KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4018-4018 ◽  
Author(s):  
Li-Tzong Chen ◽  
Jen-Shi Chen ◽  
Yee Chao ◽  
Chang-Sung Tsai ◽  
Yan-Shen Shan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Mutation Status ◽  
Randomized Phase Ii ◽  
Ecog Ps ◽  
The Impact ◽  
Kras Mutation Status

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

Impact of ROS1, ALK, and/or MET expression level on the therapeutic efficacy of GEMOX with and without cetuximab in ABTC: A post hoc analysis of a randomized phase II trial.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 267-267
Author(s):  
Nai-Jung Chiang ◽  
Chiun Hsu ◽  
Jen-Shi Chen ◽  
Hiso-Hui Tsou ◽  
Yee Chao ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Therapeutic Efficacy ◽  
Phase Ii Trial ◽  
Mutation Status ◽  
Randomized Phase Ii ◽  
Prior Surgery ◽  
Post Hoc ◽  
The Impact ◽  
Kras Mutation Status

267 Background: Our randomized phase II trial showed adding cetuximab to GEMOX marginally improved the ORR and median PFS in ABTC patients regardless their KRAS mutation status. Recently, MET overexpression was noted in 11.7% to 16.2% of BTC, and associated with poor OS. ROS1 kinase fusion has also been detected in 8.6% of IHCC.The aim of the study is to evaluate the impact of ROS1, ALK and/or MET (RAM) overexpression on the clinical outcomes of ABTC patients. Methods: FFPE tissue sections that were prospectively collected for biomarker study from all 122 patients were subjected for determining the expression of ROS1, ALK and MET by IHC in a central laboratory. Results: Of 110 patients with enough tissue section for IHC of all three markers, 18 tumors were found to over-express ROS1 (in 9), ALK (in 5) and/or MET (in 6). One tumor over-expressed all three biomarkers. As compared with RAMlow tumors, the 18 RAMhigh tumors were significantly more of IHCC and without prior surgery, and with more frequent concurrent KRAS mutation. RAMhigh tumors was associated with significant inferior median OS than RAMlow tumors, 5.7 vs 11.8 months (p=0.04). Of the latter 92 patients, adding cetuximab improved the therapeutic efficacy of GEMOX in ABTC, with ORR of 31.8% vs 10.4% (p=0.02), DCR of 61.4% vs 37.5% (p=0.04) and median PFS of 7.0 vs 4.5 months (p=0.02). OS was only marginally affected, with median OS of 12.5 vs 10.4 months (p=0.36). The ORR in KRASwt and KRASmut patients receiving C-GEMOX and GEMOX was 34.5% vs 11.8% (p=0.04) and 26.7% vs 7.1% (p=0.33), respectively; whiles the DCR was 65.5% vs 50.0% (p=0.31) and 53.3% vs 7.1% (p=0.01), respectively, and the median PFS was 7.1 vs 5.8 months (p=0.07) and 7.0 vs 1.9 months (p=0.05), respectively. The results suggest that, the presence of KRAS mutation did not preclude the benefit of adding cetuximab to GEMOX in RAMlowsubpopulation. Conclusions: ROS1/ALK/METhigh ABTC had poor survival after C-GEMOX/GEMOX; while C-GEMOX significantly improved the ORR, DCR and PFS as compared to GEMOX alone in patients with ROS1/ALK/METlow tumors regardless their KRAS mutation status. Biomarker-driven design is warranted for future ABTC trials.

ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS7615-TPS7615 ◽  
Author(s):  
Michael J. Boyer ◽  
Pasi A. Janne ◽  
Tony Mok ◽  
Kenneth John O'Byrne ◽  
Luis G. Paz-Ares ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Objective Response ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Mutation Status ◽  
Log Rank Test ◽  
Ecog Ps ◽  
Kras Mutation Status

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.

RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 489-489 ◽  
Author(s):  
Francesco Sclafani ◽  
David Gonzalez ◽  
David Cunningham ◽  
Sanna Hullki Wilson ◽  
Clare Peckitt ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Ras Mutations ◽  
Randomized Phase Ii ◽  
Exon 4 ◽  
The Impact ◽  
Kras Exon

489 Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.

Updated results of a randomized phase II trial for neoadjuvant versus adjuvant docetaxel/cisplatin chemotherapy in patients with locally advanced gastric cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 111-111
Author(s):  
Young Woo Kim ◽  
Keun Won Ryu ◽  
Il Ju Choi ◽  
Myeong-Cherl Kook ◽  
Young Iee Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Cancer Center ◽  
Locally Advanced Gastric Cancer ◽  
Randomized Phase Ii

111 Background: Recent phase III trials proved the role of adjuvant chemotherapy in patients with gastric cancer after D2 resection, but the optimal treatment sequence remains to be determined. Here we report long-term follow up results for the randomized phase II trial comparing between neoadjuvant and adjuvant docetaxel/cisplatin (DC) chemotherapy in patients with locally advanced gastric cancer (LAGC). Methods: Patients with LAGC (stage IIIA-IV) were stratified by Japanese staging system and randomized to either neoadjuvant or adjuvant weekly DC chemotherapy in the National Cancer Center of Korea from 2003 to 2005. FDG-PET/CT screening was employed to exclude patients with metastasis. Patients randomized to neoadjuvant arm received 3 cycles of DC regimen (docetaxel 36 mg/m2 and cisplatin 40 mg/m2 on days 1 and 8 every 3 weeks), followed by surgery (D2 dissection). In adjuvant arm, patients underwent surgery, followed by 3 cycles of the same DC chemotherapy regimen. Results: Neoadjuvant arm (n=43) demonstrated higher R0 resection rate than adjuvant arm (n=44) [81% v 73%], but the difference was not statistically significant. At a median follow-up for suriving patients of 7.2 years, there were no significant differences in OS and PFS between the two arms [Log rank P=0.93 and P=0.89, respectively]. Conclusions: The timing of perioperative DC chemotherapy does not affect the overall survival of patients with LAGC.

The impact of cetuximab on the gemcitabine/cisplatin combination in first-line treatment of EGFR-positive advanced pancreatic cancer (APC): A randomized phase II trial of GISCAD

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4544-4544 ◽  
Author(s):  
S. Cascinu ◽  
R. Berardi ◽  
S. Siena ◽  
R. Labianca ◽  
A. Falcone ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
First Response ◽  
Randomized Phase Ii ◽  
Meta Analyses ◽  
The Impact ◽  
Egfr Antibody

4544 Background: Cetuximab, an EGFR antibody inhibitor, has been shown to increase the activity of gemcitabine (GEM) in APC. Based on data from randomised trials and meta-analyses suggesting that the combination of a GEM with a platinum analog significantly improves survival as compared to GEM alone, we assessed the activity and feasibility of a combination of GEM/cisplatin (CDDP) plus cetuximab. Methods: Multicenter, randomised two-arm phase II trial: GEM 1,000 mg/m2 day 1,8 and CDDP 35 mg/m2 day 1,8 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 9 cycles. With 37 patients in each arm the power was 90% to select the truly better arm if the true between arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until June 2005. Results: We present here the results of 74 patients including in the study. In all the patients, the first response rate are available (investigators’ assessment after 3 cycles) as well as toxicity data. Conclusions: Cetuximab does not seem to positively interact with GEM/CDDP combination in terms of activity especially concerning time to progression. Although toxicity was not increased by cetuximab, this combination should not be assessed in a phase III trial.The trial was supported in part by by Merck KGaA. [Table: see text] No significant financial relationships to disclose.

Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

1988 ◽  
Vol 74 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Eduardo Cazap ◽  
Roberto Estevez ◽  
Mario Bruno ◽  
Daniel Levy ◽  
Carlos Algamiz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

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