Phase Ib study of gemcitabine and oxaliplatin with erlotinib in patients with advanced biliary tract cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14503-e14503 ◽  
Author(s):  
Kristen Keon Ciombor ◽  
Dana Backlund Cardin ◽  
Emily Chan ◽  
Pamela McClanahan ◽  
Kang-Hsien Fan ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ib ◽  
Tract Cancer ◽  
Disease Stabilization

e14503 Background: Gemcitabine (GEM) with a platinum agent such as oxaliplatin (OX) is standard therapy for advanced biliary tract cancers (ABTC). The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has also shown modest benefit in ABTC. Erlotinib (E) induces G1/S cell cycle arrest and may exhibit sequence-specific synergy with GEM. Given continuously, it may antagonize the action of chemotherapy against cycling tumor cells but intermittent pulsatile dosing of EGFR TKIs in combination with chemotherapy may lead to maximum efficacy. The purpose of this study is to assess the tolerability of E when pulsed with GEM and OX (GEMOX). Methods: This investigator initiated, single institution phase Ib study (NCT00987766) used a standard 3+3 dose-escalation model in patients with ABTC, pancreas cancer or duodenal cancer. The primary endpoint was to evaluate the maximum tolerated dose (MTD) of pulsatile E in combination with GEMOX. Patients received escalating doses of E starting at 50 mg daily (given on D3-8) with GEM on D1 (dose rate 10 mg/m2/min) and OX on D2 every two weeks. Dose-limiting toxicity was defined as any treatment-related, first course (28 days) non-hematologic ≥Gr3 toxicity, except nausea/vomiting or Gr4 hematologic toxicity. Results: Nineteen patients have been enrolled and 4 dose levels have been explored. Two of two patients experienced DLT [Gr3 diarrhea (n=1), Gr4 anemia (n=1)] at a dose of 150 mg E + 1000 mg/m2 GEM + 85 mg/m2 OX, exceeding the MTD. Most frequent toxicities were nausea (68%), neuropathy (68%), fatigue (63%) diarrhea (52%) and rash (52%), most Gr1 or 2. Disease stabilization occurred in 12/17 (71%) evaluable patients (5/9 ABTC, 7/8 pancreas), and partial responses were seen in 4/17 evaluable patients (24%), all with ABTC (4/9). The rate of progression-free survival at 6 months was 75% in ABTC. Conclusions: The MTD and recommended phase 2 dose of E in combination with GEMOX was E 150 mg given on days 3-8 with GEM 800 mg/m2 and OX 85 mg/m2 in this population. Clinical activity of this combination was seen in the majority of patients. An expansion cohort of an additional ten patients with ABTC at the MTD is ongoing, and correlative studies on available tissue will be performed.

Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15569-e15569
Author(s):  
Sarbajit Mukherjee ◽  
Christos Fountzilas ◽  
Patrick McKay Boland ◽  
Kristopher Attwood ◽  
Wei Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Free Survival

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

A multicenter, phase Ib/2 study of varlitinib plus gemcitabine and cisplatin (gem/cis) for treatment of naïve, advanced, or metastatic biliary tract cancer (BTC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 319-319
Author(s):  
Do-Youn Oh ◽  
Wei-Peng Yong ◽  
Li-Tzong Chen ◽  
Ji-Won Kim ◽  
Alex Yuang-Chi Chang ◽  
...  
Keyword(s):  
Safety Profile ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Her Family ◽  
Tract Cancer ◽  
First Line Therapy ◽  
Combination Methods ◽  
Response To Chemotherapy ◽  
Grade 3

319 Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.

scholarly journals Feasibility of HER2-Targeted Therapy in Advanced Biliary Tract Cancer: A Prospective Pilot Study of Trastuzumab Biosimilar in Combination with Gemcitabine Plus Cisplatin

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 161
Author(s):  
Hyehyun Jeong ◽  
Jae Ho Jeong ◽  
Kyu-Pyo Kim ◽  
Sang Soo Lee ◽  
Dong Wook Oh ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Primary Tumour ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Tract Cancer ◽  
Common Grade ◽  
Grade 3

The prognosis of advanced biliary tract cancer (BTC) is poor with the standard gemcitabine and cisplatin (GemCis) regimen. Given that the rates of human epidermal growth factor receptor 2 (HER2) positivity in BTC reaches around 15%, HER2-targeted therapy needs further investigation. This study aims to evaluate the preliminary efficacy/safety of first-line trastuzumab-pkrb plus GemCis in patients with advanced BTC. Patients with unresectable/metastatic HER2-positive BTC received trastuzumab-pkrb (on day 1 of each cycle, 8 mg/kg for the first cycle and 6 mg/kg for subsequent cycles), gemcitabine (1000 mg/m2 on day 1 and 8) and cisplatin (25 mg/m2 on day 1 and 8) every 3 weeks. Of the 41 patients screened, 7 had HER2-positive tumours and 4 were enrolled. The median age was 72.5 years (one male). Primary tumour locations included extrahepatic (N = 2) and intrahepatic (N = 1) bile ducts, and gallbladder (N = 1). Best overall response was a partial response in two patients and stable disease in two patients. Median progression-free survival (PFS) was 6.1 months and median overall survival (OS) was not reached. The most common grade 3 adverse event was neutropenia (75%), but febrile neutropenia did not occur. No patient discontinued treatment due to adverse events. Trastuzumab-pkrb with GemCis showed promising preliminary feasibility in patients with HER2-positive advanced BTC.

A phase Ib, open-label, dose-escalation study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 549-549 ◽  
Author(s):  
F. Eskens ◽  
C. N. Oldenhuis ◽  
P. Bhargava ◽  
W. Loos ◽  
B. Esteves ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Embolism And Thrombosis ◽  
Grade 3

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4117-4117 ◽  
Author(s):  
Joon Oh Park ◽  
Yin-Hsun Feng ◽  
Yen-Yang Chen ◽  
Wu-Chou Su ◽  
Do-Youn Oh ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Treatment Options ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Median Number ◽  
Clinical Activity ◽  
Open Label ◽  
Orally Bioavailable ◽  
Tumor Types

4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.

Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L)

2019 ◽  
Vol 49 (10) ◽  
pp. 947-955
Author(s):  
Tatsuo Kimura ◽  
Tomoya Kawaguchi ◽  
Yasutaka Chiba ◽  
Hiroshige Yoshioka ◽  
Katsuya Watanabe ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Sequential Administration ◽  
Grade 3

Abstract Background Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy. Methods This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2–16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients. Results In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2–32.1%) and 53.7% (95%CI: 37.4–69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1–4.5) and 11.3 (95%CI: 8.6–16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3–4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection. Conclusions Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.

scholarly journals A Pilot Study of Ponatinib in Patients With FGFR-Altered Advanced Cholangiocarcinoma

2021 ◽  
Author(s):  
Daniel H. Ahn ◽  
Pedro Luiz Serrano Uson Junior ◽  
Peter Masci ◽  
Heidi Kosiorek ◽  
Thorvardur R. Halfdanarson ◽  
...  
Keyword(s):  
Pilot Study ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Clinical Work ◽  
Clinical Activity ◽  
Related Quality ◽  
Prospective Assessment

Abstract Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Efficacy and safety of nivolumab in first-line or further treatment of advanced metastatic biliary tract cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 315-315
Author(s):  
Miaomiao Gou ◽  
Yong Zhang ◽  
Haiyan Si ◽  
Guanghai Dai
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Univariate Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Peripheral Neurotoxicity ◽  
Tract Cancer

315 Background: PD-1 inhibitors have improved efficacy in many cancers. There are few report of nivolumab for metastatic biliary tract cancer (MBTC). This study reviewed the efficacy and safety of nivolumab for MBTC to improve efficacy and survival. Methods: Thirty patients with MBTC were voluntarily treated with non-clinical nivolumab at the PLA General Hospital. Nivolumab 200 mg or 180 mg was administered according to patient tolerance. Progression free survival (PFS), overall survival (OS) was evaluated by kaplan-meier and univariate analysis were carried out among clinical characteristics. Objective response rates (ORR), disease control rates (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is 4 cycles. One case was complete response (CR), 5 cases partial response (PR), 12 cases stable (SD). ORR was 20%, DCR was 60%. PFS was 3.1m (95% CI: 2.13~4.06 months). The AEs of nivolumab monothrapy were fatigue (3 cases), fever (2 cases), hypothyroidism (1 case), skin reaction (1 case). Nivolumab combined with chemotherapy related 1-2 hematologic toxicity were leukopenia (5 cases), thrombocytopenia (2 cases), and grade 3-4 were leukopenia (3 cases). Non-hematologic toxicity grade 1-2 were nausea and vomiting (4 cases), fatigue (4 cases), fever (3 cases), peripheral neurotoxicity (3 cases), and hypothyroidism (1 case). Univariate analysis showed that PFS was 4.20m in patients older than 53 years, slightly higher than those younger than 53 years (3.0 m, P = 0.047). PFS of nivolumab combined with chemotherapy was statistically significant compared with nivolumab monothrapy (4.1 m vs 2.3 m, p = 0.031). Patients with metastatic number > 2 had a shorter PFS than those < 2 (1.4 m vs 4.1 m, P = 0.05). PD-L1 expression positive have no better PFS compared with PD-L1 negative (3.6 m vs 3.1 m , p = 0.801). Multivariate analysis show nivolumab combined with chemotherapy was only independent factor for longer PFS (HR: 0.432, P < 0.05). Conclusions: the safety of nivolumab in MBTC is controllable. Subgroup analysis suggests that further selection of superior populations is needed and sample size need to be expanded to improve the efficacy of nivolumab in MBTC.

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

Sign in / Sign up

Export Citation Format

Share Document