A randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced mucosal melanoma (NCT02023710).

9521 Background: Mucosal melanoma is rare and associated with extremely poor prognosis. There was no standard treatment for advanced mucosal melanoma patients. BEAM study had demonstrated the effectivity and safety of bevacizumab combined with carboplatin plus paclitaxel in patients with previously untreated metastatic melanoma. This study was to evaluate the activity of bevacizumab combined with carboplatin plus paclitaxel in Patients with Previously Untreated Advanced Mucosal Melanoma. Methods: This study is an open-label, multicenter, randomized phase II trial. Eligible patients had metastatic, recurrent, or unresectable mucosal melanoma and no received any systemic therapy before enrollment. Patients were randomly allocated in a 2:1 ratio to receive bevacizumab (CPB arm, 5mg/kg every two weeks) or placebo (CP arm) with carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2). Treatment was continued for both groups until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary study endpoint is progress-free survival (PFS). Overall survival, disease control rate, and safety will also be assessed. Results: The first patient visit was December 1st, 2013, and the final data cutoff was August 30th, 2018. At that time, 114 patients were randomly assigned to receive CP or CPB therapy. Median PFS was 3.2 months for the CP arm and 4.7 months for the CPB arm (HR, 0.50; 95% CI, 0.33-0.72; P = 0.001). Median OS was 9.0 months in the CP arm versus 12.9 months in the CPB arm (HR, 0.61; 95% CI, 0.40-0.92; P = 0.02). The PFS was longer in the CPB arm in the subgroups of patients with neutrophil-to-lymphocyte ratio (NLR) more than 4 and patients with abnormal lactate dehydrogenase concentration (1.2 v 3.0 months, HR, 0.38; 2.0 v 4.7 months, HR, 0.39, respectively). Multivariate analysis using the Cox model showed that combination with bevacizumab was the predictor for better disease control and survival (PFS: HR 0.400, 95% CI 0.251-0.636, P < 0.001; OS: HR 0.505, 95% CI 0.313-0.814, P = 0.005). No new safety signals were observed. Conclusions: To our knowledge this is the largest study about advanced mucosal melanoma. This study demonstrated that bevacizumab in combination with carboplatin plus paclitaxel is active and safe regimen as first line treatment in patients with in advanced mucosal melanoma. A phase III study will be necessary to confirm the benefit, especially in some special setting such as elevated NLR and elevated LDH subgroups. Clinical trial information: NCT02023710.

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Phase II study of sunitinib administered in a continuous daily dosing regimen in patients (pts) with advanced GIST

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9532 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9532-9532 ◽

Cited By ~ 7

Author(s):

S. George ◽

P. G. Casali ◽

J. Blay ◽

A. Le Cesne ◽

A. R. Tyler ◽

...

Keyword(s):

Phase Ii ◽

Clinical Benefit ◽

Kinase Inhibitor ◽

Continuous Treatment ◽

Study Endpoint ◽

Primary Study ◽

Open Label ◽

Early Results ◽

Imatinib Resistant ◽

Grade 3

9532 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities due to inhibition of KIT, VEGFRs, PDGFRs, RET, and FLT3. In previous phase I/II and III trials in pts with imatinib-resistant GIST, sunitinib demonstrated efficacy and favorable clinical tolerability when administered in 6-week treatment cycles consisting of 4 weeks sunitinib (50 mg QD), followed by 2 weeks off treatment. The current study examined continuous sunitinib dosing as a way to avoid potential reactivation of tumor cells during the off-treatment period. Methods: This open-label, multicenter, phase II trial was designed to evaluate the efficacy, safety, and tolerability of sunitinib administered once daily using a continuous-treatment regimen in pts with imatinib-resistant GIST. Treatment is initiated with 37.5 mg sunitinib daily, with the option to titrate dosing on an individual basis depending on tolerability. The primary study endpoint is clinical benefit rate, defined as percent of evaluable pts with confirmed CR, PR, or SD ≥24 weeks using RECIST. Secondary endpoints included ORR, TTP, PFS, OS, and safety/tolerability measures. Results: Of 28 pts who had started treatment at the time of this analysis, early results were available for 17 pts from two centers. The most commonly occurring treatment-related adverse events were stomatitis, hand-foot syndrome, gastroesophageal reflex, and fatigue, which were generally grade 1. Two pts experienced treatment-related grade 3 hypertension, and another exhibited grade 3 asymptomatic neutropenia. Five pts have been evaluated for benefit after 8 weeks of treatment. Stable disease (which is the clinical benefit typically observed in GIST pts treated with sunitinib) was demonstrated in all five pts. Expanded safety/tolerability and efficacy results will be available for presentation. Conclusions: Continuous dosing of sunitinib is feasible and appears to be associated with acceptable tolerability in pts with imatinib-refractory GIST, similar to the extensive experience documented with intermittent sunitinib dosing. It is possible that continuous daily dosing of sunitinib may further improve the outcomes of pts with GIST. [Table: see text]

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A randomized phase II/III study of naptumomab estafenatox plus IFN-α versus IFN-α in advanced renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3073 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3073-3073 ◽

Cited By ~ 2

Author(s):

Robert E. Hawkins ◽

Martin Eric Gore ◽

Yaroslav Shparyk ◽

Vladimir Bondar ◽

Oleg Gladkov ◽

...

Keyword(s):

Clin Oncol ◽

Phase Ii ◽

Primary Endpoint ◽

Phase 1 ◽

Risk Scores ◽

Open Label ◽

Randomized Phase Ii ◽

Secondary Endpoints ◽

To Receive

3073 Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap + IFN-α (A) vs IFN-α (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (<7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-α improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. [Table: see text]

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Bortezomib(Velcade®)-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation

Blood ◽

10.1182/blood.v116.21.3043.3043 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3043-3043

Author(s):

Laurent Garderet ◽

Simona Iacobelli ◽

Philippe Moreau ◽

Mamoun Dib ◽

Denis Caillot ◽

...

Keyword(s):

Cumulative Incidence ◽

Cox Model ◽

Autologous Transplantation ◽

Rest Period ◽

Phase Iii ◽

Rank Test ◽

Primary Study ◽

Log Rank Test ◽

One Year ◽

To Receive

Abstract Abstract 3043 Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29–76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

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Phase II trial of erlotinib in advanced pancreatic cancer (PC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4609 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4609-4609

Author(s):

P. Tang ◽

S. Gill ◽

H. J. Au ◽

E. X. Chen ◽

D. Hedley ◽

...

Keyword(s):

Disease Control ◽

Phase Ii ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Phase Ii Trial ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Study Endpoint ◽

Primary Study ◽

Kras Mutations

4609 Background: The epidermal growth factor receptor (EGFR) is a potentially important target in PC. Benefit from erlotinib (Tarceva), an oral EGFR tyrosine kinase inhibitor has been associated with the presence of a skin rash. The purpose of this study was to determine the efficacy of erlotinib, dosed to achieve a rash, in patients (pts) with PC. Methods: Erlotinib was given at an initial dose of 150 mg/day to eligible pts with locally advanced (LA) or metastatic PC who had progressed or were unable to tolerate gemcitabine-based chemotherapy. The dose of erlotinib was increased by 50mg every 2 weeks (maximum 300 mg/day) until > grade 1 rash (CTCAE v 3.0) or other dose-limiting toxicities occurred. Erlotinib pharmacokinetic (PK) studies were performed. Baseline tumor tissue was collected for analysis of Kras mutations, EGFR by IHC and FISH. The primary endpoint of this two- stage phase II trial was prolonged disease control (PR + SD > 8 wks) with a rate of >20% assumed to be significant . Results: Fifty pts were accrued (median age 61, M:F = 25:25, ECOG 0:1:2 = 5:41:4, LA:Metastatic = 5:45, prior gemcitabine none:adjuvant:palliative = 2:16:35). 47 and 40 pts were evaluable for toxicity and response, respectively. Dose-escalation to 200–300 mg of erlotinib was possible in 9 pts. Most common treatment adverse events (TAEs) of any grade were: rash (35 pts, 74.5%), diarrhea (18 pts, 38.3 %), and fatigue (8 pts, 17%). Grade 3+ TAEs were rash in 2 pts and diarrhea in 2 pts. Best response was SD in 14 pts, 0.35 (95% CI: 0.2–0.5). Prolonged disease control (SD > 8 wks) was observed in 10/40 evaluable pts, 0.25 (95% CI: 0.12–0.38), which met the primary study endpoint. Median TTP was 1.6 mo (95% CI:1.6–2.1), mOS 4.1 mo (95% CI:3.2–7.3), and 6 mo OS rate was 39% (95%CI: 24–61%). PK and correlative data are being analyzed and will be presented. Conclusions: Erlotinib is associated with prolonged stable disease in a subset of pts with advanced refractory PC. Dose escalation in the absence of toxicity is feasible and safe. [Table: see text]

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Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of Gruppo Italiano Mammella (GIM).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.504 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 504-504 ◽

Cited By ~ 3

Author(s):

Lucia Del Mastro ◽

Mauro Mansutti ◽

Giancarlo Bisagni ◽

Riccardo Ponzone ◽

Antonio Durando ◽

...

Keyword(s):

Clinical Trial ◽

Adjuvant Therapy ◽

Endocrine Therapy ◽

Cox Model ◽

Disease Free Survival ◽

Nodal Status ◽

Phase Iii ◽

Primary Study ◽

Fisher Exact Test ◽

To Receive

504 Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.

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Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.20.00902 ◽

2021 ◽

pp. JCO.20.00902 ◽

Cited By ~ 2

Author(s):

Xieqiao Yan ◽

Xinan Sheng ◽

Zhihong Chi ◽

Lu Si ◽

Chuanliang Cui ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Objective Response ◽

Area Under The Curve ◽

Progression Free Survival ◽

Mucosal Melanoma ◽

Hazard Ratio ◽

Phase Iii ◽

Open Label ◽

Open Label Phase

PURPOSE Mucosal melanoma (MM) is a highly vascularized tumor with an extremely poor prognosis. In this randomized, open-label, phase II study, we characterized the efficacy and safety of bevacizumab in combination with carboplatin plus paclitaxel (CPB) in patients with previously untreated advanced MM. PATIENTS AND METHODS Patients were randomly assigned in a 2:1 ratio to receive carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2) once every 4 weeks in combination with (CPB arm, 5 mg/kg) or without (CP arm) bevacizumab once every 2 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS), objective response rate, and adverse events. RESULTS We recruited 114 patients to our study. The median PFS was significantly longer in the CPB arm (4.8 months; 95% CI, 3.6 to 6.0 months) than in the CP arm (3.0 months; 95% CI, 1.7 to 4.3 months) (hazard ratio, 0.461; 95% CI, 0.306 to 0.695; P < .001). Objective response rates were 19.7% and 13.2%, respectively ( P = .384). The median OS was also significantly longer in the CPB arm than in the CP arm (13.6 v 9.0 months; hazard ratio, 0.611; 95% CI, 0.407 to 0.917; P = .017). No new safety signals were observed. CONCLUSION PFS and OS were significantly better in patients with metastatic MM who received bevacizumab in addition to CPB than in those who received CPB alone. A phase III study should be performed to confirm these benefits (ClinicalTrials.gov identifier: NCT02023710 ).

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Pooled safety results from SPIRITT: A multicenter, open-label, randomized, phase II study of FOLFIRI with panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.477 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 477-477 ◽

Cited By ~ 1

Author(s):

J. R. Hecht ◽

S. R. Dakhil ◽

M. N. Saleh ◽

B. Piperdi ◽

M. Cline-Burkhardt ◽

...

Keyword(s):

Disease Progression ◽

Phase Ii ◽

Human Monoclonal Antibody ◽

Objective Response ◽

Phase Iii ◽

Second Line ◽

First Line ◽

Open Label ◽

Randomized Phase Ii ◽

Patient Reported

477 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR) approved as monotherapy in pts with chemorefractory mCRC. Many pts with mCRC who have progressed on a bev-containing regimen receive second-line bev + chemotherapy despite the lack of prospective, randomized data supporting this approach. A phase III study recently showed that pmab + second-line FOLFIRI improved progression-free survival (PFS) in pts with wild-type (WT) KRAS tumors vs chemotherapy alone. This study was amended after enrollment began to focus hypothesis testing on the WT KRAS population and is evaluating the safety and efficacy of pmab + FOLFIRI vs bev + FOLFIRI in pts who received first-line therapy with an oxaliplatin-based regimen + bev. Methods: This is a randomized, phase II, open-label study in pts with mCRC with disease progression or intolerability after ≥ 4 doses of first-line oxaliplatin-based chemotherapy + bev. Pts are randomized 1:1 to receive either 6 mg/kg pmab Q2W + FOLFIRI or bev (given at institutional standard dose Q2W) + FOLFIRI. Tx is administered until disease progression (PD), death, or withdrawal from study. The primary endpoint is PFS in patients with WT KRAS tumors. Other endpoints include objective response rate, overall survival, safety, and patient-reported outcomes. Results: At the time of data cutoff, 216 of 277 planned pts were enrolled. 175 (81%) pts discontinued study tx and 39 (18%) pts remain on tx. Any grade adverse events (AEs) were reported in 197 (92%) pts. 38 (18%) pts had AEs that led to withdrawal from tx or study. Serious AEs were reported in 66 (31%) pts and included gastrointestinal disorders (13%), infections and infestations (8%), respiratory disorders (7%), and metabolism and nutrition disorders (7%). Fatal AEs were reported in 18 (8%) pts of which 9 (4%) were related to disease progression. Conclusions: The aggregate safety profile is consistent with expected toxicities of FOLFIRI in combination with an anti-EGFR or an anti-VEGF targeted therapy in second-line mCRC. Detailed pooled safety results will be presented at the meeting. [Table: see text]

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Open-label, phase I/randomized, phase II trial of the triple angiokinase inhibitor, nintedanib, versus sorafenib in previously untreated patients with advanced hepatocellular carcinoma (HCC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps4160 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS4160-TPS4160

Author(s):

Daniel H. Palmer ◽

Markus Peck-Radosavljevic ◽

Yuk Ting Ma ◽

Janet Graham ◽

Laetitia Fartoux ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Local Therapy ◽

Phase Iii ◽

Hematologic Toxicity ◽

Advanced Hepatocellular Carcinoma ◽

Open Label ◽

Advanced Hcc ◽

Randomized Phase Ii ◽

Open Label Phase

TPS4160 Background: While sorafenib is established as the standard first-line treatment for patients with advanced HCC, its use can be complicated by the occurrence of drug-related adverse events (AEs). Nintedanib, a potent, oral triple angiokinase inhibitor that targets VEGF, PDGF and FGF signaling (as well as Flt3 and RET), has demonstrated clinical activity in various advanced solid tumors with a relatively low incidence of AEs typically associated with angiogenesis inhibitors (e.g. skin toxicity, hypertension, hemorrhage, and hematologic toxicity) and is currently in phase III for non-small cell lung cancer and ovarian cancer. In the Phase I, dose-finding stage of this ongoing, multicenter, open-label Phase I/II trial (NCT01004003), 200mg twice daily (bid) was established as the maximum tolerated dose of nintedanib in previously untreated patients with advanced HCC (Palmer D, et al. Ann Oncol 2012;23(Suppl 9):ix245[Abs 740P]). Nintedanib had an acceptable liver AE profile; the most common AEs were mild/moderate gastrointestinal toxicities. Methods: The randomized Phase II stage of the trial aims to assess the efficacy, safety, and pharmacokinetics of nintedanib in comparison with sorafenib. Eligible patients have pathologically confirmed, measurable HCC that is not amenable to local therapy, ECOG Performance Status of ≤2, Child-Pugh score of 5–6 (Class A), AST/ALT levels ≤2× upper limit of normal, and no prior systemic therapy. Patients are being stratified by macrovascular invasion and/or extrahepatic spread and then randomized 2:1 to receive nintedanib 200mg bid or sorafenib 400mg bid in continuous 28-day cycles until progression or unacceptable toxicity. Overall, 93 patients were randomized between Sept 2011 and Nov 2012. The primary endpoint is time to progression (TTP) by independent review, according to RECIST 1.0. TTP will be estimated in the treated set by Kaplan–Meier methodology with treatment effects compared using a Cox proportional hazards model. Secondary endpoints include overall survival, tumor response, progression-free survival, safety and pharmacokinetics. Results are due late 2013. Clinical trial information: NCT01004003.

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