Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Trifluridine/Tipiracil (TAS-102) Monotherapy in Asian Patients With Previously Treated Metastatic Colorectal Cancer: The TERRA Study

2018 ◽  
Vol 36 (4) ◽  
pp. 350-358 ◽  
Author(s):  
Jianming Xu ◽  
Tae Won Kim ◽  
Lin Shen ◽  
Virote Sriuranpong ◽  
Hongming Pan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Biologic Therapy ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Double Blind Placebo ◽  
Asian Patients ◽  
To Receive

Purpose Trifluridine/tipiracil (TAS-102) was effective in patients with metastatic colorectal cancer (mCRC) in a phase II Japanese trial. This regional trial evaluated the efficacy and safety of trifluridine/tipiracil in Asian patients with mCRC with or without exposure to biologic therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase III trial was conducted at 30 sites in China, the Republic of Korea, and Thailand. Patients ≥ 18 years old with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and known KRAS status who were refractory or intolerant to two or more prior chemotherapy regimens were enrolled. Eligible patients were randomly assigned (2:1 ratio; minimization method) to receive trifluridine/tipiracil (twice per day orally; 5 days on and 2 days off for 2 weeks, followed by 14 days off per cycle) or placebo. The primary end point was overall survival (intent-to-treat population). Results Between October 16, 2013, and June 15, 2015, 406 patients were randomly assigned to receive trifluridine/tipiracil (n = 271) or placebo (n = 135). Risk of death was significantly lower in the trifluridine/tipiracil arm than in the placebo arm (hazard ratio for death, 0.79; 95% CI, 0.62 to 0.99; log-rank P = .035). Median overall survival was significantly longer in the trifluridine/tipiracil than in the placebo arm (7.8 months [95% CI, 7.1 to 8.8 months] v 7.1 months [95% CI, 5.9 to 8.2 months], respectively), for a median survival follow-up time of 13.8 months (95% CI, 13.1 to 15.3 months) compared with 13.4 months (95% CI, 11.6 to 17.3 months), respectively. The incidence of serious adverse events was similar between the arms (trifluridine/tipiracil, n = 63 [23.2%]; placebo, n = 32 [23.7%]). No treatment-related deaths were reported. Conclusion Trifluridine/tipiracil has a statistically significant survival benefit compared with placebo in Asian patients with mCRC refractory or intolerant to standard chemotherapies, regardless of exposure to biologic therapy. The safety profile is similar to previous reports.

Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA3501-LBA3501 ◽  
Author(s):  
Johanna C. Bendell ◽  
Thomas J. Ervin ◽  
Neil N. Senzer ◽  
Donald A. Richards ◽  
Irfan Firdaus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Phase Ii ◽  
Phase Iii Study

LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3508-3508 ◽  
Author(s):  
Jin Li ◽  
Shukui Qin ◽  
Yuxian Bai ◽  
Yanhong Deng ◽  
Lei Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Group Versus ◽  
Phase Iii ◽  
Chinese Patients ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Third Line

3508 Background: Treatment options for third-line metastatic colorectal cancer (mCRC) patients remain limited in China. Fruquintinib, an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, in a phase II study was found to significantly improve progression free survival (“PFS”) in patients with mCRC as compared to placebo (ESMO abs#2111). Based on these results, a Phase III registration trial, FRESCO, was carried out to confirm fruquintinib’s efficacy and safety in third-line mCRC patients (clinicaltrials.gov # NCT02314819). Methods: This is a randomized, double-blind, placebo-controlled, multi-center phase III trial. Patients with mCRC who have failed at least 2 lines of systemic chemotherapy were enrolled from 28 centers in China. Patients were stratified based on prior anti-VEGF therapy and K-ras status and randomized to a fruquintinib or placebo arm in a 2:1 ratio. The primary endpoint was overall survival (“OS”) which was analyzed in the intent-to-treat population. Results: Between December 12, 2014 and May 13, 2016, 416 patients were randomized. Protocol predefined number of OS events for final analysis was reached on January 17, 2017. Fruquintinib significantly improved OS comparing to placebo with a hazard ratio of 0.65 (95% CI: 0.51-0.83; two sided p<0.001). Median OS was 9.30 months [95% CI 8.18-10.45] in the fruquintinib group versus 6.57 months [95% CI 5.88-8.11] in the placebo group. Statistically significant benefits were also seen with fruquintinib in all secondary endpoints, such as PFS, objective response rate and disease control rate. The most frequent fruquintinib-related ≥ Grade 3 treatment emerged adverse events included hypertension (21.6%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (3.2%). Conclusion: In this phase III confirmatory trial, fruquintinib demonstrated a statistically significant and clinically meaningful OS benefit as compared with placebo in mCRC patients in China. Fruquintinib was well tolerated with a safety profile that is consistent with what was reported previously. Clinical trial information: NCT02314819.

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