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Clinical Trial Result Information
Protocol number
NO16966
Title of Study
2 x 2 Factorial randomized phase III study of intermittent oral capecitabine in combination with intravenous oxaliplatin (q3w) ("XELOX") with/without intravenous bevacizumab (q3w) versus bolus and continuous infusion fluorouracil/intravenous leucovorin with intravenous oxaliplatin (q2w) ("FOLFOX-4") with/without intravenous bevacizumab (q2w) as first-line treatment for patients with metastatic colorectal cancer.
Sponsor
Hoffmann-La Roche Ltd
Company division
Pharmaceutical
Product name
Xeloda
Generic name
capecitabine
Therapeutic area
Metastatic Colorectal Cancer
Clinical study summary
This was a randomized, 2-part study. In the initial 2-arm part (not blinded), patients were randomized to receive either XELOX or FOLFOX-4. In the 2x2 factorial part (blinded), a different set of patients was randomized to receive either XELOX + placebo (XELOX + P), XELOX + Avastin (bevacizumab) (XELOX + BV), FOLFOX-4 + P, or FOLFOX-4 + BV.
Study center(s)
216 centers in Australia, Austria, Brazil, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Korea, Mexico, New Zealand, Norway, Panama, Portugal, Russia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom and USA.
Phase of development
III
Objectives
Two co-primary objectives were to demonstrate that 1) the combination of Xeloda (capecitabine) and oxaliplatin (XELOX) with or without Avastin (bevacizumab (BV)) was non-inferior to the combination of fluorouracil and leucovorin and oxaliplatin (FOLFOX-4) with or without BV in terms of progression-free survival (PFS) and 2) Avastin in combination with chemotherapy (XELOX + BV/FOLFOX-4 + BV) was superior to chemotherapy alone (XELOX + P/FOLFOX-4 + P) in terms of PFS.
Methodology
The study commenced as a 2-arm, open-label, randomized Phase III comparison of XELOX versus FOLFOX-4. The protocol was amended to a placebo-controlled, double-blind (for bevacizumab), randomized, 2x2 factorial design, and bevacizumab or placebo were added to both treatment groups.
Medical history, physical examination, chest X-ray, ECG and carcinoembryonic antigen measurements were performed within 21 days prior to starting treatment. Assessments of vital signs, ECOG performance status, height, weight, routine blood analysis (hematology and biochemistry) were performed within 7 days of starting treatment. During treatment, physical examination, hematology and biochemistry analyses were repeated on day 1 of every treatment cycle.
Tumor assessment (CT scan, MRI) were made within 28 days prior to starting study treatment and repeated every two XELOX cycles and every three FOLFOX-4 cycles ie every 6th week in both arms, and at the end of treatment. RECIST guidelines were used to define all responses. Confirmation of response was required after a minimum of 4 weeks. Tumor responses were assessed by investigators and also by an independent review committee. After completion of study treatment, patients were followed every 3 months until disease progression (PD) and/or death.
Patients were evaluated for adverse events during therapy and until 28 days after the last study drug dose. Adverse events were graded according to NCI-CTC, version 3.
Treatment was recommended to continue until disease progression (PD) or for 48 weeks (ie up to 16 cycles of XELOX or 24 cycles of FOLFOX-4), whichever came first (study treatment phase). Patients who completed the 48 week treatment phase without PD were eligible to continue treatment until PD in a post-study treatment phase. Patients whose tumor became operable, and for whom resection was performed, were allowed to enter the post-treatment phase where they continued treatment on the same regimen to which they were originally randomized until progression of disease, unacceptable toxicity or withdrawal of consent.
If one of the regimen components was discontinued, treatment could be continued with the remaining components as follows:
--capecitabine or 5-FU/FA +/- bevacizumab/placebo could be given after discontinuing oxaliplatin;
--XELOX, FOLFOX-4, capecitabine or 5-FU/FA could be given after discontinuing bevacizumab/placebo;
--bevacizumab/placebo could be given after discontinuing XELOX, FOLFOX-4, capecitabine or 5-FU/FA;
--patients were not permitted to continue on oxaliplatin +/- bevacizumab/placebo.
Medical history, physical examination.
Number of patients (planned/analyzed)
A total of 2034 patients received treatment
Diagnosis and main criteria for inclusion
Male or female patients ≥18 years of age with histologically confirmed adenocarcinoma of the colon or rectum with metastatic disease.
Test product, dose and mode of administration or test procedure
XELOX: Oxaliplatin 130mg/m2 i.v. infusion (day 1 every 3 weeks) before first dose of capecitabine. Capecitabine 1000mg/m2 bid orally, daily for 2 weeks followed by 1-week without treatment.
XELOX + P: Placebo control for BV i.v. infusion followed by oxaliplatin 130mg/m2 i.v. infusion (day 1 every 3 weeks) in combination with capecitabine 1000mg/m2 bid. Cycle length was 3 weeks (2 weeks of capecitabine followed by 1 week without treatment).
XELOX + BV: Bevacizumab 7.5mg/kg i.v. followed by oxaliplatin 130mg/m2 i.v. infusion (day 1 every 3 weeks) in combination with capecitabine as described above for XELOX.
Duration of treatment
48 weeks primary study treatment phase
Reference therapy, dose and mode of administration or reference procedure
FOLFOX-4: On day 1, oxaliplatin, 85mg/m2 i.v. infusion (on day 1 of a 2-week cycle); concomitantly with LV, 200mg/m2 infusion, followed by 5-FU, 400mg/m2 bolus injection, and then 600mg/m2 continuous infusion. On day 2, LV 200mg/m2 (alone), followed by 5-FU 400mg/m2 bolus injection, and 5-FU 600mg/m2 continuous infusion. Cycle length was 2 weeks (48h of infusion and 12 days of rest).
FOLFOX-4 + P: Placebo control for BV (Volume equivalent to 5mg/kg BV) i.v. infusion followed by FOLFOX-4 administered as described above.
FOLFOX-4 + BV: On day 1, bevacizumab 5mg/kg i.v. infusion followed by oxaliplatin 85mg/m2 i.v. infusion (on day 1 only); concomitantly with LV, 200mg/m2 infusion, followed by 5-FU, 400mg/m2 bolus injection, and then as a 600mg/m2 continuous infusion. On day 2, LV 200mg/m2 (alone), followed by 5-FU 400mg/m2 bolus injection, and 5-FU 600mg/m2 continuous infusion. Cycle length was 2 weeks (48h infusion and 12 days of rest).
Criteria for evaluation (efficacy, safety)
Primary efficacy endpoint: Progression free survival (PFS), defined as the time from date of randomization to the first documentation of disease progression by the investigators, or death from any cause.
Secondary efficacy endpoint: Overall survival; PFS on treatment (takes into account only progression or death events occurring within 28 days from the last dose of any component of study treatment); overall rate of best response (BOR); time to response; duration of response; duration of complete response; time to treatment failure.
Safety: Exposure to trial treatment, AEs, SAEs, deaths, dose modifications, premature withdrawals, laboratory abnormalities.
Statistical methods
The intent-to-treat (ITT) patient population included all patients who underwent randomization and signed the informed consent form. The eligible patient population (EPP) was the ITT population minus patients who did not receive at least one dose study drug, and those who violated major protocol inclusion/exclusion criteria. All patients receiving at least one dose of study drug were included in the safety analysis.
As a first step, the analysis of pooled XELOX-containing compared with pooled FOLFOX-4-containing arms was performed. If positive, an interaction test was performed on PFS to check for any interaction between the different treatment components (FOLFOX-4, XELOX, bevacizumab, non-bevacizumab). Independent of the interaction test, a clinical assessment of treatment effect was also performed. An interaction could be ruled out if the statistical interaction test was not significant and the clinical assessment revealed no clinically relevant difference. If an interaction was ruled out, the pooled analysis remained the primary analysis for non-inferiority and superiority. If an interaction could not be ruled out, then results in the bevacizumab and non-bevacizumab treatment subgroups would have had to be considered for non-inferiority and the results in the XELOX and FOLFOX-4 subgroups had to be considered for superiority.
The interaction test was repeated for the two secondary parameters of OS (based on Cox proportional hazards regression) and BOR (based on logistic regression). PFS was the primary endpoint of the study and was used to assess non-inferiority of XELOX with/without BV to FOLFOX-4 with/without BV and superiority of BV in combination with chemotherapy over chemotherapy alone. For testing non-inferiority for the primary endpoint of PFS, the hazard ratio (HR) and associated 97.5% confidence interval (CI) were calculated based on a proportional hazards model. Non-inferiority was concluded if the upper limit of the two-sided 97.5% CI for the HR did not exceed 1.23. Non-inferiority hypotheses were also tested for the secondary endpoints. Best overall response was assessed by logistic regression on the rate of PR or CR. The analysis was based on the two-sided 97.5% CI and non-inferiority was concluded if the lower limit of this CI was above 0.66. Superiority of BV in combination with chemotherapy (XELOX + BV/FOLFOX-4 + BV) to chemotherapy alone (XELOX + P/FOLFOX-4 + P) was based on the stratified log-rank test and used a two-sided significance level of 2.5%. The safety profile for chemotherapy without BV (XELOX compared with FOLFOX-4) was analysed using 95% CI based in the Anderson-Hauck approach for the difference in frequencies of adverse events of special interest to chemotherapy. The same approach was used to assess the safety profile of BV plus chemotherapy based on frequencies of adverse events of special interest to BV.
Summary (efficacy, safety, other results)
Primary Analysis of Efficacy (clinical cut off January 31st 2006):
Both co-primary objectives were met :
XELOX with/without BV (XELOX/XELOX + P/XELOX + BV) was non-inferior to FOLFOX-4 with/without BV (FOLFOX-4/FOLFOX-4 + P/FOLFOX-4 + BV) in terms of PFS. In EPP, the HR=1.05, 97.5% CI = [0.94;1.18]. In ITT, the HR=1.04, 97.5%CI = [0.93;1.16]. The upper limit of the 97.5% CI was below the pre-specified non-inferiority margin of 1.23.
BV in combination with chemotherapy (XELOX + BV/FOLFOX-4 + BV) was superior to placebo plus chemotherapy (XELOX + P/FOLFOX-4 + P) in terms of PFS. In ITT, the HR = 0.83, 97.5% CI = [0.72;0.95], p=0.0023.
Any statistically significant or clinically relevant interaction between BV and the chemotherapy backbone was ruled out, therefore justifying the pooling of the treatment subgroups in the primary analysis.
Secondary analyses non-inferiority.
Non-inferiority was also demonstrated in the treatment subgroup comparison of XELOX/XELOX + P versus FOLFOX-4/FOLFOX-4 + P. In EPP the HR=1.06, 97.5% CI = [0.92; 1.22]. In ITT the HR = 1.05, 97.5% CI = [0.92; 1.20].
Non-inferiority was supported by the results of the pre-specified exploratory subgroup comparison of XELOX + BV versus FOLFOX-4 + BV. In EPP the HR=1.04, 97.5% CI = [0.84; 1.27] . In ITT the HR = 1.01, 97.5% CI = [0.83;1.23].
The on-treatment PFS analysis was not confirmatory for the primary non-inferiority analysis. In the pooled comparison, the HR=1.24, 97.5% CI = [1.07; 1.44]. (Sensitivity analyses showed that differences in regimen schedule between XELOX and FOLFOX-4 impact the on-treatment analysis. To a lesser extent a difference due to more tumor delays in FOLFOX-4, may also contribute to this result).
Secondary analyses superiority
Improvements in PFS were seen in the treatment subgroup comparisons of FOLFOX 4 + BV versus FOLFOX 4 + P (HR= 0.89, 97.5% CI = [0.73; 1.08], p= 0.1871) and XELOX + BV versus XELOX + P. Superiority of the addition of bevacizumab reached statistical significance in the subgroup comparison of XELOX + BV versus XELOX + P for the primary endpoint of PFS (HR= 0.77, 97.5% CI = [0.63; 0.94], p= 0.0026).
In the on-treatment PFS analysis chemotherapy + BV was significantly superior to chemotherapy alone (HR=0.63, 97.5% CI = [0.52; 0.75], p<0.0001).
In addition, in the on-treatment PFS analysis statistically significant superiority was demonstrated for both chemotherapy subgroups (XELOX + BV vs XELOX + P: HR=0.61, 97.5% CI = [0.48; 0.78], p<0.0001 and FOLFOX-4 + BV vs FOLFOX-4 + P : HR = 0.65, 97.5% CI = [0.50; 0.84], p=0.0002).
Additional 12 months of follow-up (clinical cut-off January 31st 2007)—Key findings:
The median OS in the ITT population was 19.8 months in the pooled XELOX arms (XELOX/XELOX + P/XELOX + BV) and 19.6 months in the pooled FOLFOX-4 arms (FOLFOX/FOLFOX-4 + P/FOLFOX-4 + BV) with a corresponding HR =0.99, 97.5% CI = [0.88;1.12]. The result of the OS analysis supports the non-inferiority of XELOX compared with FOLFOX-4).
The median OS was 21.3 months with BV plus chemotherapy and 19.9 months with P plus chemotherapy. Although a trend for improved OS was observed in the BV compared with the P group, the difference did not reach statistical significance (HR = 0.89 , 97.5% CI = [0.76; 1.03]; p=0.077).
Safety: Pooled XELOX/XELOX+P and pooled FOLFOX 4/FOLFOX-4+P groups
Tolerability was similar in both treatment groups, with a similar incidence of AEs, SAEs, and withdrawals due to AEs. The following key findings were observed:
1) A lower incidence of grade 3/4 AEs occurred in the XELOX group compared to the FOLFOX 4 group (71.5% vs. 78.3%). The incidence of grade 4 AEs was also lower in the in the XELOX group compared to the FOLFOX 4 group (12.4% vs. 24.8%), a difference driven primarily by hematological events.
2) The incidence of all hematological AEs (47.6% vs. 69.2%), grade 3/4 hematological AEs (15.9% vs. 49.3%), and grade 4 hematological AEs (2.1% vs. 19.1%) were lower in the XELOX group compared with the FOLFOX 4 group.
a) Neutropenia/granulocytopenia occurred in 27.5% of patients in the pooled XELOX group compared with 58.6% of patients in the pooled FOLFOX 4 group, and grade 3/4 neutropenia/granulocytopenia occurred in 7.0% of patients in the pooled XELOX group compared with 43.8% of patients in the pooled FOLFOX 4 group.
b) Grade 3/4 febrile neutropenia occurred in 0.9% of patients in the pooled XELOX group compared with 4.8% of patients in the pooled FOLFOX 4 group.
3) Consistent with this, infections were less common in the XELOX group: all grade (32.2% vs. 45%) and grade 3/4 (7% vs. 10.5%).
4) Thrombocytopenia (laboratory grade 3/4 abnormalities) was more common in the XELOX group (8.2% vs. 4.3%).
5) The incidence of grade 3/4 increased bilirubin was higher in the XELOX group (3.7% vs. 1.2%); however, this was not accompanied by increased ALT or AST.
6) The incidence of neurosensory toxicity was similar between the FOLFOX 4 and XELOX groups for all AEs and grade 3/4 AEs.
7) All grade and grade 3/4 venous thromboembolic AEs were lower in the XELOX group compared with the FOLFOX 4 group (8.1% vs. 12.9% and 3.8% vs. 6.3%).
8) Cardiac AEs had a lower incidence in the XELOX group compared with the FOLFOX 4 group (all grade: 4.1% vs. 6.2%, grade 3/4: 0.9% vs. 1.4%).
9) Overall, grade 3/4 gastrointestinal disorders were more common in the XELOX group (32.7% vs. 25.4%), mainly due to diarrhea (20.2% vs. 11.2%); however, stomatitis was lower in the XELOX group (21.4% vs. 37.3%).
10) All grade PPE was higher in the XELOX group (30.2%) compared to the FOLFOX 4 group (10.2%), as was grade 3 PPE (6.1% vs. 1.2%).
The percentage of all related deaths and related deaths within 28 days of the last dose of study medication was similar between treatment groups (2.4% vs. 2.2% and 2.1% vs. 1.7%). The incidence of death within 60 days of treatment start was low and similar between the pooled treatment groups: 3.4% of XELOX patients and 2.3% of FOLFOX 4 patients.
Chemotherapy + BV versus Chemotherapy Alone:
The following key results were observed with the addition of BV to chemotherapy:
1) The incidence of grade 3/4 AEs was higher in the chemotherapy + BV arms than in the chemotherapy + P arms (80.0% vs. 74.8%).
2) AEs of special interest to chemotherapy, as predefined in the protocol, were seen in a similar proportion of patients in the chemotherapy + BV and chemotherapy + P arms, with the following exceptions:
a) The incidence of PPE was increased in the chemotherapy + BV arms (grade 3/4: 7.1% vs 3.4%), essentially in the XELOX arms only.
b) The incidence of gastrointestinal disorders was increased in the chemotherapy + BV arms (grade 3/4: 32.4% vs. 27.1%), due to higher incidences in a number of different events (eg, diarrhea, vomiting, and stomatitis) in the BV groups.
c) The incidence of grade 3/4 cardiac events was increased in the chemotherapy + BV arms compared with the chemotherapy + P arms (all grades: 7.8% vs. 5.2%; grade 3/4: 3.5% vs. 0.4%, respectively). The increase was seen in both treatment subgroups (FOLFOX 4 2.9% vs. 0.3%; XELOX 4.0% vs. 0.6%, respectively).
3) The incidences of AEs of special interest defined for BV were the following:
a) The incidence of bleeding was higher in the chemotherapy + BV arms compared with chemotherapy + P (30.5% vs. 25.9%); the majority of events were grade 1/2.
b) Thromboembolic events were increased in the chemotherapy + BV arms vs. the chemotherapy + P arms, respectively:
i) Grade 3/4 arterial thromboembolic events: 12 patients (1.7%) vs. 7 (1.0%).
ii) Grade 3/4 venous thromboembolic events: 54 patients (7.8%) vs. 33 (4.9%).
c) Hypertension was higher in the chemotherapy + BV arms compared with chemotherapy + P (grade 3/4: 3.7% vs. 1.2%, respectively).
d) Grade 3/4 gastrointestinal perforations, proteinuria, and wound healing complications were all uncommon.
4) A higher proportion of patients were discontinued from study treatment for AEs in the BV treatment arms (approximately 31% vs. 21%) mainly due to chemotherapy-related toxicity; however, 21% of the patients in the BV treatment arms versus 15% in the placebo arms discontinued therapy due to grade 3/4 AEs, showing that discontinuations due to AEs that were not severe or life-threatening were not uncommon. Only 5% of the patients in the BV treatment arms and 2% in the placebo arms had the study treatment discontinued due to AEs of special interest to BV.
5) The incidence of treatment-related deaths was similar in the chemotherapy + BV arms and chemotherapy + P arms (2.0% [14 patients] and 1.5% [10 patients], respectively) as was the 60-day mortality rate (2.0% [14 patients] and 1.6% [11 patients], respectively).
Conclusions
Both primary objectives of this phase III study were met:
1) XELOX was non-inferior to FOLFOX-4 in terms of PFS.
2) Chemotherapy + BV was superior to chemotherapy + P in terms of PFS.
Considering the similar efficacy of XELOX and FOLFOX-4, no excess of toxicity of XELOX compared with FOLFOX-4, and the advantage of oral administration of capecitabine compared with 5-FU infusion, a positive benefit/risk ratio for XELOX and XELOX + BV has been established.
Considering the statistically significantly superior and clinically meaningful efficacy when BV was added to chemotherapy versus chemotherapy + P, together with a toxicity profile generally consistent with that described in previous trials, a positive benefit/risk ratio for oxaliplatin-based chemotherapy (FOLFOX-4 or XELOX) + BV has been established in this study.
Date of report
2/1/2007
Click here for the protocol registry listing of this trial.
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