urgently needed. Studies have shown that combination of sorafenib with TACE could imorove survival for the treatment of locoregional HCCs. Apatinib is a novel and highly selective inhibitor of VEGFR2 tyrosine kinase. We were aiming to explore the efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Methods: This was a single-center single-arm phase 2 study. The key inclusion criteria included: (1) Histologicaly and cytologicaly diagnosed as Hepatocellular carcinoma of the liver ( HCC ) and with at least one imaging examination of measurable lesions, CT or MR scan long diameter of tumor ≥ 10 mm. (2) BCLC B / C; (3) Progressed after at least twice TACE. Eligible pts received apatinib at 500 mg/day for a maximum after TACE 4-7 days, and TACE treatment was performed after 4 days of discontinuation of apatinib until unacceptable toxicity or tumor recurrence. The primary endpoint was time to progression (TTP), which was defined as the time from enrollment to disease progression. The secondary endpoint was overall survival (OS) and treatment safety. Results: From May 27, 2018 to Oct 12, 2019, 22 pts wereenrolled. 5 pts received TACE more than 5 times, and 17 pts received TACE within 4 times. For 20 evaluable pts, two pts achieved partial response (10%), and 13 patients achieved stable disease. The ORR and DCR were 10% and 75%, respectively. At the cutoff data of Nov 4, 2019, 5 pts were still on treatment. 16 recurrenced and 5 death occurred. The mTTP was 5.09 months (95% CI, 3.48-7.16), and the mOS was not reached. Treatment-related adverse events occurred in 12 pts (60%). Seven grade 3 or 4 adverse events were reported (35%), respectively wereascites (2), platelet count decrease (1), elevated ALT/AST (1), hypertension (1), proteinuria (1) and nausea (1). None of the treatment related AEs was fatal. Conclusions: Apatinib combined with TACE might be effective and tolerant in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Clinical trial information: NCT03510416.

Randomized Controlled Trial of Tamoxifen in Advanced Hepatocellular Carcinoma

2005 ◽  
Vol 23 (19) ◽  
pp. 4338-4346 ◽  
Author(s):  
Jean-Claude Barbare ◽  
Olivier Bouché ◽  
Franck Bonnetain ◽  
Jean-Luc Raoul ◽  
Philippe Rougier ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Performance Status ◽  
Univariate Analysis ◽  
Local Treatment ◽  
Cox Proportional Hazards Model ◽  
Tamoxifen Treatment ◽  
Control Group ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Pugh Class

Purpose Randomized studies on tamoxifen treatment of hepatocellular carcinoma (HCC) produced conflicting results. The aim of this study was to assess the efficacy of tamoxifen administration in improving overall survival of patients with advanced HCC. Patients and Methods A total of 420 patients with HCC who were not suitable for surgery or local treatment were randomly assigned between April 1995 and May 2000: 210 in the control group and 210 in the tamoxifen group (20 mg/d orally). Patients with WHO performance status greater than 2, belonging to Child-Pugh class C, or with serum creatinine greater than 130 μmol/L were not eligible. Results Tolerance was good and the main reported adverse effects were thrombophlebitis (three patients), nausea (two patients), and hot flushes (three patients). Outcome did not differ between the two treatment arms: estimated median survival was 4.8 and 4.0 months in the tamoxifen and in the control groups, respectively (P = .25). Univariate analysis showed significant association of survival with age, Okuda stage, WHO performance status, Child-Pugh class, intrahepatic tumor stage, alpha-fetoprotein serum concentration, and presence of extrahepatic spread, portal vein thrombosis, hepatomegaly, or hepatalgia. In a Cox proportional hazards model we found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda I or II stages. Conclusion In this large study, tamoxifen did not improve the survival of patients with advanced HCC, but there is a suggestion that patients without major hepatic insufficiency seem to have some survival benefit. New trials involving this specific population are warranted.

scholarly journals Gemcitabine Plus Carboplatin in Patients with Advanced Hepatocellular Carcinoma: Results of a Phase II Study

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5
Author(s):  
Aly M. Azmy ◽  
Khalid E. Nasr ◽  
Nagy S. Gobran ◽  
M. Yassin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Stage ◽  
Survival Times ◽  
Advanced Hcc ◽  
Disease Stabilization ◽  
Grade 3

Objectives. Assessment of gemcitabine/carboplatin combination in patients with advanced-stage hepatocellular carcinoma (HCC) in a phase II trial for safety and efficacy. Methods. Forty patients with previously untreated advanced-stage HCC were prospectively enrolled and subjected to gemcitabine/carboplatin regimen which consisted of gemcitabine 1000 mg/m2 on days 1 and 8, and carboplatin AUC 6 on day 1. The treatment was repeated every 3 weeks until disease progression or limiting toxicity. Results. Forty patients were assessable for efficacy and toxicity. In all, 276 treatment cycles were administered. No toxic deaths occurred. Hematological grade 3-4 toxicity consisted of thrombocytopenia (27% of patients) and neutropenia (24%), including 2 febrile neutropenia and anemia (9%). Grade 3 carboplatin-induced neurotoxicity was observed in 3 (9%) patients. ORR was 23% (95% CI, 0.10–0.29) with 9 partial responses and disease stabilization was observed in 46% (95% CI, 0.22–0.42) of patients, giving a disease control rate of 69%. Median progression-free and overall survival times were, respectively, 5 months (95% CI: 3–8 months) and 8 months (95% CI: 6–18 months). Conclusion. The gemcitabine/carboplatin regimen seems to be effective, well tolerated, and active in advanced HCC.

A phase I/II study of AZD6244 in combination with sorafenib in advanced hepatocellular carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4100-4100
Author(s):  
Su Pin Choo ◽  
Quan Sing Ng ◽  
Wallace Jian Jun Chen ◽  
Chee Kian Tham ◽  
Wei-Peng Yong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Level ◽  
Response To Treatment ◽  
Advanced Hepatocellular Carcinoma ◽  
Mri Imaging ◽  
Tumor Vascularity ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Area Product

4100^ Background: Preclinical studies have shown that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. We conducted this study to determine tolerability, pharmacokinetics, and pharmacodynamics of AZD6244 when combined with sorafenib in advanced HCC. Methods: Patients with biopsy-proven unresectable BCLC B/C hepatocellular carcinoma were recruited. Only those with Childs-Pugh A or B (7) liver cirrhosis and without prior systemic therapy were included. Sorafenib at 400mg bd was given 1 week before initiation of AZD6244 which was escalated in subsequent cohorts from 75mg om based on 3+3 design. PK and PD studies and QOL assessments were performed. DCE-MRI imaging was performed to assess tumor vascularity in response to treatment. Results: Fourteen patients were recruited (including 2 replaced). 11 had evaluable disease. Characteristics: all male, all Chinese, 12 were BCLC C stage. Two DLTs were seen out of 6 patients at dose level 1 (AZD6244 at 50mg bd) which were grade 3 fatigue and grade 3 abdominal pain with elevated transaminases. When an additional dose level 1A was added (ADZ6244 at 100mg om), 2 out of 3 patients had DLTs of grade 3 raised aspartate transaminase and grade 3 diarrhea. Thus, the MTD was determined to be AZD6244 at 75mg om when combined with sorafenib 400mg bd. Common toxicities were diarrhea (83%), rash (58%), fatigue (50%), hypertension (42%), anorexia/vomiting/thrombocytopenia (25%). Two patients had reversible LVEF dysfunction and there were no eye toxicities. PK of AZD6244 showed oral clearance of 11.2 + 6.8 L/h and terminal half-life of 6.0 +2.0 h.Objective responses were 3 PR, 6 SD and 2 PD.DCE-MRI measurements demonstrated significant reductions in permeability surface area product (PS, ml/100ml/min) and fractional intravascular blood volume (v1, ml/100ml) seven days after starting sorafenib. No additional antivascular activity was observed when AZD6244 was added to sorafenib. Conclusions: The recommended phase II dose for AZD6244 is 75mg om when combined with sorafenib 400mg bd for advanced HCC patients. This combination is feasible, shows activity and warrants further investigation.

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