Metastatic Colorectal CancerPhase 2PASSIONNCT02119026

Efficacy And Safety Of Xeliri + Avastin Followed By Xelox + Avastin Or Reverse Sequence In Metastatic Colorectal Cancer

A Phase 2 study testing Capecitabine, Bevacizumab and Oxaliplatin in people with Metastatic Colorectal Cancer, run by Prof. Dr. Werner Scheithauer at 1 site in Austria.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Metastatic Colorectal Cancer
What is being tested?: Capecitabine, Bevacizumab and Oxaliplatin
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 120 participants
Where: 1 siteAustria
Study dates: Feb 2011to 31 Aug 2017
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Written informed consent
Age >=18 years
Patient must be able to comply with the protocol
Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of metastases. 5 )Diagnosis of metastatic disease according to Response Evaluation Criteria in Solid Tumours (RECIST) not more than 3 months prior to enrolment.
6) Life Expectancy of at least 3 months 7) At least one measurable metastatic lesion (as per RECIST criteria) 8) Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy allowed if completed more than 6 months before inclusion. 9) Eastern Collaborative Oncology Group (ECOG) performance score of 0 or 1 10) Adequate haematological function: absolute neutrophil count (ANC) >= 1.5 x 109/L; platelets >= 100 x 109/L, Hb >= 9 g/dL 11) international normalized ratio (INR) <=1.5 and activated partial thromboplastin time (aPTT) <=1.5 x ULN within 7 days prior to starting study treatment 12) Adequate liver function: Serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <=2.5 x ULN (in case of liver metastases < 5 x ULN) 13) Serum Creatinine <=1.5 x ULN 14) Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24- hour urine must demonstrate <=1 g of protein in 24 hours 15) Negative serum pregnancy test within 7 days of starting study treatment in pre- menopausal women and women < 2 years after the onset of menopause. This test has to be reconfirmed by a urine test, should the 7 days window be exceeded. Fertile women (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).

Who cannot join

Prior chemotherapeutic treatment for metastatic CRC
Symptomatic central nervous system (CNS) metastases
Significant vascular disease (e.g. aortic aneurysm potentially requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 months prior start of study treatment.
History of haemoptysis (= a half teaspoon of bright red blood per episode) within 1 month prior start of study treatment
Past or current history (within the last 2 years prior to treatment start) of other malignancies (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
Clinically significant cardiovascular disease, for example central venous access (CVA) (<=6 months before treatment start), myocardial infarction (<=6 months before treatment start), unstable angina, New York Heart Association (NYHA) >= grade 2, congestive heart failure (CHF), arrhythmia requiring medication, or uncontrolled hypertension.

Show all 21Show fewer

Prior history of hypertensive crisis or hypertensive encephalopathy
Treatment with any other investigational agent or any other biological agent (e.g.cetuximab), or participation in another clinical trial within 30 days prior to entering this study.
Known hypersensitivity to any of the study drugs
Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day)
Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes.
Evidence of bleeding diathesis or coagulopathy.
Serious, non healing wound, ulcer, or bone fracture.
Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study. If central venous access device (CVAD) is required for chemotherapy administration, it should be inserted within 2 days prior to study treatment cycle.
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior start of study therapy
History of abdominal fistula, trachea-oesophageal fistula or any grade 4 non gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess before 1st line therapy.
History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures
Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy)
Pregnancy or lactation
Fertile women (<2 years after last menstruation) and men not willing to use effective means of contraception.

Trial locations and contacts

1 site in 1 country.

Austria1 site

Medical University of Vienna
Vienna, 1090

Other trials in Austria

About this study

Official title: A Phase II Study to Assess Efficacy and Safety of Capecitabine and Irinotecan Plus Bevacizumab Followed by Capecitabine and Oxaliplatin Plus Bevacizumab or the Reverse Sequence in Patients With Metastatic Colorectal Cancer

Since its introduction, 5-fluorouracil (5-FU) has been the cornerstone of treatment for metastatic colorectal cancer (mCRC). Meanwhile the oral 5FU pro-drug Capecitabine (Xeloda®) proved equivalence to 5-FU and is a well tolerated alternative combination partner for Irinotecan (XELIRI) or Oxaliplatin (XELOX) which are widely used for first line treatment of mCRC. Recent advances in molecular biology have resulted in the development of an inhibitor of the vascular endothelial growth factor (VEGF) by the monoclonal humanized antibody bevacizumab (Avastin®).

XELOX or XELIRI +bevacizumab have been investigated in several trials, but not in an approach with clearly defined cross-wise XELIRI-XELOX change criteria. This trial investigates two different sequential treatment options with XELIRI/ XELOX in first and second line with the addition of bevacizumab and tries to give answer to the question if there is an optimal sequence for the benefit of the patient.

This is a prospective, randomized, open-label, 2-arm pilot trial in patients with mCRC who did not receive systemic treatment for their metastatic disease. The study is designed to evaluate the efficacy of XELIRI followed by XELOX and XELOX followed by XELIRI + bevacizumab in terms of Duration of Disease Control (DDC).

Patients will be treated with an established first line therapy consisting of either XELOX or XELIRI + bevacizumab. The chemotherapy treatment will be given for 6 months except prior disease progression, unacceptable toxicity or patient refusal. Bevacizumab will be given until disease progression, unacceptable toxicity or patient refusal.

Capecitabine can be given in addition at the investigators' discretion until disease progression, unacceptable toxicity or patient refusal.

If serious side effects occur despite adequate dose reduction, Oxaliplatin or Irinotecan should be discontinued. In case of Oxaliplatin or Irinotecan-related discontinuation Capecitabine and Bevacizumab should be continued. If Capecitabine also has to be discontinued in first line treatment bevacizumab should be continued. In case of permanent discontinuation of bevacizumab for toxicities, chemotherapy should be continued.

Upon completion of first line chemotherapy patients with disease control will receive bevacizumab maintenance treatment. On investigators decision patients can receive Capecitabine as additional maintenance treatment.

The primary endpoint is to determine the efficacy of a modified XELIRI + bevacizumab followed by XELOX + bevacizumab scheme at progression in comparison with the reverse sequence based on DDC.

Secondary endpoints are first line progression-free survival (PFS), second line PFS, overall response rate, time to response, duration of response, overall survival, tumor assessments (based on RECIST criteria) using CT scans, MRI scans, X-ray, bone scan, clinical examination.

Conditions: Metastatic Colorectal Cancer
Being tested: Capecitabine, Bevacizumab, Oxaliplatin, Irinotecan
Keywords: metastatic colorectal cancer, Patients with metastatic colorectal cancer who did not receive, systemic treatment for their metastatic disease
Medical subject headings: Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CapecitabineDrug
Also called Brand Name: Xeloda
800mg/m2 bid d1-14
± 1000 mg/m2 bid,days 1-14 q3w: maintenance
CapecitabineDrug
Also called Brand name: Xeloda
1000mg/m2 bid d1-14,
BevacizumabDrug
Also called Brand name: Avastin
7,5 mg/kg given on d1 q3w
OxaliplatinDrug
130mg/m2 iv. d 1 q3w
IrinotecanDrug
200mg/m2 iv. d 1 q3w .

Study groups in NCT02119026
Study group	Role	What they receive
A: XELIRI + BEV Followed by XELOX + BEV	Active comparator	capecitabine and irinotecan (XELIRI) plus bevacizumab (AVASTIN; BEV) Capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w . Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression irinotecan will be replaced by oxaliplatin (arm A). Bevacizumab will be continued. Receives: Drug: Capecitabine; Drug: Bevacizumab; Drug: Irinotecan
B: XELOX + BEV followed by XELIRI + BEV	Active comparator	capecitabine and oxaliplatin (XELOX) plus bevacizumab (Avastin; BEV) Arm B: Capecitabine: 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression oxaliplatin will be replaced by irinotecan (arm B). Bevacizumab will be continued. Receives: Drug: Capecitabine; Drug: Bevacizumab; Drug: Oxaliplatin

What is being measured

The primary outcome is the main question the study is designed to answer.

Efficacy Duration of Disease Control by Tumor Assessment (CT/MRI/Clinical Examination)
The primary variable was duration of disease control (DDC) and was defined as the sum of progression free survival intervals during first line and second line treatment (= time from the beginning of first line treatment until onset of progression during second line treatment). Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date).
Measured: screening, every 8 to 9 weeks until progression, at end of treatment (other than progression), every 3 months until progression, death or up to 24 months (whatever comes first)

Secondary outcomes (8)

First Line Progression Free Survival (PFS)
The first line PFS was defined as the progression free survival interval during first line treatment. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date). Missing onset of progression data because of refusal or because of death was replaced. If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
Measured: at progression of disease (PD) in first line therapy or at 28 days safety follow-up in cases without PD
Second Line PFS
The second line PFS was defined as the progression free survival interval during second line treatment. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date). Missing onset of progression data because of refusal or because of death was replaced.
If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
Measured: at progression of disease (PD) in second line therapy or at 28 days safety follow-up in cases without PD
Overall Response Rate (Number of Participants With Response)
The rate of overall response was measured as the response rate from randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first).
Measured: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Time to Response
Time to overall response was measured from the time of randomization until the day of documented complete response (CR) or partial response (PR) (whichever status is recorded first). Patients without response were censored at the date of the last tumor assessment, the date of death or the date of refusal.
Measured: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Duration of Response
Duration of overall response was measured from the time that measurement criteria are met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the onset of progression. Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date).
Missing onset of progression data because of refusal or because of death was replaced.
If several response evaluations for a patient showed progressive disease (PD), the time to PD was assessed by using the first of these measurements.
Measured: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Overall Survival of XELIRI Plus Bevacizumab and XELOX Plus Bevacizumab
Overall survival was measured as the time from the randomization date to the date of death. Patients without death date were censored at the date of the last tumor assessment (exception: availability of validated information about a later exitus date or a prolonged survival - in such a case the date of the follow-up assessment was either defined as the exitus date or replaced the last tumor assessment date) or the date of refusal.
Measured: date of death or date of last tumor assessment (28d safety f-u) in patients without death
Tumour Assessments (Based on RECIST Criteria) in 1st-line
Best response in first line was based on the tumor assessments (based on RECIST criteria) for target lesions and assessed by CT scans, MRI scans, X-ray, bone scan and clinical examination: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (sum LD) of target lesions; Progressive Disease (PD), >= 20% increase in the sum of the LD of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Measured: Baseline, every 8-9 weeks, 28d Safety follow-up
Tumour Assessments (Based on RECIST Criteria) in 2nd-line
Best response in second line was based on the tumor assessments (based on RECIST criteria) for target lesions and assessed by CT scans, MRI scans, X-ray, bone scan and clinical examination: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter (sum LD) of target lesions; Progressive Disease (PD), >= 20% increase in the sum of the LD of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Measured: Baseline, every 8-9 weeks, 28d Safety follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 201131 Aug 2017

First posted21 Apr 2014 (estimated)
Study startFeb 2011
Primary completion31 Aug 2017
Study completion31 Aug 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (18)Papers the sponsor has linked to this study.
Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 120 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02119026
Sponsor's protocol ID: ML25153_PASSION
Acronym: PASSION
Status last verified: Sep 2019
First submitted: 1 Apr 2014
Last updated: 25 Sep 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Publications

Arnold D, Petersen , Kindler M, et al. Patterns of maintenance treatment (Tx) following firstline bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study. J Clin Oncol 29: 2011 (suppl 4; abstr 502)
Benbow U, Maitra R, Hamilton JW, Brinckerhoff CE. Selective modulation of collagenase 1 gene expression by the chemotherapeutic agent doxorubicin. Clin Cancer Res. 1999 Jan;5(1):203-8.
PubMed 9918220
Yalcin S, Uslu R, Dane F, et al. A Randomized, multicenter phase III trial of bevacizumab plus capecitabine were given as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer. J Clin Oncol 29: 2011 (suppl 4; abstr 474)
Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995 Apr;95(4):1789-97. doi: 10.1172/JCI117857.
PubMed 7535799
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. doi: 10.1200/JCO.2004.05.113. Epub 2003 Dec 2.
PubMed 14657227
The Criteria Committee of the New York Heart Association. Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th ed. Boston, MA: Little Brown, 1964
Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). Clin Oncol 28:7s, 2010 (suppl; abstr 3501), Abstract No: 3501
Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. doi: 10.1038/sj.bjc.6603011.
PubMed 16508637
Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ. 2000 Sep 2;321(7260):531-5. doi: 10.1136/bmj.321.7260.531.
PubMed 10968812
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930.
PubMed 18421054
A. C. Reinacher-Schick, S. Kubicka, W. Freier, et al. Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4030)
Mabro M, Artru P, Andre T, Flesch M, Maindrault-Goebel F, Landi B, Lledo G, Plantade A, Louvet C, de Gramont A. A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer. 2006 May 8;94(9):1287-92. doi: 10.1038/sj.bjc.6603095.
PubMed 16622455
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. doi: 10.1016/S0140-6736(07)61086-1.
PubMed 17630036
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841-4. doi: 10.1038/362841a0.
PubMed 7683111
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
PubMed 15175435

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 25 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase II Study to Assess Efficacy and Safety of Capecitabine and Irinotecan Plus Bevacizumab Followed by Capecitabine and Oxaliplatin Plus Bevacizumab or the Reverse Sequence in Patients With Metastatic Colorectal Cancer
ClinicalTrials.gov ID: NCT02119026
Acronym / sponsor ID: PASSION / ML25153_PASSION
Conditions: Metastatic Colorectal Cancer
Keywords: metastatic colorectal cancer, Patients with metastatic colorectal cancer who did not receive, systemic treatment for their metastatic disease
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 120 participants (actual)
Lead sponsor: Prof. Dr. Werner ScheithauerUniversity, hospital or other
Study start: Feb 2011
Primary completion: 31 Aug 2017 (actual)
Study completion: 31 Aug 2017 (actual)
First posted: 21 Apr 2014 (estimated)
Results: Posted 25 Sep 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Capecitabine can be given in addition at the investigators' discretion until disease progression, unacceptable toxicity or patient refusal.

The primary endpoint is to determine the efficacy of a modified XELIRI + bevacizumab followed by XELOX + bevacizumab scheme at progression in comparison with the reverse sequence based on DDC.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
A: XELIRI + BEV Followed by XELOX + BEV	Active comparator	Drug: Capecitabine, Drug: Bevacizumab, Drug: Irinotecancapecitabine and irinotecan (XELIRI) plus bevacizumab (AVASTIN; BEV) Capecitabine : 800mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on day 1 q3w combined with irinotecan 200mg/m2 iv. d 1 q3w . Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression irinotecan will be replaced by oxaliplatin (arm A). Bevacizumab will be continued.
B: XELOX + BEV followed by XELIRI + BEV	Active comparator	Drug: Capecitabine, Drug: Bevacizumab, Drug: Oxaliplatincapecitabine and oxaliplatin (XELOX) plus bevacizumab (Avastin; BEV) Arm B: Capecitabine: 1000mg/m2 bid d1-14, bevacizumab 7,5 mg/kg given on d1 q3w combined with oxaliplatin 130mg/m2 iv. d 1 q3w Bevacizumab (7.5 mg/kg q3w) ± Capecitabine (1000 mg/m2 bid, days 1-14 q3w) maintenance At disease progression oxaliplatin will be replaced by irinotecan (arm B). Bevacizumab will be continued.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Written informed consent
Age >=18 years
Patient must be able to comply with the protocol
Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of metastases. 5 )Diagnosis of metastatic disease according to Response Evaluation Criteria in Solid Tumours (RECIST) not more than 3 months prior to enrolment.
6) Life Expectancy of at least 3 months 7) At least one measurable metastatic lesion (as per RECIST criteria) 8) Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy allowed if completed more than 6 months before inclusion. 9) Eastern Collaborative Oncology Group (ECOG) performance score of 0 or 1 10) Adequate haematological function: absolute neutrophil count (ANC) >= 1.5 x 109/L; platelets >= 100 x 109/L, Hb >= 9 g/dL 11) international normalized ratio (INR) <=1.5 and activated partial thromboplastin time (aPTT) <=1.5 x ULN within 7 days prior to starting study treatment 12) Adequate liver function: Serum bilirubin <=1.5 x ULN; alkaline phosphatase and transaminases <=2.5 x ULN (in case of liver metastases < 5 x ULN) 13) Serum Creatinine <=1.5 x ULN 14) Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2+, 24- hour urine must demonstrate <=1 g of protein in 24 hours 15) Negative serum pregnancy test within 7 days of starting study treatment in pre- menopausal women and women < 2 years after the onset of menopause. This test has to be reconfirmed by a urine test, should the 7 days window be exceeded. Fertile women (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).

Key exclusion criteria (21 listed)

Prior chemotherapeutic treatment for metastatic CRC
Symptomatic central nervous system (CNS) metastases
Significant vascular disease (e.g. aortic aneurysm potentially requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 months prior start of study treatment.
History of haemoptysis (= a half teaspoon of bright red blood per episode) within 1 month prior start of study treatment
Past or current history (within the last 2 years prior to treatment start) of other malignancies (Patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CapecitabineAlso: Brand Name: Xeloda800mg/m2 bid d1-14 ± 1000 mg/m2 bid,days 1-14 q3w: maintenance	Drug	A: XELIRI + BEV Followed by XELOX + BEV
CapecitabineAlso: Brand name: Xeloda1000mg/m2 bid d1-14,	Drug	B: XELOX + BEV followed by XELIRI + BEV
BevacizumabAlso: Brand name: Avastin7,5 mg/kg given on d1 q3w	Drug	A: XELIRI + BEV Followed by XELOX + BEV, B: XELOX + BEV followed by XELIRI + BEV
Oxaliplatin130mg/m2 iv. d 1 q3w	Drug	B: XELOX + BEV followed by XELIRI + BEV
Irinotecan200mg/m2 iv. d 1 q3w .	Drug	A: XELIRI + BEV Followed by XELOX + BEV

Primary outcome

Efficacy Duration of Disease Control by Tumor Assessment (CT/MRI/Clinical Examination)
Time frame: screening, every 8 to 9 weeks until progression, at end of treatment (other than progression), every 3 months until progression, death or up to 24 months (whatever comes first)
The primary variable was duration of disease control (DDC) and was defined as the sum of progression free survival intervals during first line and second line treatment (= time from the beginning of first line treatment until onset of progression during second line treatment). Patients without progression at the last tumor assessment date during their study participation were censored at this last tumor assessment date (exception: availability of validated information about a later onset of progression or a longer progression free interval - in such a case the date of the follow-up assessment was either defined as the onset of progression or replaced the last tumor assessment date).

8 secondary outcomes

First Line Progression Free Survival (PFS)
Time frame: at progression of disease (PD) in first line therapy or at 28 days safety follow-up in cases without PD
Second Line PFS
Time frame: at progression of disease (PD) in second line therapy or at 28 days safety follow-up in cases without PD
Overall Response Rate (Number of Participants With Response)
Time frame: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Time to Response
Time frame: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Duration of Response
Time frame: at the day of documented complete or partial response or at 28 days safety follow-up in cases without PD
Overall Survival of XELIRI Plus Bevacizumab and XELOX Plus Bevacizumab
Time frame: date of death or date of last tumor assessment (28d safety f-u) in patients without death
Tumour Assessments (Based on RECIST Criteria) in 1st-line
Time frame: Baseline, every 8-9 weeks, 28d Safety follow-up
Tumour Assessments (Based on RECIST Criteria) in 2nd-line
Time frame: Baseline, every 8-9 weeks, 28d Safety follow-up

Results and safety

Results posted to the registry on 25 Sep 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
A: XELIRI + BEV Followed by XELOX + BEV	58	32
B: XELOX + BEV Followed by XELIRI + BEV	62	24

Primary outcome: Efficacy Duration of Disease Control by Tumor Assessment (CT/MRI/Clinical Examination)

Time frame: screening, every 8 to 9 weeks until progression, at end of treatment (other than progression), every 3 months until progression, death or up to 24 months (whatever comes first). Median (95% Confidence Interval). Unit: days

Measure	A: XELIRI + BEV Followed by XELOX + BEV n = 58	B: XELOX + BEV Followed by XELIRI + BEV n = 62
Value	373.00 (321.52 to 424.48)	370.00 (253.255 to 486.745)

A: XELIRI + BEV Followed by XELOX + BEV vs B: XELOX + BEV Followed by XELIRI + BEV: p = 0.967, Mantel Haenszel

Population analysed: ITT-Population

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: From enrollment until 28 days of last study treatment for the individual patient. Adverse events/serious adverse events still ongoing after that timepoint were followed until last patient last visit (31-Aug-2017).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
A: XELIRI + BEV Followed by XELOX + BEV	43 of 58 (74.1%)	55 of 58 (94.8%)	4 of 58
B: XELOX + BEV Followed by XELIRI + BEV	51 of 62 (82.3%)	61 of 62 (98.4%)	8 of 62

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
BackgroundArnold D, Petersen , Kindler M, et al. Patterns of maintenance treatment (Tx) following firstline bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study. J Clin Oncol 29: 2011 (suppl 4; abstr 502)
Background: PubMed 9918220Benbow U, Maitra R, Hamilton JW, Brinckerhoff CE. Selective modulation of collagenase 1 gene expression by the chemotherapeutic agent doxorubicin. Clin Cancer Res. 1999 Jan;5(1):203-8.
BackgroundYalcin S, Uslu R, Dane F, et al. A Randomized, multicenter phase III trial of bevacizumab plus capecitabine were given as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer. J Clin Oncol 29: 2011 (suppl 4; abstr 474)
Background: PubMed 7535799Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995 Apr;95(4):1789-97. doi: 10.1172/JCI117857.
Background: PubMed 14657227Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. doi: 10.1200/JCO.2004.05.113. Epub 2003 Dec 2.
BackgroundThe Criteria Committee of the New York Heart Association. Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th ed. Boston, MA: Little Brown, 1964
BackgroundTabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). Clin Oncol 28:7s, 2010 (suppl; abstr 3501), Abstract No: 3501
Background: PubMed 16508637Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. doi: 10.1038/sj.bjc.6603011.
Background: PubMed 10968812Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ. 2000 Sep 2;321(7260):531-5. doi: 10.1136/bmj.321.7260.531.
Background: PubMed 18421054Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930.
BackgroundA. C. Reinacher-Schick, S. Kubicka, W. Freier, et al. Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4030)
Background: PubMed 16622455Mabro M, Artru P, Andre T, Flesch M, Maindrault-Goebel F, Landi B, Lledo G, Plantade A, Louvet C, de Gramont A. A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer. 2006 May 8;94(9):1287-92. doi: 10.1038/sj.bjc.6603095.
ethical review committeeLink provided by the sponsor.
Regulatory authority AustriaLink provided by the sponsor.
Medical University Vienna/Clin. Division of OncologyLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Werner Scheithauer, Prof. Dr. principal investigator

Medical University of Vienna

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Capecitabine, Bevacizumab and Oxaliplatin in people with Metastatic Colorectal Cancer, run by Prof. Dr. Werner Scheithauer at 1 site in Austria.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy Duration of Disease Control by Tumor Assessment (CT/MRI/Clinical Examination) (time frame: screening, every 8 to 9 weeks until progression, at end of treatment (other than progression), every 3 months until progression, death or up to 24 months (whatever comes first)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02119026, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2019.