NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or Temozolomide

2009 ◽  
Vol 27 (35) ◽  
pp. 5874-5880 ◽  
Author(s):  
Wolfgang Wick ◽  
Christian Hartmann ◽  
Corinna Engel ◽  
Mandy Stoffels ◽  
Jörg Felsberg ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Patient Characteristics ◽  
Extent Of Resection ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Intention To Treat ◽  
Anaplastic Gliomas ◽  
Mgmt Promoter

Purpose The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas. Patients and Methods Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence. Results Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O6-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm. Conclusion Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.

Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): Results of a multicenter, randomized phase III trial (the UK ABC-02 trial)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4503-4503
Author(s):  
J. W. Valle ◽  
H. S. Wasan ◽  
D. D. Palmer ◽  
D. Cunningham ◽  
D. A. Anthoney ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Performance Status ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Patient Characteristics ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Phase Iii Trial

4503 Background: There is no established standard chemotherapy for pts with inoperable ABC. We previously reported an improvement in progression-free survival (PFS) in a randomised phase II trial of 86 pts (ABC-01) using gemcitabine/cisplatin (GemCis) vs. gemcitabine (Gem) (Valle ASCO-GI 2006, abstr. 98). This study was extended into ABC-02, a phase III trial, to recruit a further 314 pts with overall survival (OS) as the primary end-point. Methods: Consenting pts with histologically/cytologically-confirmed ABC, aged ≥18 years, ECOG performance status 0 - 2, and adequate haematological, hepatic and renal function were randomised to receive either Cis (25 mg/m2) followed by Gem (1000 mg/m2 D1, 8 q21d) for 8 cycles, or Gem alone (1000 mg/m2 on D1, 8, 15 q28d) for 6 cycles, stratified by extent of disease, site of primary tumour, ECOG score and centre. The trial had an 80% power to detect an OS hazard ratio of 0.73. Results: From May 2005 to October 2008, 324 pts were randomised to ABC- 02 from 34 UK centres. We report the pre-planned combined analysis of ABC-01 and ABC-02 based on 410 pts (GemCis=206/Gem=204). Patient characteristics: median age 64 yrs (range 23–85); male (47%); metastatic disease (75%), locally advanced (25%); gallbladder (36%), bile duct (59%), ampulla (5%); and ECOG 0–1 (87%), 2 (12%). With a median follow-up of 6.1 months and 263 deaths, the median OS was greater with GemCis than Gem, 11.7 vs. 8.2 months (log rank p=0.002), with hazard ratio 0.68 (95%-CI 0.53, 0.86). The median PFS was greater with GemCis than Gem, 8.5 vs. 6.5 months (log rank p=0.003), with hazard ratio 0.70 (95%-CI 0.56, 0.88).Toxicity was similar between the arms (by week 12, 57% had a grade 3/4 toxicity in each arm), though there was a slight excess of neutropenia using GemCis. Conclusions: This is the largest ever study in ABC and demonstrates a clear survival advantage for GemCis without added clinically significant toxicity, setting a new international standard of care. No significant financial relationships to disclose.

scholarly journals Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84)

2020 ◽  
Vol 38 (29) ◽  
pp. 3377-3387
Author(s):  
Pieternella Johanna Lugtenburg ◽  
Peter de Nully Brown ◽  
Bronno van der Holt ◽  
Francesco A. D’Amore ◽  
Harry R. Koene ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Intention To Treat ◽  
Large B Cell Lymphoma ◽  
Large B Cell

PURPOSE Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.

scholarly journals Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39)

2021 ◽  
pp. JCO.21.00306
Author(s):  
Kathleen N. Moore ◽  
Michael Bookman ◽  
Jalid Sehouli ◽  
Austin Miller ◽  
Charles Anderson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Figo Stage ◽  
Phase Iii ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Intention To Treat ◽  
To Receive

PURPOSE To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). METHODS This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100 ) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1–positive populations. RESULTS Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1–positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). CONCLUSION Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.

Three versus four cycles of neoadjuvant gemcitabine cisplatin for muscle invasive bladder cancer (MIBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16524-e16524
Author(s):  
Catherine Kendall Major ◽  
Michael Brandon Williams ◽  
Mark T. Fleming
Keyword(s):  
Radical Cystectomy ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Patient Characteristics ◽  
Intention To Treat ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Muscle Invasive ◽  
Dose Dense

e16524 Background: The standard of care for MIBC is neoadjuvant (NAC) cisplatin-based chemotherapy with either 3-4 cycles of dose dense MVAC or 4 cycles of gemcitabine/cisplatin (GC) followed by radical cystectomy. However, due to toxicity some patients are unable to complete intention to treat full course chemotherapy. We aim to identify any variation in overall survival (OS) and progression-free survival (PFS) with 3 vs 4 cycles of neoadjuvant GC in the setting of miUCB. We hypothesize that there will be a statistically significant difference in OS and PFS with three vs four cycles of neoadjuvant GC. Methods: A consecutive retrospective chart review of patients with MIBC treated with three or four cycles of neoadjuvant cisplatin-based chemotherapy from 2009-2020 was performed. R Studio was used to generate Kaplan-Meier curves representing OS and PFS with p-values. Results: One hundred and twenty-one patients were identified. Patient characteristics are described in the table below. Eighty-six patients received 4 cycles of GC and thirty-five patients received 3 cycles. Ninety-five patients proceeded to cystectomy: 93 received a radical cystectomy, 1 received a partial cystectomy, and 1 was aborted due to positive lymph nodes. There was a statistically significant difference in OS between those who got 3 or 4 cycles (p=0.03) and PFS (p=0.014). Median OS for those who got 3 cycles and 4 cycles was 52 months and 92 months respectively. Conclusions: Toxicity can preclude patients from receiving four cycles of GC and this study demonstrates a significant difference in overall OS and PFS between those who receive 3 vs 4 cycles of GC.[Table: see text]

scholarly journals Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial

2018 ◽  
Vol 36 (30) ◽  
pp. 3031-3039 ◽  
Author(s):  
Shukui Qin ◽  
Jin Li ◽  
Liwei Wang ◽  
Jianming Xu ◽  
Ying Cheng ◽  
...  
Keyword(s):  
Survival Time ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
End Points ◽  
Phase Iii Trial ◽  
Free Survival

Purpose Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. Patients and Methods TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt ( KRAS/ NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. Results In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. Conclusion The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.

scholarly journals Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Iyad Alnahhas ◽  
Mouaz Alsawas ◽  
Appaji Rayi ◽  
Joshua D Palmer ◽  
Raju Raval ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Current Standard ◽  
Prospective Data ◽  
Free Survival ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract Background The current standard of care for the management of patients with newly diagnosed glioblastoma (GBM) includes maximal safe resection followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). While it is well established that TMZ has better efficacy in patients with MGMT promoter methylation, it remains an area of debate whether TMZ should be omitted when treating GBM patients with unmethylated MGMT. Methods We conducted a systematic review and meta-analysis to provide separate estimates of median overall survival (OS) and progression-free survival (PFS) for patients with methylated and unmethylated GBM treated with RT with or without TMZ. We searched multiple databases from inception to January 13, 2020. Results The median OS for patients with unmethylated GBM treated with RT/TMZ pooled from 5 phase III studies (N = 655) was 14.11 months (95% confidence interval [CI], 13.18–15.04) with a median PFS of 4.99 months (95% CI, 4.25–5.72). In contrast, the median OS for patients with methylated GBM pooled from 6 studies (N = 753) was 24.59 months (95% CI, 22.19–26.99) with a median PFS pooled from 7 studies (N = 805) of 9.51 months (95% CI, 7.41–11.61). There is a paucity of prospective data pertaining to OS/PFS in unmethylated patients treated with RT only and therefore a direct comparison was not possible. Conclusions This meta-analysis provides estimates of survival for patients with MGMT methylated or unmethylated GBM treated with RT/TMZ. Further research is needed to delineate whether TMZ should be withheld for patients with unmethylated GBM outside of the setting of clinical trials.

scholarly journals SS-1 Therapeutic challenges for glioblastoma: Temozolomide and its issues?

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii1-ii1
Author(s):  
Motoo Nagane
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Standard Of Care ◽  
Phase Iii ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Who Grade ◽  
Phase Iii Trial ◽  
Mgmt Gene

Abstract Glioblastoma (GBM), the most malignant form (WHO grade IV) of gliomas, remains incurable despite recent advances in medical technologies and molecular knowledge, with 5-year survival rate being just beyond 10%, thus undoubtedly leaving unmet needs to develop effective therapeutics to improve outcome. Current standard of care for patients with newly diagnosed GBM is maximum safe resection of the enhancing tumor bulk, followed by involved-field radiotherapy with temozolomide (TMZ) given concomitantly and as an adjuvant therapy thereof with or without Tumor-Treating Fields (TTF). The efficacy of TMZ for GBM was proved in 2005 by a randomized phase III trial (EORTC25981) for the first time ever in history, since then, however, any other agents have failed to show benefit to improve survival until now. O6-methylguanine-DNA methyltransferase (MGMT), a specific DNA repair enzyme, has been shown to restore the cytotoxic O6-methylguanine lesion induced by TMZ to normal, responsible for a major reason of TMZ resistance. Expression of MGMT is tightly regulated by methylation of the promoter region of the MGMT gene, where promoter methylation results in suppression of its expression. Accordingly, the promoter methylation of the MGMT gene (meth-MGMT) has been consistently associated with a better response to and outcome by TMZ treatment, and furthermore a favorable prognostic factor for patients with newly diagnosed GBM in a number of prospective clinical trials. In this line, efforts have been made to overcome TMZ resistance including intensifying dose schedulings of TMZ, one of which has been currently tested in a multi-institutional prospective phase III trial in Japan (JCOG1308C). TMZ has also been investigated in lower grade gliomas. A major issue in treating lower grade glioma with TMZ is potential development of the hypermutated tumors by virtue of O6-methylguanine-induced mutagenesis. The clinical and molecular consideration related to TMZ in glioma treatment will be presented.

Efficacy and safety findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5- FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4029-4029 ◽  
Author(s):  
M. Ducreux ◽  
J. Bennouna ◽  
M. Hebbar ◽  
M. Ychou ◽  
G. Lledo ◽  
...  
Keyword(s):  
Dose Intensity ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Comparable Efficacy ◽  
First Line ◽  
Phase Iii Trial ◽  
Intention To Treat ◽  
First Line Therapy ◽  
Best Response ◽  
Grade 3

4029 Background: X has comparable efficacy, safety and convenience benefits over 5-FU/LV (Mayo clinic) in adjuvant colon cancer and first-line MCRC. A recent phase III trial in first line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 for progression-free survival (PFS) [Cassidy ESMO 2006]. Methods: We initiated a phase III trial to demonstrate non inferiority in terms of best response rates (RR, RECIST) of XELOX versus FOLFOX-6 as first-line therapy in patients (pts) with MCRC. Between 16 May 03 and 31 Aug 04, 306 patients (intention to treat), were randomized to receive either XELOX (n=156: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Efficacy results are presented in the per protocol population (PP) (n=284:144 pts XELOX; 140 pts FOLFOX-6). Results: Baseline characteristics were well balanced. Pts received a median of 8 and 11 cycles of XELOX (range 0–8) and FOLFOX-6 (range 0–12), respectively. Dose intensity (median) for oxaliplatin was 99.6% and 95.4% with XELOX and FOLFOX-6, respectively. Best RR (independent review, PP) was 42% and 46% with XELOX and FOLFOX-6, respectively. Difference between groups for RR was 4.7%; upper limit of 95% unilateral CI (14.4%) was below non-inferiority margin of 15%. RR by investigators (PP) was 46% for each arm. With a median follow up of 16.5 months (range 0.4–38.3), median PFS and overall survival (PP) were 9.3/19.9 vs. 9.7/18.4 months with XELOX and FOLFOX-6, respectively. In the safety population (n=304), XELOX pts had more grade 3/4 hand-foot syndrome (3 vs. 0%, p=0.21), thrombocytopenia (12 vs. 5% p=0.052), and diarrhea (12% vs. 7% p=0.1), but less grade 3/4 febrile neutropenia (0 vs. 6% p=0.001), neuropathy (8 vs. 19% p=0.003), than those on FOLFOX-6. Treatment discontinuation for toxicity was 19% and 23% in XELOX and FOLFOX-6 arms, respectively. Conclusions: The primary endpoint has been met: XELOX is non inferior to FOLFOX-6, with a good safety profile in first-line MCRC. No significant financial relationships to disclose.

TACE 2: A randomized placebo-controlled, double-blinded, phase III trial evaluating sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma (HCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4150-TPS4150 ◽  
Author(s):  
Tim Meyer ◽  
Richard Fox ◽  
Deborah Bird ◽  
Anthony Watkinson ◽  
Nigel Hacking ◽  
...  
Keyword(s):  
Study Drug ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Intermediate Stage ◽  
Primary Outcome Measure ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Current Standard ◽  
Double Blind ◽  
Phase Iii Trial

TPS4150 Background: TACE is regarded as the standard of care for patients with intermediate stage HCC (BCLC B), while sorafenib (S) is the current standard for advanced disease (BCLC C). The combination of S with TACE for intermediate disease is rational since sorafenib inhibits the action of VEGF which may be induced by tumour hypoxia following TACE, and S also has direct anti-tumour effect. The combination has been shown to be safe in and active in phase I and II studies. Phase III trials are now required to determine whether TACE + S is superior to TACE alone in terms of survival. Methods: We are conducting a double blind multicentre trial to determine if the addition of S to TACE is superior to TACE alone. This is a UK NCRI trial sponsored by University College London (UCL) (EudraCT 2008-005073-36). Patients with intermediate stage HCC are randomised 1:1 to continuous S (400mg BD) or placebo (P). Key inclusion criteria include unresectable HCC confined to the liver, patent main portal vein, ECOG PS ≤1 and Child Pugh A liver score. After randomisation patients commence study drug and TACE is performed at 2-5 weeks using drug eluting beads loaded with 150mg doxorubicin (Biocompatibles UK Ltd) according to a standard protocol. Further TACE is performed at the discretion of the investigator based on radiological response and patient tolerance. The primary outcome measure is progression free survival and central, external, real time radiology review is required to confirm progression. Secondary outcome measures are overall survival, time to progression, toxicity, disease control, quality of life and number of TACE procedures performed in 12 months. The target recruitment is 412 in order to detect a hazard ratio of 0.72 using a 2-sided level of significance of α=0.05 with 85% power. The trial was reviewed by the IDMC after the presentation of the SPACE trial (Lencioni et al J Clin Oncol 30, 2012). The IDMC concurred with the conclusion of the SPACE investigators that the combination is tolerated and results required confirmation in a phase III trial. Thus recruitment into the TACE2 trial will continue as planned.

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