Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4112-4112 ◽  
Author(s):  
Andrew X. Zhu ◽  
Marek Ancukiewicz ◽  
Jeffrey G. Supko ◽  
Lawrence Scott Blaszkowsky ◽  
Jeffrey A. Meyerhardt ◽  
...  
Keyword(s):  
Steady State ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Eligibility Criteria ◽  
Advanced Hcc ◽  
Baseline Levels ◽  
Grade 3

4112 Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage occurred in 1 pt each. Steady-state PK parameters (mean±SD) were, Cmin, 22±21 ng/mL; Cmax, 55±33 ng/mL; AUCτ, 887±503 ng*h/mL. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased significantly after cediranib treatment (p<0.05). PFS was inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha and CD34+CD133+ hematopoietic progenitor cells (p<0.05). Conclusions: Cediranib at 30 mg daily is associated with high frequency of grade 3 hypertension and shows preliminary evidence of antitumor activity in advanced HCC pts. Exploratory studies confirmed potential PD and response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in HCC pts as in those with other tumor types and normal/near normal hepatic function. This study was stopped by AstraZeneca after discontinuation of cediranib development for unrelated factors.

Phase II study of intrabuccally-administered amplitude-modulated electromagnetic fields in patients with advanced hepatocellular carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15573-e15573
Author(s):  
F. P. Costa ◽  
A. C. de Oliveira ◽  
R. Meirelles ◽  
M. M. Machado ◽  
R. Surjan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Electromagnetic Fields ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Hepatic Function ◽  
Advanced Hepatocellular Carcinoma ◽  
Free Survival ◽  
Advanced Hcc ◽  
Independent Review

e15573 Background: Over the past few years we have identified tumor-specific frequencies for several common forms of cancer. The goal of this study was to assess the tolerability and effectiveness of electromagnetic fields amplitude-modulated at tumor-specific frequencies and administered by means of an intrabuccal spoon-shaped probe in patients with advanced hepatocellular carcinoma (HCC). Methods: From October 2005 to July 2007, patients with advanced HCC and Child-Pugh A or B were recruited in a phase II study. Three daily 60 min outpatient treatments were administered until disease progression or death. Imaging studies were performed every eight weeks. The primary efficacy end point was progression-free survival ≥ 6 months. Secondary efficacy end points were progression-free survival and overall survival. Results: A total of 41 patients were enrolled, 17 had Child-Pugh A, 20 Child-Pugh B disease. The median age was 64.0 years. Seventeen patients (34.1%) were progression-free for more than 6 months. Median progression-free and overall survivals were 4.8 months (95% CI 2.3–6.0) and 6.9 months (95 CI 4.8–11.1). As of December 2008, four patients are alive and two patients, who are still undergoing therapy, remain progression-free for 30.4 and 30.7 months, respectively. Four patients had partial response (9.8%) and sixteen had stable disease for at least 12 weeks (39.0%) according to the RECIST criteria resulting in 48.8% disease control. All responses were confirmed by independent review. There were no NCI grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient grade 1 fatigue. Conclusions: In patients with advanced HCC and impaired hepatic function, treatment with amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of anti-tumor effects, which are long-lasting in some patients. No significant financial relationships to disclose.

A phase II study of sorafenib in combination with tegafur/uracil (UFT) for Asian patients with advanced hepatocellular carcinoma (HCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4589-4589
Author(s):  
Y. Shen ◽  
C. Hsu ◽  
C. Hsu ◽  
Z. Lin ◽  
P. Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Metronomic Chemotherapy ◽  
Progression Free Survival ◽  
Molar Ratio ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Advanced Hcc ◽  
Asian Patients ◽  
Ecog Ps

4589 Background: Sorafenib, a multikinase inhibitor with antiangiogenic activity, has recently been approved for the treatment of unresectable HCC. Combination of sorafenib with metronomic chemotherapy has theoretic advantage in improving antitumor activity without increasing toxicities. UFT (tegafur: uracil = 4:1 in molar ratio), an oral fluoropyrimidine, is active in various gastrointestinal cancers. We conducted a phase II study to evaluate the efficacy and safety of sorafenib plus low-dose UFT in advanced HCC patients (pts). Methods: Pts with histologically or cytologically proven unresectable/metastatic HCC, ECOG PS 0–2, Child-Puch class A, platelets ≥ 100 K/μl, transaminases ≤ 5 × ULN, bilirubin ≤ 3 mg/dl, INR ≤ 2.3 and creatinine ≤ 1.5 × ULN were enrolled. Prior systemic therapy for advanced disease is not allowed. Sorafenib (400 mg bid) and UFT (125 mg/m2 based on tegafur bid) were taken per os continuously. Tumor assessment was performed q8w by RECIST criteria. Primary endpoint is progression-free survival (PFS). Results: Between April 2007 and April 2008, 53 pts were enrolled. Baseline pts characteristics were: M/F, 47/6; median age 57 (range, 31–83); CLIP score 0–3/4, 48/5; extrahepatic spread/macroscopic vascular invasion, 33/30; and HBsAg(+)/anti-HCV(+)/both(+), 38/13/4. 89% of pts were BCLC stage C. Pts received a median of 3.7 (range 0.3- 18.9+) months of treatment. There were 3 (6%) PR and 27 (51%) SD. The median PFS and OS were of 3.7 months (95% C.I., 1.9- 5.5) and 7.4 months (95% C.I., 3.4- 11.4), respectively. Adverse events (AEs) were summarized in Table . Hand-foot skin reaction (HFSR), fatigue, and diarrhea were most common AEs. HFSR was the major AE resulting in dose reduction (19%) or treatment delay (21%). Grade 3/4 neutropenia occurred in 2 pts (4%). Conclusions: Adding metronomic UFT chemotherapy to sorafenib may improve therapeutic efficacy of the latter in pts with advanced HCC. The toxicity profile of the combination is similar to that of sorafenib alone. [Table: see text] [Table: see text]

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.

Phase II Study of Gemcitabine and Oxaliplatin in Combination With Bevacizumab in Patients With Advanced Hepatocellular Carcinoma

2006 ◽  
Vol 24 (12) ◽  
pp. 1898-1903 ◽  
Author(s):  
Andrew X. Zhu ◽  
Lawrence S. Blaszkowsky ◽  
David P. Ryan ◽  
Jeffrey W. Clark ◽  
Alona Muzikansky ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Vascular Tumor ◽  
Advanced Hepatocellular Carcinoma ◽  
Close Monitoring ◽  
Grade 3 ◽  
Transient Elevation

Purpose Hepatocellular carcinoma (HCC) is a vascular tumor with poor prognosis. Given the reported activity of gemcitabine and oxaliplatin (GEMOX) in HCC and the potential benefits of targeting the vascular endothelial growth factor pathway with bevacizumab (B), a phase II study of GEMOX-B was undertaken to define efficacy and toxicity profiles in HCC patients. Patients and Methods Eligible patients had pathologically proven measurable unresectable or metastatic HCC. For cycle 1 (14 days), bevacizumab 10 mg/kg was administered alone intravenously on day 1. For cycle 2 and beyond (28 days/cycle), bevacizumab 10 mg/kg was administered on days 1 and 15, gemcitabine 1,000 mg/m2 was administered as a dose rate infusion at 10 mg/m2/min followed by oxaliplatin at 85 mg/m2 on days 2 and 16. Results Thirty-three patients were enrolled and 30 patients were assessable for efficacy. The objective response rate was 20%, and 27% of patients had stable disease. Median overall survival was 9.6 months (95% CI, 8.0 months to not available) and median progression-free survival (PFS) was 5.3 months (95% CI, 3.7 to 8.7 months); the PFS rate at 3 and 6 months was 70% (95% CI, 54% to 85%) and 48% (95% CI, 31% to 65%), respectively. The most common treatment-related grade 3 to 4 toxicities included leukopenia/neutropenia, transient elevation of aminotransferases, hypertension, and fatigue. Conclusion GEMOX-B could be safely administered with close monitoring and had moderate antitumor activity for patients with advanced HCC. The high 6-month PFS rate is encouraging, and this regimen is worthy of further investigation.

A multicenter phase II study of sorafenib, capecitabine, and oxaliplatin (SECOX) in patients with advanced hepatocellular carcinoma: Final results of Hong Kong-Singapore Hepatocellular Carcinoma Research Collaborative Group study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4117-4117 ◽  
Author(s):  
Thomas Cheung Yau ◽  
Foon Yiu Cheung ◽  
Francis Lee ◽  
Su Pin Choo ◽  
Hilda Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Asian Population ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Collaborative Group ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Grade One

4117 Background: This is a single arm, multi-center, phase II study to assess the efficacy and tolerability of sorafenib, oxaliplatin and capecitabine combination for the treatment of advanced hepatocellular carcinoma (HCC) patients. Methods: Eligible patients received SECOX regime—sorafenib 400 mg bid (Day one-fourteen), oxaliplatin 85 mg/m2 (Day one) and capecitabine 1700 mg/m2(Day one-seven) every two weeks. Response assessment was based on RECIST 1.0 criteria. The primary endpoint was time-to-progression (TTP) and the secondary endpoints were tumor response rate (RR), progression-free survival (PFS), overall survival (OS) and tolerability. Results: A total of 51 patients were enrolled in the trial.The median age was 58 years (range, 28-81) and 84% of patients were chronic hepatitis B carriers. Ninety percent of recruited patients belonged to BCLC stage C disease and 41 (80%) patients had extra-hepatic metastasis. The best RR was 16% and they were all partial response. Another 62% of patients achieved stable disease for at least eight weeks. The median TTP was 5.29 months (95% CI 3.81-5.88 months), PFS 5.26 months (95% CI 3.75-5.88 months) and OS was 11.73 months (95% CI 8.87- 15.38 months). Diarrhea (75%), Hand-foot-skin reaction (73%) and transient liver function derangement were the most commonly encountered adverse events, with the majority of patients having grade one or two. No treatment-related death was reported. Conclusions: The SECOX regime indicates preliminary promising activity and safety in Asian population with advanced HCC. Our data support a randomized trial comparing SECOX versus sorafenib alone for treatment of advanced HCC. Clinical trial information: NCT00752063.

Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): A phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4574-4574 ◽  
Author(s):  
W. Sun ◽  
D. G. Haller ◽  
K. Mykulowycz ◽  
M. Rosen ◽  
M. Soulen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Female Ratio ◽  
Advanced Hcc ◽  
Standard Chemotherapy Regimen ◽  
Hand Foot Syndrome ◽  
Number Of Treatment

4574 Background: Hepatocellular carcinoma (HCC) is one of the most common cancers globally and its incidence of in USA is increasing. Unfortunately, most patients with HCC are unsuitable for surgical resection or transplantation. Because of the heterogeneity of this disease and poor liver function in many patients, there is no generally accepted standard chemotherapy regimen for HCC. Efforts have been made to investigate effective and tolerable therapy for patients with advanced HCC. We conducted a phase II study to evaluate the efficacy and feasibility of the combination of bevacizumab, oxaliplatin and capecitabine in patients with advanced or metastatic HCC. The primary goal of the study was to evaluate the progression-free survival rate. The secondary endpoints include response, overall survival and toxicity. Methods: Patients with advanced or unresectable untransplantable metastatic HCC who had adequate bone marrow, liver and renal function (ANC ≥ 1,500/mm3, platelets ≥ 75,000/mm3, serum creatinine ≤ 2.0 mg/dl, total bilirubin ≤ 3.0 mg/dl, transaminases ≤ 5 upper limit of normal, and INR ≤ 1.5) were eligible to the study. Bevacizumab (5 mg/kg) and oxaliplatin (130 mg/m2) were administered intravenously day 1 of each 21- day cycle. Capecitabine (825 mg/m2, twice a day) was administered days 1 to 14. Results: Thirty patients (male/female ratio of 23/7) have been enrolled, with a median age of 57 (range 23–85). The average number of treatment cycles was 8 (2–25 cycles). Of evaluable patients, 3 patients (11%) achieved partial response, 21 patients had stable disease (78%) with a disease control rate of 89%. The mean PFS was 5.4 months with 3- and 6- months PFS of 70%, and 40%. There were 33% Gr. 2/3 oxaliplatin-related peripheral neuropathy and 11 % capecitabine-related Gr. 2/3 hand- foot syndrome. One patient had gastrointestinal perforation and sepsis after his first administration of bevacizumab and oxaliplatin. Two patients had esophageal varices-related bleeding, likely disease-related. Conclusions: The results demonstrate that the combination of bevacizumab, oxaliplatin and capecitabine is effective and tolerable in treatment of advanced HCC and should be considered for the further investigation. [Table: see text]

Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Mark Andrew Dickson ◽  
William D. Tap ◽  
Mary Louise Keohan ◽  
Sandra P. D'Angelo ◽  
Mrinal M. Gounder ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Promising Result ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Eligibility Criteria ◽  
Well Differentiated ◽  
Grade 3

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.

scholarly journals Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study

2009 ◽  
Vol 27 (18) ◽  
pp. 3027-3035 ◽  
Author(s):  
Andrew X. Zhu ◽  
Dushyant V. Sahani ◽  
Dan G. Duda ◽  
Emmanuelle di Tomaso ◽  
Marek Ancukiewicz ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Sunitinib Treatment

PurposeTo assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.Patients and MethodsWe conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.ResultsThirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1α, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.ConclusionSunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

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.

DEDUCTIVE: A study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma—Phase Ib results.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 294-294
Author(s):  
Renuka V. Iyer ◽  
Daneng Li ◽  
Farshid Dayyani ◽  
Alexandria T. Phan ◽  
Michael N. Needle ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Primary Objective ◽  
Advanced Hepatocellular Carcinoma ◽  
Cross Sectional ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Improve Patient

294 Background: A recent ph3 study combining bevacizumab (VEGF-A Mab) with atezolizumab (PD-L1 inhibitor) has shown significant improvements in OS and PFS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over sorafenib. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase II 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 HCV and significant organ dysfunction. The starting dose is 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 adverse event (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 in cycle 1. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be AEs per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Seven patients were enrolled in phase I. Six were male; the median age was 75 (range 40 to 82). One patient had mild elevation of LFTs and did not complete the 21-day course of T and was replaced. No patient experienced a >=grade 3 AE in cycle 1. The most common AEs, each seen in two of seven patients, were anorexia, cough, diarrhea, dysphonia, fatigue, hypertension, and palmar-plantar erythrodysesthesia. Two of seven have achieved a partial response. Conclusions: The combination of T with D in patients with untreated advanced HCC is well tolerated. The RP2D for the combination is T 1 mg orally for 21 days on treatment followed by 7 days off treatment and D 1500 mg intravenously every 28 days. In the phase II portion of the study an additional 30 patients will be treated at the RP2D. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Clinical trial information: NCT03970616.

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