Information obtained from ClinicalTrials.gov on May 19, 2013Link to the current ClinicalTrials.gov record.http://clinicaltrials.gov/show/NCT00069095NO16966NCT00069095A Study of Capecitabine (Xeloda) as a First-line Therapy in Patients With Metastatic Colorectal CancerA 2x2 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 CancerHoffmann-La RocheIndustryHoffmann-La RocheUnited States: Food and Drug Administration
This 4 arm study assessed the efficacy and safety of oral capecitabine (Xeloda) or
intravenous (iv) fluorouracil/leucovorin, in combination with iv oxaliplatin (Eloxatin) with
or without iv bevacizumab (Avastin), as a first-line treatment in patients with metastatic
colorectal cancer. Patients were randomized to receive 1) XELOX (Xeloda 1000 mg/m^2 orally
[po] twice a day [bid] on Days 1-15 + oxaliplatin in 3 week cycles), 2) FOLFOX-4
(oxaliplatin + leucovorin + fluorouracil [5-FU] in 2 week cycles), 3) XELOX + bevacizumab
(7.5 mg iv on Day 1 in 3 week cycles), or 4) FOLFOX-4 + bevacizumab (5 mg iv on Day 1 in 2
week cycles).
This study was conducted in 2 parts: An initial 2-arm part in which patients were randomized
to 1 of 2 different treatment groups (XELOX or FOLFOX-4), and a subsequent 2 x 2 factorial
part, added to the study through a protocol amendment, in which additional patients were
randomized into one of 4 different treatment groups (XELOX + placebo, FOLFOX-4 + placebo,
XELOX + bevacizumab, or FOLFOX-4 + bevacizumab). Due to the comparison of the oral agent
capecitabine with bolus and infused fluorouracil, the study was not blinded with respect to
these 2 treatments. The study was double-blind with regard to the administration of
bevacizumab, ie, there was a placebo control for bevacizumab in the second part of the
study.
The study consisted of 3 phases, a Primary Study Treatment Phase, a Post-Study Treatment
Phase, and a Follow-Up Phase.
Primary Study Treatment Phase
Patients were to receive up to 16 cycles (2-arm part of the study) or 24 cycles (4-arm part
of the study) of treatment during the Primary Study Treatment Phase (48 weeks).
Post-Study Treatment Phase
Patients who completed the 48-week primary study treatment phase without progressive disease
were eligible to enter the post-study treatment phase at the discretion of the investigator
and the sponsor. Patients who entered this phase were to continue treatment on the same
regimen to which they were initially randomized until either progression of disease was
documented, unacceptable toxicity occurred, or the patient withdrew consent.
Follow-up Phase
Patients who terminated study treatment during the primary or post-study treatment phase
were followed until disease progression or death.
CompletedJuly 2003April 2009January 2006Phase 3InterventionalAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: TreatmentProgression-free survival (PFS) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoPFS was defined as the time from randomization to disease progression (PD) or death. All measurable lesions (maximum of 5 per organ and 10 in total, those with the longest diameter and suitability for accurate repeated measurements) were identified as target lesions (TL). A sum of the longest diameter for all TLs was calculated and reported as the baseline sum longest diameter(SLD). All other lesions were identified as non-TLs and recorded at baseline. PD for TLs was defined as ≥ 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Patients with neither PD nor death were censored at the date of the last tumor assessment that confirmed no PD. Patients who underwent surgical resection with curative intent without prior progression were censored at the date of surgery.Progression-free survival (PFS) as assessed by the Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoPFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Patients with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Patients who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the Independent Review Committee.Best overall response (BOR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoBOR in an individual patient was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments by the investigator made up to 28 days after the last study treatment in the primary study treatment phase not later than the date of the first curative surgery were included in the analysis. Responders were defined as the percentage of patients with a complete response (CR) or partial response (PR). For target lesions (TL), a CR was defined as the disappearance of all TLs and a PR was defined as ≥ 30% decrease in the SLD of target lesions, taking as reference the baseline SLD. For non-TLs, a CR was defined as the disappearance of all non-TLs and a PR was defined as the persistence of 1 or more non-TLs.Best overall response (BOR) as assessed by the Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoOnly tumor assessments by the Independent Review Committee made up to 28 days after the last study treatment in the primary study treatment phase not later than the date of the first curative surgery were included in the analysis. Responders were defined as the percentage of patients with a complete response (CR) or partial response (PR).Overall survivalBaseline to the 30 May 2008 data cut-off (up to 4 years 10 months)NoOverall survival was defined as the time from the date of randomization to the date of death. Patients who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive.Time to response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoFor patients whose best overall response was CR or PR, time to response was defined as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status is recorded first) were met. Results are reported as the percentage of patients achieving a response in 8 time categories from Week 1 to Week 54.Duration of response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoDuration of response was defined as the time that measurement criteria are first met for complete response (CR) or partial response (PR) (whichever status is recorded first) until the first date that progressive disease (PD) or death is documented. PD for target lesions was defined as ≥ 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. PD for non-target lesions was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-targets.Duration of complete response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoDuration of complete response was defined as the time measurement criteria are first met for a complete response until the date that progressive disease (or death) is documented.Time to treatment failure as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST)Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months)NoTime to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, patient refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurs first.42035Colorectal CancerXELOX (oxaliplatin+capecitabine)ExperimentalPatients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.XELOX (oxaliplatin+capecitabine) + bevacizumabExperimentalPatients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)Active ComparatorPatients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumabActive ComparatorPatients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.DrugOxaliplatin 130 mg/m^2Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.XELOX (oxaliplatin+capecitabine)XELOX (oxaliplatin+capecitabine) + bevacizumabEloxatinDrugCapecitabine 1000 mg/m^2Capecitabine was taken within 30 min after the end of breakfast and dinner.XELOX (oxaliplatin+capecitabine)XELOX (oxaliplatin+capecitabine) + bevacizumabXelodaDrugBevacizumab 7.5 mg/kgBevacizumab was administered in a 30 to 90 min infusion.XELOX (oxaliplatin+capecitabine) + bevacizumabAvastinDrugPlacebo for bevacizumab 7.5 mg/kgPlacebo control for bevacizumab (volume equivalent to 7.5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.XELOX (oxaliplatin+capecitabine)DrugOxaliplatin 85 mg/m^2Oxaliplatin 85 mg/m^2 was administered simultaneously with leucovorin in a 2 h infusion.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumabEloxatinDrugLeucovorin 200 mg/m^2Leucovorin was administered simultaneously with oxaliplatin 85 mg/m^2 in a 2 h infusion.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumabDrugFluorouracil 400 mg/m^2FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumabEfudexDrugBevacizumab 5 mg/kgBevacizumab was administered in a 30 to 90 min infusion.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumabAvastinDrugPlacebo for bevacizumab 5 mg/kgPlacebo control for bevacizumab (volume equivalent to 5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Inclusion Criteria:
- Adult patients ≥ 18 years of age.
- Metastatic colorectal cancer.
- ≥ 1 target lesion.
Exclusion Criteria:
- Previous treatment with oxaliplatin or bevacizumab.
- Previous systemic chemotherapy or immunotherapy for advanced or metastatic disease.
- Progressive disease during or within 6 months of completion of previous adjuvant
therapy.
Both18 YearsN/ANoClinical TrialsStudy DirectorHoffmann-La RocheBerkeleyCalifornia94704United StatesFountain ValleyCalifornia92708United StatesFullertonCalifornia92835United StatesGilroyCalifornia95020United StatesGreenbraeCalifornia94904United StatesLos AngelesCalifornia90057United StatesOrangeCalifornia92868United StatesPalo AltoCalifornia94304United StatesSan DiegoCalifornia92123United StatesNorwichConnecticut06360United StatesWaterburyConnecticut06708United StatesBoca RatonFlorida33486United StatesGainesvilleFlorida33610-0277United StatesJacksonvilleFlorida32207United StatesNew Port RicheyFlorida34652United StatesTampaFlorida33607United StatesTampaFlorida33647United StatesAtlantaGeorgia30341United StatesChicagoIllinois60640United StatesElk Grove VillageIllinois60007United StatesPeoriaIllinois61615-7828United StatesLexingtonKentucky40536-0098United StatesNew OrleansLouisiana70121United StatesScarboroughMaine04074United StatesBostonMassachusetts02135United StatesAnn 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Hill3128AustraliaBrisbane4101AustraliaCamperdown2050AustraliaFitzroy3065AustraliaFootscray3011AustraliaKurralta Park5037AustraliaMalvern3144AustraliaMelbourne3002AustraliaMelbourne3181AustraliaPerth6000AustraliaPort Macquarie2444AustraliaSt. Leonards2065AustraliaSydney2031AustraliaSydney2139AustraliaWels4600AustriaWien1090AustriaJAÚ17210-080BrazilRio de Janeiro20231-050BrazilSao Paulo05403-000BrazilCalgaryAlbertaT2N 4N2CanadaEdmontonAlbertaT6G 1Z2CanadaKelownaBritish ColumbiaV1Y 5L3CanadaNorth VancouverBritish ColumbiaV7L 2L7CanadaSurreyBritish ColumbiaV3V 1Z2CanadaVancouverBritish ColumbiaV5Z 1H5CanadaVictoriaBritish ColumbiaV8R 6V5CanadaWinnipegManitobaR2H 2A6CanadaHalifaxNova ScotiaB3H 1V7CanadaHamiltonOntarioL8V 5C2CanadaLondonOntarioN6A 4L6CanadaMississaugaOntarioL5M 2N1CanadaOshawaOntarioL1G 2B9CanadaOttawaOntarioK1H 8L6CanadaSt. CatharinesOntarioL2R 7C6CanadaTorontoOntarioM5G 2M9CanadaTorontoOntarioM5G 1X5CanadaTorontoOntarioM4N 3M5CanadaTorontoOntarioM9N 1N8CanadaLevisQuebecG6V 3Z1CanadaMontrealQuebecH2L 4M1CanadaMontrealQuebecH1T 2M4CanadaMontrealQuebecH4J 1C5CanadaQuebec CityQuebecG1R 2J6CanadaBeijing100853ChinaBeijing100021ChinaGuangdong510515ChinaGuangzhou510060ChinaJiangsu210009ChinaJiangxi330000ChinaShandong250117ChinaShanghai200025ChinaShanghai200092ChinaTianjin300060ChinaWuhan430030ChinaBrno656 53Czech RepublicChomutov430 12Czech RepublicHradec Kralove500 36Czech RepublicOstrava708 52Czech RepublicHerlev2730DenmarkKøbenhavn2100DenmarkOdense5000DenmarkHelsinki00029FinlandTampere33520FinlandTurku20520FinlandBesancon25030FranceBobigny93009FranceBoulogne-billancourt92104FranceBrest29609FranceChambray Les Tours37171FranceColmar68024FranceDijon21079FranceGrenoble38100FranceLyon69373FranceMetz57072FranceNice06189FranceNice06202FranceNimes30029FranceParis75651FranceParis75475FranceParis75679FrancePierre Benite69495FranceRouen76031FranceSaint Herblain44805FranceSaint Herblain44093FranceToulouse31052FranceBochum44892GermanyHalle06120GermanyHannover30625GermanyHerne44625GermanyLeipzig04129GermanyMainz55131GermanyMannheim68167GermanyRegensburg93053GermanyStralsund18435GermanyTrier54290GermanyGuatemala01009GuatemalaGuatemala City01015GuatemalaHong KongHong KongBudapest1082HungaryBudapestH-1122HungaryGyor9002HungaryKecskemet6000HungaryCorkIrelandDublin8IrelandDublin4IrelandGalwayIrelandHaifa31096IsraelJerusalem91120IsraelPetach Tikva49100IsraelTel Aviv64239IsraelZerifin70300IsraelAncona60121ItalyGenova16132ItalyModena41100ItalyPadova35100ItalyParma43100ItalyPavia27100ItalyReggio Emilia42100ItalySassari07100ItalySeoul135-170Korea, Republic ofMexico City14000MexicoChristchurchNew ZealandBergen5021NorwayOslo0407NorwayTromsø9038NorwayPanama CityPanamaBeja7801-849PortugalLisboa1649-035PortugalSan Juan00907Puerto RicoMoscow115478Russian FederationMoscow117837Russian FederationMoscow105229Russian FederationSt Petersburg198255Russian FederationSt Petersburg197758Russian FederationCape Town7506South AfricaPretoria0001South AfricaSandton2199South AfricaBarcelona08035SpainBarcelona08036SpainCórdoba14004SpainGranada18014SpainLeganes28911SpainMadrid28046SpainMadrid28040SpainMadrid28007SpainMadrid28041SpainMadrid28034SpainMálaga29010SpainSantander39008SpainValencia46009SpainValencia46026SpainValencia46010SpainZaragoza50009SpainGaevle80187SwedenKarlstad65185SwedenStockholm17176SwedenUppsala751 85SwedenVästerås72189SwedenBern3010SwitzerlandGeneve1205SwitzerlandKueishan333TaiwanTaipei100TaiwanTaipei114TaiwanTaipei112TaiwanBangkok10700ThailandBangkok10110ThailandKhon Kaen40002ThailandIstanbul34300TurkeyIzmir35100TurkeyAberdeenAB25 2ZNUnited KingdomBirminghamB18 7QHUnited KingdomCardiffCF14 2TLUnited KingdomDerbyDE1 2QYUnited KingdomGlasgowG12 0YNUnited KingdomGuildfordGU2 7XXUnited KingdomHullHU8 9HEUnited KingdomLondonSW3 6JJUnited KingdomMaidstoneME16 9QQUnited KingdomNewcastle Upon TyneNE7 7DNUnited KingdomNorthwoodHA6 2RNUnited KingdomNottinghamNG5 1PBUnited KingdomPlymouthPL6 8DHUnited KingdomSalisburySP2 8BJUnited KingdomSouthamptonSO9 4PEUnited KingdomSuttonSM2 5PTUnited KingdomTauntonTA1 5DAUnited KingdomUnited StatesAustraliaAustriaBrazilCanadaChinaCzech RepublicDenmarkFinlandFranceGermanyGuatemalaHong KongHungaryIrelandIsraelItalyKorea, Republic ofMexicoNew ZealandNorwayPanamaPortugalRussian FederationSouth AfricaSpainSwedenSwitzerlandTaiwanThailandTurkeyUnited KingdomPuerto RicoGreeceJanuary 2013January 30, 2013September 15, 2003SponsorYesYesNoColorectal NeoplasmsFluorouracilCapecitabineOxaliplatinBevacizumabLeucovorinLevoleucovorin