Clinical Trial Results:
Phase II clinical trial of capecitabine and oxaliplatin plus bevacizumab as neoadjuvant treatment for patients with previously untreated unresectable liver-only metastases from colorectal cancer
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Summary
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EudraCT number |
2005-004505-29 |
Trial protocol |
GB |
Global end of trial date |
10 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Sep 2016
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First version publication date |
25 Sep 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
2676
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Royal Marsden NHS Foundation Trust
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Sponsor organisation address |
Downs Road, Sutton, London, United Kingdom, sm2 5pt
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Public contact |
Jacqui Oates, Royal Marsden NHS Foundation Trust, 0208 661 3279, jacqui.oates@rmh.nhs.uk
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Scientific contact |
Dr Khurum Khan, Royal Marsden NHS Foundation Trust
, 0208 661 3279 , jacqui.oates@rmh.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 May 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Feb 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Feb 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the response rate of patients with previously untreated unresectable liver-only metastases from colorectal cancer treated with neoadjuvant capecitabine and oxaliplatin plus bevacizumab.
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Protection of trial subjects |
The rate of liver resection correlated significantly with objective response rates (ORRs) of neoadjuvant chemotherapy . FOLFOXIRI (5-FU–LV–oxaliplatin–irinotecan) as well as the addition of cetuximab to FOLFOX or FOLFIRI (LV–5-FU–irinotecan) in Kras wild-type population resulted in a higher response rate compared with two-drug chemotherapy regimens . These improved response rates led to an increased rate of surgical metastases resection. Bevacizumab did not significantly improve ORR when added to oxaliplatin–fluoropyrimidine compared with oxaliplatin or fluoropyrimidine alone, and there were no statistically significant differences in resection rates in patients treated with bevacizumab compared with placebo . Nevertheless, these are subgroup (post hoc) analyses nested in large randomised, controlled trials of unselected patients not limited to liver-only metastases.
As prospective bevacizumab data were lacking in this setting, a multicentre study of CAPOX (capecitabine–oxaliplatin) plus bevacizumab in patients with high-risk colorectal liver-only metastases (CLMs) considered to be unsuitable for upfront liver resection in order to assess the efficacy and safety of this approach was conducted. In our BOXER (bevacizumab, oxaliplatin, xeloda in unresectable liver metastases) study, CAPOX plus bevacizumab was used as it was considered an accepted first-line treatment of advanced CRC , and high-risk disease was based on large size, poorly located, multinodular, and synchronous presentation of liver metastases.
This was considered standard approach at the time and thus no additonal safety risks were anticipated. However, all the routine safety procedures such as standard dose reductions or interruptions were conducted according to standrard hospital policies; moreover, a Trial Management Group (TMG) examined the safety of the study on regular basis.
Ref: http://annonc.oxfordjournals.org.ezproxy.icr.ac.uk/content/22/9/2042.long
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Background therapy |
Oxaliplatin (130 mg/m2) and bevacizumab (7.5 mg/kg) were administered i.v. on day 1 every 3 weeks. Capecitabine was given orally at a dose of 1700 mg/m2/day divided into two split doses for 14 days followed by 7 days' rest repeated every 3 weeks. Dose adjustment was made in the event of toxicity assessed according to National Cancer Institute—Common Terminology Criteria for Adverse Events (NCI–CTCAE) version 3.0. Operability was reassessed every four cycles (12 weeks) with CT and MRI scans and this would then be rediscussed at liver MDT meetings. Nonprogressors who remained unresectable would proceed to a further four cycles of treatment. surgery. Patients deemed to be resectable would undergo surgery at an 8-week interval from last dose of bevacizumab (6 weeks from last dose of chemotherapy). Patients with in situ primary tumours could have either synchronous or staged resection of primary tumour and liver metastases as per local practice. postoperative chemotherapy. After recovery from surgery, patients received another 12 weeks of CAPOX plus bevacizumab at the same dose schedule as preoperative block. | ||
Evidence for comparator |
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Actual start date of recruitment |
26 Jun 2006
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 46
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Worldwide total number of subjects |
46
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EEA total number of subjects |
46
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
26
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From 65 to 84 years |
20
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||
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Pre-assignment
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Screening details |
Appropriate patients were identified through multi-disciplinary meetings, which included representation from all disciplines including oncology, radiotherapy, surgery, histopathology and radiology. Patients were also idenfitied from new patient clinics by the sub-investigators. | ||||||||||
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Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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All Patients | ||||||||||
Arm description |
capecitabine & oxaliplatin with bevacizumab | ||||||||||
Arm type |
single arm study | ||||||||||
Investigational medicinal product name |
bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Bevacizumab 7.5mg/kg every 3 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Treatment
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Reporting group description |
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End points reporting groups
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Reporting group title |
All Patients
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Reporting group description |
capecitabine & oxaliplatin with bevacizumab | ||
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End point title |
Overall Response Rate [1] | ||||||
End point description |
Sum of complete and partial responses
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End point type |
Primary
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End point timeframe |
Best observed response rate
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a phase II study with only one arm, so no statistical comparisons can be made. This phase II study was designed using the optimal two-stage design with A'Hern exact P value. The primary end point was the best achieved ORR, calculated as the sum of observed complete and partial responses. An ORR rate of 60% was considered acceptable (p1) and ORR rate of 40% was ruled out as unacceptable (p0). |
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of treatment to 30 days post treatment end
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Adverse event reporting additional description |
Grade 3-5 related to treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
No dictionary | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
All Patients
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Reporting group description |
All subjects receiving a study drug | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Jul 2006 |
dose of capecitabine/oxaliplatin in combination chemotherapy reduced to 1700mg/m2 in two divided doses D1-14 in keeping with hospital guidelines |
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01 Nov 2007 |
dose adjustements for chemotherapy in patients above 75 years of age in keeping with the local guildelines |
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02 Sep 2009 |
clarification on follow up details on the study and additional PIS for patients participating in translational substudy |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| single arm non-randomised syudy with no comparatar arm | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/2128 |
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