Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): Impact of crossover on survival

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4524-4524 ◽  
Author(s):  
T. Eisen ◽  
R. M. Bukowski ◽  
M. Staehler ◽  
C. Szczylik ◽  
S. Oudard ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Secondary Analysis ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
The Usa ◽  
Level Of Significance ◽  
Improvement In Survival

4524 Background: Sorafenib was approved for advanced RCC in the USA December 2005. A Phase III randomized double-blind, placebo-controlled trial demonstrated an estimated 39% improvement in survival for patients receiving sorafenib versus placebo (HR= 0.72, p = 0.018) (ECCO 2005). These data supported independently reviewed doubling of PFS to 24 weeks in RCC patients receiving sorafenib compared with placebo (12 weeks) (p < 0.000001) (ASCO 2005). Based on the statistical significance and magnitude of PFS benefit, patients were unblinded and placebo patients allowed to crossover to sorafenib in April 2005. A prospectively planned interim OS analysis reflecting impact of crossover of placebo patients is presented. Methods: OS data up to November 30, 2005, were analyzed in this interim analysis using a stratified log-rank test comparing the two treatment groups. In order to examine the effect of crossover on OS, a secondary analysis was performed censoring data from patients randomized to placebo at June 30, 2005. Results: A total of 903 patients were randomized (451 to sorafenib, 452 to placebo) and >200 placebo patients crossed over to sorafenib. Baseline characteristics were similar between treatment arms. There were 367 deaths. The median OS was 19.3 months for sorafenib versus 15.9 months for placebo (HR = 0.77; 95% CI 0.63, 0.95; p = 0.015); although this did not attain the level of significance specified for the interim analysis (α = 0.009), a continued favorable trend in survival benefit was observed. With censoring of crossover data, the median OS was 19.3 months for sorafenib versus 14.3 months for placebo (HR = 0.74, 95% CI 0.58, 0.93; p = 0.010). Conclusion: Sorafenib is the first novel, oral approved treatment for advanced RCC in more than a decade. Previous information on the effect of crossover on OS in randomized oncology studies is limited. The lower HR observed after censoring placebo patients crossed over to sorafenib suggests a continued beneficial effect of sorafenib. Final results await more mature data. [Table: see text]

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.

A multicenter, randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7517-7517 ◽  
Author(s):  
S. V. Rajkumar ◽  
M. Hussein ◽  
J. Catalano ◽  
W. Jedrzejcak ◽  
S. Sirkovich ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Controlled Trial ◽  
Data Monitoring Committee ◽  
Rank Test ◽  
P Value ◽  
Primary Therapy ◽  
Double Blind ◽  
Significance Level

7517 Background: Thalidomide plus dexamethasone (Thal/Dex) yields superior response rates versus dexamethasone (Dex) but its impact as primary therapy for multiple myeloma (MM) is unknown. Methods: Patients (pts) with previously untreated, symptomatic MM were eligible and were randomized in this double-blind trial to Thal/Dex (Arm A) or placebo plus Dex (Arm B). Pts in Arm A received Thal 50 mg PO daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; Dex 40 mg PO was given on days 1–4, 9–12, and 17–20. Pts in Arm B received placebo instead of Thal, and Dex as in Arm A. Cycles were 28 days long, repeated until progression or undue toxicity. The primary endpoint was time to progression (TTP) defined using EBMT criteria. All analyses were intent to treat. Planned sample size was 218 eligible pts in each arm. Full information for one-sided log rank test with significance level of 0.025 (allowing for 1interim analysis) to have 80% power to detect a 40% improvement in TTP (16.8 mo in Arm A vs. 12 mo in Arm B) would be achieved when 282 pts have progressed. A pre-planned interim analysis of the primary endpoint and safety was performed by an independent Data Monitoring Committee (DMC). P value < 0.0015 at this interim analysis would indicate that Arm A is superior to Arm B based on an alpha-spending function of the O’Brien-Fleming type. The DMC recommended release of results. Results: 470 pts were enrolled: 235 randomized to Thal/Dex and 235 to placebo/Dex. Median follow-up was 25 months. Median age was 65 yrs. TTP was significantly superior with Thal/Dex vs placebo/Dex, median TTP 17.4 months (95% CI: 8.1 months-NE) vs 6.4 months (95% CI: 5.6–7.4 months), respectively, P < 0.000065, crossing the upper boundary for superiority. DVT was higher with Thal/Dex vs placebo/Dex, 15.4% vs 4.3%, respectively. Median survival was not reached in either arm. Conclusions: Thal/Dex is significantly superior to Dex alone as first-line therapy for multiple myeloma. [Table: see text] [Table: see text]

Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7629-7629 ◽  
Author(s):  
H. Tsukada ◽  
A. Yokoyama ◽  
Y. Nishiwaki ◽  
T. Shinkai ◽  
M. Harada ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Statistical Power ◽  
Controlled Trial ◽  
Single Agent ◽  
Phase Iii ◽  
Stage Iii ◽  
Rank Test ◽  
P Value ◽  
Platinum Based Chemotherapy ◽  
Study Results

7629 Background: Platinum-based chemotherapy is currently recommended as the standard approach for pts with advanced NSCLC. However prospective clinical trials specifically designed for elderly pts demonstrating the P benefit are still lacking. Therefore, we conducted a phase III trial to determine whether the addition of P to single agent-chemotherapy for elderly NSCLC pts could improve survival. Methods: Eligibility criteria included; chemotherapy-naive; stage III/IV NSCLC; age=70 and PS 0–1. Pts were randomized to receive either DP or D with minimization method balancing site, age (=74/=75) and stage (III/IV), and both regimens were given every 4 weeks. DP comprised D (20 mg/m2) and P (25 mg/m2) iv on days 1, 8, 15. D comprised D (25 mg/m2) iv on the same schedule. Primary endpoint was overall survival (OS). The planned sample size was 115 pts in each arm to provide 80% power to detect 0.667 hazard ratio for DP to D in OS and 2.5% one-sided alpha. Results: Between Apr 2003 and Apr 2006, 126 pts were randomized (D/DP: 63/63). The second planned interim analysis was performed on 112 assessable pts (D/DP:56/56, median age 76, =74/=75: 39/61%, male/female: 77/23%, PS 0/1: 39/61%, III/IV: 30/70%). Maturity of information, defined proportion of interim events to the planned events, was 26% (=49/191). As the one-sided p-value(p=0.00515) of the stratified log-rank test by age and stage was not lower than the critical value for the interim analysis, the formal criterion for stopping the trial failed to meet. However the Data and Safety Monitoring Board recommended study termination and disclosure of the results based on the strong interaction (two-sided p=0.077, hazard ratios [95% C.I.] for =74/=75: 0.23 [0.09–0.62]/0.72 [0.35- 1.49]) that DP may be beneficial for subgroup of age between 70- 74. Major Grade 3–4 toxicities were (%D/DP): neutropenia 4.9/13.1, anemia 1.6/16.4, anorexia 8.3/24.2, infection 11.7/8.1, pneumonitis 1.7/1.6. TRD occurred in 1 pt in DP arm. Conclusions: The interpretation of study results is limited due to early stopping and resultant loss of statistical power. But these data indicated that =74 young elderly have no more need to evaluate tolerability and efficacy of P. No significant financial relationships to disclose.

Evaluation of daily breakthrough chemotherapy-induced nausea and vomiting (CINV) rates in a phase III study of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen.

2017 ◽  
Vol 35 (31_suppl) ◽  
pp. 120-120 ◽  
Author(s):  
Eric Roeland ◽  
Gary Binder ◽  
Joseph Ma ◽  
Corinna Lanzarotti ◽  
Li Zhang
Keyword(s):  
Statistical Significance ◽  
Secondary Analysis ◽  
Complete Response ◽  
Phase Iii ◽  
Double Blind Study ◽  
Close Monitoring ◽  
Double Blind ◽  
Treatment Groups ◽  
The Difference ◽  
Delayed Phase

120 Background: Antiemetic trials typically evaluate CINV control during acute (Day 1), delayed (Days 2-5), and overall (Days 1-5) phases post-chemotherapy; the daily course of events is often unstudied in the delayed phase. In a head-to-head study evaluating NK1RA-containing regimens, a single dose of NEPA, an oral fixed combination of the NK1RA netupitant and 5-HT3RA palonosetron, was non-inferior to a 3-day regimen of APR and GRAN for overall complete response (no emesis/no rescue use) rates (74% NEPA vs 72% APR/GRAN) in 828 patients receiving cisplatin-based highly emetogenic chemotherapy (HEC). This secondary analysis explores daily rates of breakthrough CINV in this study. Methods: This was a double-blind study in chemotherapy-naïve patients with solid tumors. Daily rates of breakthrough CINV, defined as the % of patients with emesis and/or rescue use were calculated with differences between treatment groups evaluated by the Cochran-Mantel-Haenszel method stratified by sex. Results: While daily rates of patients with breakthrough CINV remained stable between 13%-15.1% for APR/GRAN, they declined from 15.5% to 8% over the 5 days for NEPA, with the difference between groups reaching statistical significance on Day 5 (Table). Percent of total patient days with CINV events were 11.7% [NEPA] and 14.0% [APR/GRAN]. The % of patients with ≥ 3 days of breakthrough CINV were 8.5% and 12.3%, respectively. Conclusions: In this study evaluating guideline-recommended antiemetic regimens for HEC, CINV was prevented in most patients during the overall phase yet breakthrough CINV on individual days differed between treatment groups. APR/GRAN showed a relatively constant rate over time, while NEPA rates decreased and patients had fewer total days with breakthrough. This suggests the need for close monitoring of CINV events during the delayed phase. [Table: see text]

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