Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. LBA3-LBA3 ◽  
Author(s):  
Eric Van Cutsem ◽  
Kun-Huei Yeh ◽  
Yung-Jue Bang ◽  
Lin Shen ◽  
Jaffer A. Ajani ◽  
...  
Keyword(s):  
Systemic Chemotherapy ◽  
Study Drug ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Double Blind ◽  
Common Grade ◽  
Previously Treated ◽  
Grade 3

LBA3 Background: The prognosis for patients with AGC after failure of first-line chemotherapy is poor. Currently, there is no level 1 evidence established for second-line treatment. EVE inhibits the PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, metabolism, and angiogenesis, and has shown efficacy against AGC in preclinical and phase I/II studies. Methods: In a randomized, double-blind, multicenter, phase III study, patients age ≥18 years with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to oral EVE 10 mg/d plus best supportive care (BSC) or placebo (PBO) plus BSC. Randomization was stratified by region (Asia vs rest of world) and previous lines of chemotherapy (1 vs 2). Study drug was discontinued upon progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. The final analysis was performed when 526 deaths occurred. Results: A total of 656 patients from 23 countries were enrolled from Jul 2009 to Dec 2010; 439 were randomized to EVE, 217 to PBO. Baseline characteristics were well balanced between arms; 73.6% were men, 55.3% were enrolled in Asia, 47.7% received 1 previous line of chemotherapy, and 50.6% had a gastrectomy. Median OS was 5.39 months with EVE vs 4.34 months with PBO (HR, 0.90; 95% CI, 0.75-1.08; P=0.1244). Median PFS per local investigator assessment was 1.68 months with EVE vs 1.41 months with PBO (HR, 0.66; 95% CI, 0.56-0.78; p<0.0001). Six-month PFS estimates were 12.0% with EVE and 4.3% with PBO. OS and PFS results were consistent across the various subgroups. ORR (95% CI) was 4.5% (2.6%-7.1%) with EVE vs 2.1% (0.6%-5.3%) with PBO. The most common grade 3/4 adverse events were anemia (16.0% with EVE vs 12.6% with PBO), decreased appetite (11.0% vs 5.6%), and fatigue (7.8% vs 5.1%). Conclusions: EVE monotherapy did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. EVE did improve PFS. Results for OS and PFS were consistent across the various subgroups. The safety profile was consistent with that previously observed with EVE.

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 193-202 ◽  
Author(s):  
Richard S. Finn ◽  
Baek-Yeol Ryoo ◽  
Philippe Merle ◽  
Masatoshi Kudo ◽  
Mohamed Bouattour ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Interim Analysis ◽  
Statistical Significance ◽  
Study Drug ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Double Blind ◽  
Previously Treated

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA2-LBA2
Author(s):  
Rui-hua Xu ◽  
Hai-Qiang Mai ◽  
Qiu-Yan Chen ◽  
Dongping Chen ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Double Blind ◽  
Grade 3 ◽  
First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8009-8009
Author(s):  
R. B. Natale ◽  
S. Thongprasert ◽  
F. A. Greco ◽  
M. Thomas ◽  
C. M. Tsai ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Double Blind ◽  
Equivalent Efficacy ◽  
Secondary Endpoints ◽  
Previously Treated ◽  
Grade 3 ◽  
To Receive

8009 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This phase III study compared the efficacy of vandetanib vs erlotinib in patients (pts) with advanced, previously treated NSCLC. Methods: Eligible pts (stage IIIB/IV NSCLC, PS 0–2, 1–2 prior chemotherapies; all histologies permitted) were randomized 1:1 to receive vandetanib 300 mg/day or erlotinib 150 mg/day until progression/toxicity. The primary objective was to show superiority in progression-free survival (PFS) for vandetanib vs erlotinib. Secondary endpoints included overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS; EORTC QoL Questionnaire) and safety. Results: Between Oct 06-Nov 07, 1240 pts (mean age 61 yrs; 38% female; 22% squamous) were randomized to receive vandetanib (n=623) or erlotinib (n=617). Baseline characteristics were similar in both arms. Median duration of follow-up was 14 months, with 88% pts progressed and 67% dead. There was no difference in PFS for pts treated with vandetanib vs erlotinib (hazard ratio [HR] 0.98, 95.22% CI 0.87–1.10; P=0.721), and no difference in the secondary endpoints of OS (HR 1.01, 95.08% CI 0.89–1.16; P=0.830), ORR (both 12%) and TDS (pain: HR 0.92, P=0.289; dyspnea: HR 1.07, P=0.407; cough: HR 0.94, P=0.455). A preplanned non-inferiority analysis for PFS and OS demonstrated equivalent efficacy for vandetanib and erlotinib. The adverse events (AEs) observed for vandetanib were generally consistent with previous NSCLC studies with vandetanib 300 mg. There was a higher incidence of some AEs (any grade) with vandetanib vs erlotinib, including diarrhea (50% vs 38%) and hypertension (16% vs 2%); rash was more frequent with erlotinib (38% vs 28%). The overall incidence of CTCAE grade ≥3 AEs was also higher with vandetanib (50% vs 40%). The incidence of protocol-defined QTc prolongation in the vandetanib arm was 5%. Conclusions: The study did not meet its primary objective of demonstrating PFS prolongation with vandetanib vs erlotinib in pts with previously treated advanced NSCLC. However, vandetanib and erlotinib showed equivalent efficacy for PFS and OS in a preplanned non-inferiority analysis. [Table: see text]

Everolimus in metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients (pts) with one versus two prior vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapies enrolled in the phase III RECORD-1 study.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 304-304 ◽  
Author(s):  
R. A. Figlin ◽  
E. Calvo ◽  
R. J. Motzer ◽  
T. E. Hutson ◽  
S. Oudard ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Double Blind ◽  
Risk Of Disease ◽  
Previously Treated ◽  
Endothelial Growth Factor

304 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the only medication to have shown efficacy in a randomized, controlled, phase III clinical trial (RECORD-1) in pts with mRCC after progression on VEGFR-TKIs. Everolimus more than doubled progression-free survival (PFS) vs. placebo (4.9 vs 1.9 months) and reduced the risk of disease progression by 67%. This analysis evaluated the effect of everolimus on survival in pts who had received 1 vs 2 prior VEGFR-TKIs. Methods: Pts with mRCC who progressed on sunitinib (SU) and/or sorafenib (SOR) were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care in the double- blind, phase III RECORD-1 study (ClinicalTrials.gov: NCT00410124 ). Results: Before enrollment, the majority of pts received only 1 VEGFR- TKI (317 pts, 74%), with 317 pts receiving either SU or SOR (everolimus = 211; placebo = 106) and 99 pts receiving both SU and SOR (everolimus = 66; placebo = 33). Median PFS was 5.42 mo (95% confidence interval [CI]: 4.30, 5.82) in pts receiving everolimus who had received 1 prior VEGFR-TKI and 1.87 mo (95% CI: 1.84, 2.14) in those receiving placebo (hazard ratio [HR]: 0.31; 95% CI: 0.23, 0.42; p < .001). Median PFS was 3.78 mo (95% CI: 3.25, 5.13) for the everolimus group in pts who received 2 prior VEGFR-TKIs, versus 1.87 mo (95% CI: 1.77, 3.06) for the placebo group (HR: 0.37; 95% CI: 0.22, 0.63; p < 0.001). Conclusions: Pts in all stratified subgroups derived significant clinical benefit from everolimus treatment, including pts previously treated with either 1 or 2 VEGFR-TKIs. However, there was a trend toward a longer PFS in pts treated with 1 prior VEGFR-TKI compared with 2 VEGFR-TKIs. [Table: see text]

EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 172-172 ◽  
Author(s):  
Andrew X. Zhu ◽  
Masatoshi Kudo ◽  
Eric Assenat ◽  
Stéphane Cattan ◽  
Yoon-Koo Kang ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Options ◽  
Study Drug ◽  
Final Analysis ◽  
Best Supportive Care ◽  
Hbv Reactivation ◽  
Advanced Hcc ◽  
Common Grade ◽  
Load Increase ◽  
Grade 3

172 Background: No effective treatment options exist for advanced HCC following sorafenib failure. Preliminary data suggest everolimus may provide benefit after sorafenib. EVOLVE-1 (NCT01035229) assessed the efficacy and safety of everolimus for advanced HCC after sorafenib failure. Methods: Pts aged ≥18 y with BCLC stage B or C HCC and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were sorafenib intolerant were randomized 2:1 to everolimus 7.5 mg/d or placebo. All pts received best supportive care. Randomization was stratified by region (Asia v rest of world) and macrovascular invasion (yes v no). Study drug was given continuously until disease progression or intolerable toxicity. CT/MRI was performed every 6 wk. Primary endpoint was OS. Secondary endpoints were TTP, disease control rate (DCR; percentage of pts with best overall response of CR, PR, or SD per RECIST 1.0), and safety. Final analysis was performed when 454 deaths occurred. Results: 546 pts from 18 countries enrolled from Apr 2010 to Mar 2012 (everolimus = 362, placebo = 184). Baseline characteristics were balanced between arms; median age was 66.0 y, 84.8% of pts were male, 86.3% had BCLC stage C disease, 16.7% were from Asia, 32.8% had macrovascular invasion, and 74.0% had extrahepatic disease. Prior sorafenib was discontinued for disease progression in 80.8% of pts and intolerance in 19.0%. Median OS was 7.56 mo with everolimus and 7.33 mo with placebo (HR 1.05; 95% CI 0.86-1.27; P = .675). Median TTP was 2.96 mo and 2.60 mo, respectively (HR 0.93; 95% CI 0.75-1.15). DCR was 56.1% and 45.1%, respectively (P = .010). The most common grade 3/4 AEs with everolimus (v placebo) were anemia (7.8% v 3.3%), asthenia (7.8% v 5.5%), decreased appetite (6.1% v 0.5%), and hepatitis B viral load increase or reappearance (6.1% v 4.4%). No pts experienced HCV flare. HBV reactivation was experienced by 39 pts (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Conclusions: Everolimus did not improve OS in pts with advanced HCC whose disease progressed on or after sorafenib or who were sorafenib intolerant. The safety profile was consistent with that previously observed with everolimus. Clinical trial information: NCT01035229.

Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study.

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA7005-LBA7005 ◽  
Author(s):  
Asher Alban Akmal Chanan-Khan ◽  
Paula Cramer ◽  
Fatih Demirkan ◽  
Graeme Fraser ◽  
Rodrigo Santucci Silva ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Double Blind ◽  
Major Hemorrhage ◽  
End Point ◽  
First Results ◽  
Risk Of Progression ◽  
Previously Treated ◽  
Grade 3

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.

Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric cancer (AGC) enrolled in the phase III GRANITE-1 study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4081-4081
Author(s):  
Kun-Huei Yeh ◽  
Eric Van Cutsem ◽  
Atsushi Ohtsu ◽  
Lin Shen ◽  
Jaffer A. Ajani ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Mammalian Target Of Rapamycin ◽  
Study Drug ◽  
Asian Population ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Double Blind ◽  
Risk Of Death ◽  
Grade 3

4081 Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the oral mammalian target of rapamycin inhibitor EVE showed that incidences of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; however, the number of Asian pts enrolled was small. GRANITE-1 provides an opportunity to evaluate EVE safety in a broader Asian population. Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts aged ≥18 y with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d + best supportive care (BSC) or placebo + BSC. Randomization was stratified by region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was continued until disease progression or unacceptable toxicity. Adverse events (AEs) were collected throughout the study and for 28 d after final dose of study drug and assessed according to the Common Terminology Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 (55%) were enrolled in Asia and received EVE (n=243) or placebo (n=120). EVE did not significantly reduce the risk of death in the overall (HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 35%). Among EVE-treated pts, rates of any-grade rash, infections, and pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt (from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The safety profile of EVE in Asian pts with AGC was similar to that observed in ROW pts with AGC and with EVE in other cancers. No new safety signals were identified. Pneumonitis was relatively uncommon in Asian and ROW pts.

Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3502-3502 ◽  
Author(s):  
Eric Van Cutsem ◽  
Alberto F. Sobrero ◽  
Salvatore Siena ◽  
Alfredo Falcone ◽  
Marc Ychou ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Cox Regression ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Comparable Efficacy ◽  
Correct Trial ◽  
Common Grade ◽  
Grade 3

3502 Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Results: 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm: hazard ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p=0.0052), median OS 6.4 vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p<0.000001), median PFS 1.9 vs 1.7 mos. Comparable OS and PFS benefits were observed in exploratory subgroup analyses by region, age, time from diagnosis of mCRC to randomization, prior lines of treatment, and KRAS status (shown in table). The most common grade 3+ AEs related to REG were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea (7.2%) and rash/desquamation (5.8%). QoL data will be presented. Conclusions: REG demonstrated statistically significant improvement in OS and PFS over PL, as well as comparable efficacy benefits across pt subgroups analyzed. [Table: see text]

Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. LBA385-LBA385 ◽  
Author(s):  
Axel Grothey ◽  
Alberto F. Sobrero ◽  
Salvatore Siena ◽  
Alfredo Falcone ◽  
Marc Ychou ◽  
...  
Keyword(s):  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Correct Trial ◽  
Double Blind ◽  
Multikinase Inhibitor ◽  
Secondary Endpoints ◽  
Grade 3

LBA385 Background: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in pts with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented. Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

scholarly journals Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

2013 ◽  
Vol 31 (31) ◽  
pp. 3935-3943 ◽  
Author(s):  
Atsushi Ohtsu ◽  
Jaffer A. Ajani ◽  
Yu-Xian Bai ◽  
Yung-Jue Bang ◽  
Hyun-Cheol Chung ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Advanced Gastric Cancer ◽  
Safety Profile ◽  
Systemic Chemotherapy ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Double Blind ◽  
Previously Treated

Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.

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