Sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (HCC): Safety and efficacy in Child-Pugh (CP) class A and B patients.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 306-306
Author(s):  
Tiziana Pressiani ◽  
Corrado Boni ◽  
Lorenza Rimassa ◽  
Roberto Labianca ◽  
Stefano Fagiuoli ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Safety And Efficacy ◽  
Advanced Hcc ◽  
Class A ◽  
Tolerability Data ◽  
Prospective Trials ◽  
Open Label Trial ◽  
Grade 3

306 Background: S is the first systemic agent that has been shown to prolong survival in pts with CP A advanced HCC. However, its safety and efficacy have not been extensively evaluated in pts with CP B cirrhosis. Methods: We performed a descriptive analysis on pts with histologically documented advanced HCC and CP A/B cirrhosis, enrolled in a multicenter phase II randomized, open-label trial (data reported elsewhere), in order to assess the feasibility and efficacy of treatment with S in CP B pts. Written informed consent was obtained from all pts. Results: From April 2007 to July 2008, 297 pts were prospectively treated with S 400 mg bid, 234 (78.8%) CP A, 63 (21.2%) CP B. 232 pts were male (76%), median age was 68.3 yrs (range 19.8-89.2 yrs), 217 pts had no extra hepatic disease (73.1%). The two subgroups, according to CP class A or B, were homogeneous for all considered parameters. Median treatment duration was >3 months (mos) for 59.4% of CP A pts and for 27% of CP B pts (p <0.001). Median PFS for the total population was 3.9 mos, 4.3 mos for CP A pts and 2.1 mos for CP B pts (p<0.001). Median OS was 10 mos for CP A pts and 3.8 mos for CP B pts (p<0.001). Adverse events (all grades) were similar in type and incidence for CP A and B pts, with fatigue, stomatitis, diarrhea and weight loss having the highest incidence (44%, 41%, 38% and 38%, respectively). Specifically, no differences in terms of grade 3-4 events have been documented between the two groups. Conclusions: This study supports the feasibility of S also in advanced HCC pts with CP B status. Tolerability data suggest that pts with CP B status might potentially be treated safely with S for its potential survival benefits. Further prospective trials, specifically designed to investigate S in CP B pts, are eagerly advocated.

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.

A phase II feasibility study of sorafenib and gemcitabine combination therapy in advanced hepatocellular carcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 298-298
Author(s):  
N. Naqi ◽  
S. Ahmad ◽  
S. Murad ◽  
J. Khattak
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Protocol ◽  
Uncontrolled Hypertension ◽  
Hematological Toxicity ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Advanced Hcc ◽  
Class A ◽  
Frequent Dose ◽  
Child Class

298 Background: Sorafenib is considered standard of care in advanced hepatocellular carcinoma (HCC) giving survival benefit of around 4 months. Its combination with gemcitabine, a pyrimidine analogue with limited friendly hepatic profile, may improve results. The primary objective of this study was to evaluate the efficacy and safety of sorafenib and gemcitabine combination in advanced HCC. Methods: 30 patients of advanced HCC were enrolled in this non-randomized, open-label treatment protocol. Sorafenib 400 mg orally twice daily with gemcitabine 1,000mg/m2 intravenous on day 1 and 8 of a 4 week cycle for 4 months. Inclusion criteria: Child class A and B, adequate liver, marrow and renal functions, at least one uni-dimensional measureable lesion, Exclusion criteria: uncontrolled hypertension, serious infections, brain metastasis, bleeding diathesis, pregnant or lactating. National Cancer Institute criteria for adverse events (NCI CTCAE) Version 3.0, and Response evaluation criteria for solid tumors (RECIST) was used for assessment. Results: 30 patients: 23 male and 7 female. 24 (80%) Child class A and 6 (20%) class B. All had chronic liver disease. 22 (73.3%) had significantly high alfa-fetoprotein levels (≥ 500). 20 (66.7%) positive for hepatitis C, 4 (13.3%) for hepatitis B. 6 (20%) had no evidence of viral infection. 19 (63.3%) had multifocal lesions and 11 (36.7%) unifocal. 18 (60%) completing 4 cycles of treatment were assessed for response. 2 partial responses (PR) and 8 stable disease (SD) were seen. No complete response (CR) was observed. 8 patients had progressive disease, 4 progressing on interim assessment were taken off protocol. Toxicity: primarily hematological. Gemcitabine related thrombocytopenia being the most common (40%) requiring frequent dose modifications and delays. Sorafenib specific, hand foot skin reaction and anorexia were next most frequent. Conclusions: Sorafenib and gemcitabine combination is not feasible in advanced HCC due to its hematological toxicity especially thrombocytopenia, requiring frequent dose reductions and delays. No significant financial relationships to disclose.

A phase IB, multicenter, open-label study to assess the safety, tolerability, and efficacy of the pleiotropic pathway modifier CC122 administered orally to patients with advanced HCC.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 379-379
Author(s):  
Robin Kate Kelley ◽  
Kent C. Shih ◽  
Fadi S. Braiteh ◽  
Drew W. Rasco ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Activated T Cells ◽  
Advanced Hcc ◽  
Duration Of Response ◽  
Grade 3 ◽  
Expansion Cohort

379 Background: CC122 is a novel cereblon-modulating agent with multiple biologic activities including potent immunomodulatory and antiangiogenic effects. CC-122 binding to cereblon promotes ubiquitination and subsequent degradation of lymphoid transcription factors Ikaros and Aiolos resulting in activation of T cells. Methods: Following establishment of oral CC122 3 mg daily (QD) as the MTD in phase 1a (Blood 122:2905 2013), an expansion cohort of advanced Hepatocellular Carcinoma (HCC) subjects was enrolled. All subjects had progressed on or were intolerant to sorafenib. Efficacy was assessed per RECIST 1.1 criteria. Results: As of Jan. 13, 2016, 25 advanced HCC subjects were enrolled. The median age was 59.6 years, median Child-Pugh score was 5 (range 5-8) and all were ECOG 0-1. Viral status was HBV 28%, HCV 28%, HBV/HCV 12% and non-viral 32%. 52% had alpha-fetoprotein ≥ 200. CC122 was well tolerated. Two subjects discontinued due to AEs. Dose reductions occurred in 32% (n = 8). The most common ( ≥ 5%) grade 3/4 AEs were neutropenia, ALT elevation (each n = 4, 16%), AST elevation (n = 3, 12%), asthenia, ascites, anemia, hyperbilirubinemia, pneumonia, and rash (each n = 2, 8%). Drugrelated serious AEs included vomiting and rash. 19 subjects were evaluable for efficacy. ORR was 10.5% (n = 2 PR, 1 confirmed) and Disease Control Rate (CR+PR+SD > 7 weeks) was 36.8%. The duration of response was 108 and 125 days in the 2 PRs. The median PFS was 57 days (MinMax: 28334, 95% CI: 45-135). CC122 treatment resulted in a median increase from baseline in peripheral blood activated and memory cytotoxic T cells by 64% (range: 17-213%, n = 6) and 78% (range: 30-111%, n = 6 (p < 0.05), respectively, and activated helper T cells by 106% (range: 62-218%, n = 7 (p < 0.05). CC122-activated T cells from the blood increased IFNg (2.73 fold; range: 0.45-26.1, n = 13) and IL2 (9.5 fold; range: 0.85-24.3, n = 11) production when compared to baseline (both P < 0.05) upon ex-vivo stimulation. Conclusions: CC122 3 mg QD appears to be well tolerated and activates cytotoxic T cells in HCC patients. Combination studies with sorafenib or nivolumab are recommended and underway. Clinical trial information: NCT01421524.

KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 209-209 ◽  
Author(s):  
Andrew X. Zhu ◽  
Richard S. Finn ◽  
Stéphane Cattan ◽  
Julien Edeline ◽  
Sadahisa Ogasawara ◽  
...  
Keyword(s):  
Response Duration ◽  
Immune Checkpoint Blockade ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Advanced Hcc ◽  
Phase 2 Trial ◽  
Tolerability Data ◽  
Open Label Phase ◽  
Previously Treated ◽  
Ecog Ps

209 Background: Immunotherapy approaches, including immune checkpoint blockade, have shown initial promising results in HCC. Anti PD-1 therapy with pembrolizumab has demonstrated antitumor activity and manageable safety in multiple cancers. KEYNOTE-224 (NCT02702414), an open label, phase 2 trial assessed the efficacy and safety of pembrolizumab in pts with advanced HCC previously treated with sorafenib. Methods: Eligible pts were age ≥18 y with confirmed HCC, radiographic progression after sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and predicted life expectancy > 3 mo. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, unacceptable toxicity, withdrawal of consent or investigator decision. Response was assessed every 9 wk (RECIST v1.1, central review). Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints included DOR, DCR, PFS, OS, and safety and tolerability. Data cutoff date was Aug 24, 2017. Results: Of 104 treated pts, 23 continued therapy (median follow up 8.4 mo, range 0.4-13.6). Median age of pts was 68y (range 43-87), 21.2% were HBV+, 26% were HCV+, 94.2% were Child Pugh A, 79.8% had PD on sorafenib and 63.5% had extrahepatic disease. ORR was 16.3% (95% CI, 9.8 to 24.9) and similar across subgroups with different etiology. Median time to response was 2.1 mo (range 1.8-4.8) and 94% of responders were estimated to have a response duration ≥6 mo. Best responses were CR in 1 patient (1.0%), PR in 16 (15.4%), SD in 47 (45.2%) and PD in 34 (32.7%); DCR was 61.5%. Median PFS was 4.8 mo (95% CI, 3.4 to 6.6) and median OS (9.4 to NA) was not reached. The 6 mo PFS and OS rates were 43.1% and 77.9%, respectively. Treatment related (TR) AE occurred in 73.1% of pts; fatigue (21.2%) and increased aspartate aminotransferase (12.5%) were seen in ≥10% of pts and grades 3-5 TRAE in 25% including 1 death (ulcerative esophagitis). No cases of HBV/HCV flare occurred; immune mediated hepatitis occurred in 3 (2.9%) pts. Conclusion: Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in pts with advanced HCC previously treated with sorafenib. Safety was generally comparable to that established for pembrolizumab monotherapy. Clinical trial information: NCT02702414.

A phase Ib/II, open-label study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16599-e16599
Author(s):  
Renuka V. Iyer ◽  
Daneng Li ◽  
Farshid Dayyani ◽  
Michael N. Needle ◽  
Thomas Adam Abrams
Keyword(s):  
Patient Outcomes ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Standards Of Care ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase 2 ◽  
Safety And Efficacy ◽  
Advanced Hcc ◽  
Grade 3

e16599 Background: VEGFR TKIs and checkpoint inhibitors are current standards of care in HCC as single agents, however treatment options are limited, and significant unmet need remains. A recent ph3 study combining bevacizumab (VEGF-A Mab) with a PDL1 inhibitor have shown promising improvements in OS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over single agent treatment. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvlaumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies to enhance patient outcomes in other tumor types. It is hypothesized that more complete inhibition of the VEGF pathway by tivozanib compared to bevacizumab combined with PDL1 inhibition may further enhance patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase 2 dose (RP2D) and provide preliminary safety and efficacy data. Methods: Major eligibility criteria are adults with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria are co-infection with HBV and either HDV or HCV and significant organ dysfunction. Six patients with untreated advanced HCC will be treated with the combination of T 1 mg orally for 21 days followed by 7 days off treatment and D 1500 mg intravenously every 28 days. A DLT is generally defined as the occurrence of any Grade ≥3 immune or non-immune AE in Cycle 1 that is at least possibly related to the investigational regimen other than any grade of vitiligo or alopecia or Grade 3 controllable hypertension. If two or more patients have a DLT then the dose of tivozanib will be reduced to 1 mg every other day without interruption for the second cohort. In the Phase 2 portion of the study an additional 30 patients will be treated at the RP2D. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be adverse events per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Phase 1 safety and efficacy findings for this novel combination will be reported at the meeting. Conclusions: Phase 1 safety and efficacy findings for this novel combination will be reported at the meeting. Clinical trial information: NCT03970616 .

A phase II study of palbociclib (PD-0332991) in adult patients with advanced hepatocellular carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 277-277 ◽  
Author(s):  
Susan Joy Littman ◽  
Christina Brus ◽  
Ashlie Burkart
Keyword(s):  
Disease Progression ◽  
Primary Endpoint ◽  
Advanced Hepatocellular Carcinoma ◽  
Management Problem ◽  
First Line ◽  
Open Label ◽  
Advanced Hcc ◽  
First Line Therapy ◽  
Treatment Naïve ◽  
Grade 3

277 Background: The oral MKI sorafenib has been shown to significantly increase PFS, OS and DCR in treatment-naïve HCC in randomized Ph 3 trials. Despite these landmark studies OS benefit is modest, particularly for those with C-P cirrhosis grades B/C and toxicity is a major management problem. We report results of second-line treatment with palbociclib, PD-0332991, an orally available selective inhibitor of cyclin dependent kinases 4 and 6, which has potent anti-proliferative activity in pre-clinical studies. Methods: This is an open-label, nonrandomized single institution trial for pts with inoperable, advanced HCC, who have failed or are intolerant of first line therapy with sorafenib. Eligible subjects were treated with 125 mg PD-0332991 orally/day, 1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, withdrawal from study or death. Tumor response by CT or MRI was assessed using mRECIST v1.1. Toxicity assessments were per NCI CTCAE v4.0. The primary endpoint is TTP. Secondary endpoints are safety/tolerability, OS & RR. Results: 21 pts (18 M, 3 F) have been enrolled. Median age: 62 (32-78) yrs. 47% Cauc, 19% AA and 33% Asian. 17 C-P A, 4 C-P B. ETOH 19%, HCV 48%, HBV 24%, NASH 5%, unknown 10%. 71% had >1 metastatic site. All had pathologically confirmed Retinoblastoma-positive HCC. Median duration of therapy was 17 (8-69) wks and (4.25 (2-17) cycles. Most common grade 3/4 AEs were neutropenia and thrombocytopenia. Non-serious AEs were anemia, pain, ascites and fatigue. 4 pts were non-evaluable, median OS = 10.5 (5.5-14) wks. In evaluable pts, there was 1 PR and 0 CRs. 6 pts died of ESLD without observable disease progression by RECIST, median OS = 19 (4 - 43) wks. Nine pts had disease control (PR or SD) followed by disease progression, median TTP was 24 (4-64) wks. Prolonged stability was seen in 3 pts. OS was 40 (24-96) wks, excluding 2 pts who are alive at 120 and 59 wks. 2 pts remain on trial. Conclusions: Palbociclib demonstrates activity in patients with advanced HCC after failure of first-line sorafenib. This trial will meet its primary endpoint. Consistent with a cytostatic MOA, some pts experienced HCC stabilization and OS was determined by ESLD. Palbociclib is well tolerated in cirrhotic patients with advanced HCC. Clinical trial information: NCT01356628.

An Open-Label Trial of Aripiprazole Treatment in Dual Diagnosis Individuals: Safety and Efficacy

2009 ◽  
Vol 5 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Aimee L. McRae-Clark ◽  
Marcia L. Verduin ◽  
Bryan K. Tolliver ◽  
Rickey E. Carter ◽  
Amy E. Wahlquist ◽  
...  
Keyword(s):  
Dual Diagnosis ◽  
Open Label ◽  
Safety And Efficacy ◽  
Open Label Trial
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