Colorectal Cancer MetastaticPhase 2VISNU-2NCT01640444
Influence of BRAF and PIK3K Status on the Efficacy of 5-Fluorouracil/Leucovorin/Oxaliplatin (FOLFIRI) Plus Bevacizumab or Cetuximab in Patients With RAS Wild-type Metastatic Colorectal Carcinoma and < 3 Circulating Tumor Cells (CTC)
A Phase 2 study testing FOLFIRI + bevacizumab and FOLFIRI + cetuximab in people with Colorectal Cancer Metastatic, run by Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) at 1 site in Spain.
Trial summary
The purpose of the study is to explore the influence of BRAF and PIK3K status on the efficacy of FOLFIRI plus Bevacizumab or Cetuximab, as first line therapy of patients with RAS wild-type metastatic colorectal carcinoma and < 3 circulating tumor cells Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Colorectal Cancer Metastatic
- What is being tested?
- FOLFIRI + bevacizumab and FOLFIRI + cetuximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 240 participants
- Where
- 1 siteSpain
- Study dates
- Jul 2012to Nov 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient's Informed consent in written.
- Age between 18-70 years old.
- ECOG 0-1.
- Life expectancy of at least 3 months.
- Histological confirmation of adenocarcinoma of the colon or rectum.
- Sample of tumour tissue available for evaluation of genes RAS, BRAF and PI3K. To be included in the study patients should present < 3 CTC in peripheral blood and RAS wild-type present in the sample of tumor tissue.
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- Measurable metastatic stage IV disease with at least 1 measurable metastatic lesion following RECIST criteria v 1.1 (non suitable for radical surgery at the inclusion time).
- Prior radiotherapy is allowed but must be completed at least 4 weeks before randomization (if applicable).
- Adequate bone marrow, liver and renal function.
- Women of childbearing potential must have a negative serum or urine pregnancy test. Postmenopausal women must have been amenorrheic for at least 12 months.Both men and women participating in this study must use adequate contraception.
- Subject must have the ability, in the opinion of the investigator, to comply with all the study procedures and follow-up examinations.
Who cannot join
- Previous chemotherapy for metastatic disease.
- Prior treatment with Bevacizumab, or EGFR inhibitors
- Any anticancer treatment (chemotherapy, hormonal treatment, radiation treatment, surgery , immunotherapy, biologic therapy or tumour embolization) within 4 weeks before randomization.
- Use of any investigational drug within 4 weeks before start the treatment.
- Clinical or radiographic evidence of brain metastasis.
- Uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on repeated measurement) despite optimal medical management.
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- Previous history of hypertensive encephalopathy or hypertensive crises.
- Current or history of peripheral neuropathy > or equal to 1 NCICTCAE.
- Patients classified as fragile according to criteria listed in the protocol.
- Significant cardiovascular disease (e.g. AVC, myocardial infarction, within 6 months before randomization). Unstable angina, congestive heart failure New York Heart Association (NYHA) ≥ class II, arrhythmia that requires treatment within 3 months before randomization.
- Significant vascular disease (e.g. aortic aneurism requiring surgical intervention, pulmonary embolic, peripheral arterial thrombosis) within 6 months before randomization.
- Previous history of significant haemorrhage /severe, within 1 month before randomization.
- Major surgery, open surgical biopsy or significant traumatic injury within 4 weeks before randomization.
- Large bore needle biopsy of a major organ within 14 days before randomization. Placement of central venous access port > or equal to 7 days before randomization is permitted.
- Evidence or history of bleeding diathesis or coagulopathy.
- INR >1.5 within 14 days prior to starting study treatment. EXEMPTION: patients on full anticoagulation must have an in-range INR[usually between 2-3]. Any anticoagulation therapy must be at stable dosing prior to enrolment.
- History of previous abdominal fistula or gastrointestinal perforation within 6 months before randomization.
- Serious non-healing wound, ulcer or bone fracture.
- Acute or sub-acute of intestinal occlusion or history of intestinal inflammatory disease.
- History of uncontrolled convulsive crises.
- History of pulmonary fibrosis, acute lung disease or interstitial pneumonia.
- Chronic, actual o recent use (10 days prior first drug administration) of acetylsalicylic acic (aspirin) > 325 mg/day or clopidogrel (75mg/day) or other treatments that can cause gastrointestinal ulcer (low-dose aspirin is permitted < or equal to 325 mg/day).
- Urinary protein excretion > or equal to 2+ (dipstick). If > or equal 2 g proteinuria is detected with dipstick, a 24-hour period urine test will be performed and the result should be < or equal to 1 g/24 hours to permit the inclusion of the patient in the clinical trial
- Known human immunodeficiency virus infection or chronic hepatitis B or C infection or other uncontrolled, severe concurrent infection .
- Current infection > or equal to Grade 2 (NCI-CTCAE).
- Any previous or concurrent cancer different to colorectal carcinoma within 5 years before to start the treatment. Subjects with successfully treated, non-invasive cancers, including cervical cancer in situ, basal cell carcinoma will be allowed to participate in the clinical trial. Or those cancer treated with curative intention without disease evidence in the last 5 years at least
- Known or suspected allergy or hypersensitivity to any component of bevacizumab, cetuximab, irinotecan, or 5-FU/LV.
- Any medical, psychological, or social condition that may interfere with the subject's participation in the study or evaluation of the study results.
- Any psychological, familial or geographic situation that interferes in the adequate follow-up and adherence to the study protocol.
- Women who are pregnant or breast-feeding.
Trial locations and contacts
1 site in 1 country.
Spain1 site
Spanish Cooperative Group for Digestive Tumour Therapy
Madrid, 28046
About this study
Official title: Randomized Phase II Study to Explore the Influence of BRAF and PIK3K Status on the Efficacy of FOLFIRI Plus Bevacizumab or Cetuximab, as First Line Therapy of Patients With RAS Wild-type Metastatic Colorectal Carcinoma and < 3 Circulating Tumor Cells
The purpose of the study is to explore the influence of BRAF and PIK3K status on the efficacy of FOLFIRI plus Bevacizumab or Cetuximab, as first line therapy of patients with RAS wild-type metastatic colorectal carcinoma and < 3 circulating tumor cells
- Conditions
- Colorectal Cancer Metastatic
- Being tested
- FOLFIRI + bevacizumab, FOLFIRI + cetuximab
- Keywords
- colorectal carcinoma, BRAF and PIK3K, FOLFIRI -Bevacizumab -Cetuximab, circulating tumor cells
- Medical subject headings
- Colorectal Neoplasms, Hereditary Sensory and Autonomic Neuropathies, Neoplastic Cells, Circulating
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FOLFIRI + bevacizumabDrug
- Bevacizumab 5 mg/kg iv, followed by
- Irinotecan 180 mg/m2 iv administered over a period of 30-90 minutes, followed by
- Leucovorin (LV) 400 mg/m2 iv administered over a period of 2 hours, followed by
- 5-FU 400 mg/m2 iv bolus, followed by
- 5-FU 2,400 mg/m2 for 46 h continuous infusion. This treatment will start on day 1 and will be repeated every 2 weeks (1 cycle).
FOLFIRI + cetuximabDrug
- Cetuximab in an initial 120-minute infusion on day 1 of 400 mg/m2, followed by 60-minute infusions of cetuximab at a dose of 250 mg/m2, once weekly
- FOLFIRI:
- Irinotecan 180 mg/m2 iv administered over a period of 30-90 minutes, followed by
- Leucovorin (LV) 400 mg/m2 iv administered over a period of 2 hours, followed by
- 5-FU 400 mg/m2 iv bolus, followed by
- 5-FU 2,400 mg/m2 for 46 h continuous infusion FOLFIRI will be given after the cetuximab infusion on day 1 of each period (every 2 weeks: 1 cycle).
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | FOLFIRI+bevacizumab Receives: Drug: FOLFIRI + bevacizumab |
| B | Experimental | FOLFIRI + cetuximab Receives: Drug: FOLFIRI + cetuximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
progression free survival (PFS)
Measured: 5 years
Secondary outcomes (6)
Overall survival (OS)
Measured: 5 years
Response rate (RR)
Measured: 5 years
Radical Resection (R0) surgery rate
Measured: 5 years
CTC count basal and correlate to PFS, OS, RR
Measured: 5 years
Adverse events
Measured: 5 years
Correlation of molecular status of bio markers related to the cellular and tumoral reproduction and/or mode of action and clinical anti-tumour activity outcome ( PFS, OS, RR)
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jul 2012 (estimated)
- Study startJul 2012
- Primary completionNov 2018
- Study completionNov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Colorectal Cancer MetastaticStudies 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
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 240 participants (actual)
Sponsor and investigators
- Lead sponsor
- Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
- Sponsor type
- University, hospital or other
- Collaborators
- Roche Pharma AG
- Responsible party
- Sponsor
- Investigators
- Eduardo Díaz-Rubio, MD-PhD, Study chair, Hospital San Carlos, MadridEnrique Aranda, MD-PhD, Study chair, Hospital Reina SofíaJavier Sastre, MD-PhD, Study chair, Hospital San Carlos, Madrid
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01640444
- Sponsor's protocol ID
- TTD-12-02
- Other IDs
- 2012-000840-90
- Acronym
- VISNU-2
- Status last verified
- Aug 2018
- First submitted
- 13 Jun 2012
- Last updated
- 11 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Valladares-Ayerbes M, Toledano-Fonseca M, Grana B, Jimenez-Fonseca P, Pulido-Cortijo G, Gil S, Sastre J, Salud A, Rivera F, Salgado M, Garcia-Alfonso P, Lopez Lopez R, Guillen-Ponce C, Rodriguez-Ariza A, Vieitez JM, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). Associations of blood RNA biomarkers and circulating tumour cells in patients with previously untreated metastatic colorectal cancer. BMC Cancer. 2025 Apr 21;25(1):743. doi: 10.1186/s12885-025-14098-9.
PubMed 40259317Jimenez-Fonseca P, Sastre J, Garcia-Alfonso P, Gomez-Espana MA, Salud A, Gil S, Rivera F, Reina JJ, Quintero G, Valladares-Ayerbes M, Safont MJ, La Casta A, Robles-Diaz L, Garcia-Paredes B, Lopez Lopez R, Guillot M, Gallego J, Alonso-Orduna V, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNU-1 and Phase II VISNU-2 Randomized Trials. Clin Colorectal Cancer. 2023 Jun;22(2):222-230. doi: 10.1016/j.clcc.2023.02.004. Epub 2023 Feb 21.
PubMed 36944559Sastre J, Orden V, Martinez A, Bando I, Balbin M, Bellosillo B, Palanca S, Peligros Gomez MI, Mediero B, Llovet P, Moral VM, Vieitez JM, Garcia-Alfonso P, Calle SG, Ortiz-Morales MJ, Salud A, Quintero G, Lopez C, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). Association Between Baseline Circulating Tumor Cells, Molecular Tumor Profiling, and Clinical Characteristics in a Large Cohort of Chemo-naive Metastatic Colorectal Cancer Patients Prospectively Collected. Clin Colorectal Cancer. 2020 Sep;19(3):e110-e116. doi: 10.1016/j.clcc.2020.02.014. Epub 2020 Mar 6.
PubMed 32278676
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase II Study to Explore the Influence of BRAF and PIK3K Status on the Efficacy of FOLFIRI Plus Bevacizumab or Cetuximab, as First Line Therapy of Patients With RAS Wild-type Metastatic Colorectal Carcinoma and < 3 Circulating Tumor Cells
- ClinicalTrials.gov ID
- NCT01640444
- Acronym / sponsor ID
- VISNU-2 / TTD-12-02
- Conditions
- Colorectal Cancer Metastatic
- Keywords
- colorectal carcinoma, BRAF and PIK3K, FOLFIRI -Bevacizumab -Cetuximab, circulating tumor cells
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 240 participants (actual)
- Lead sponsor
- Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)University, hospital or other
- Collaborators
- Roche Pharma AG
- Study start
- Jul 2012 (actual)
- Primary completion
- Nov 2018 (actual)
- Study completion
- Nov 2018 (actual)
- First posted
- 13 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to explore the influence of BRAF and PIK3K status on the efficacy of FOLFIRI plus Bevacizumab or Cetuximab, as first line therapy of patients with RAS wild-type metastatic colorectal carcinoma and < 3 circulating tumor cells
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: FOLFIRI + bevacizumabFOLFIRI+bevacizumab |
| B | Experimental | Drug: FOLFIRI + cetuximabFOLFIRI + cetuximab |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Patient's Informed consent in written.
- Age between 18-70 years old.
- ECOG 0-1.
- Life expectancy of at least 3 months.
- Histological confirmation of adenocarcinoma of the colon or rectum.
Key exclusion criteria (30 listed)
- Previous chemotherapy for metastatic disease.
- Prior treatment with Bevacizumab, or EGFR inhibitors
- Any anticancer treatment (chemotherapy, hormonal treatment, radiation treatment, surgery , immunotherapy, biologic therapy or tumour embolization) within 4 weeks before randomization.
- Use of any investigational drug within 4 weeks before start the treatment.
- Clinical or radiographic evidence of brain metastasis.
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 |
|---|---|---|
| FOLFIRI + bevacizumab* Bevacizumab 5 mg/kg iv, followed by * Irinotecan 180 mg/m2 iv administered over a period of 30-90 minutes, followed by * Leucovorin (LV) 400 mg/m2 iv administered over a period of 2 hours, followed by * 5-FU 400 mg/m2 iv bolus, followed by * 5-FU 2,400 mg/m2 for 46 h continuous infusion. This treatment will start on day 1 and will be repeated every 2 weeks (1 cycle). | Drug | A |
| FOLFIRI + cetuximab* Cetuximab in an initial 120-minute infusion on day 1 of 400 mg/m2, followed by 60-minute infusions of cetuximab at a dose of 250 mg/m2, once weekly * FOLFIRI: * Irinotecan 180 mg/m2 iv administered over a period of 30-90 minutes, followed by * Leucovorin (LV) 400 mg/m2 iv administered over a period of 2 hours, followed by * 5-FU 400 mg/m2 iv bolus, followed by * 5-FU 2,400 mg/m2 for 46 h continuous infusion FOLFIRI will be given after the cetuximab infusion on day 1 of each period (every 2 weeks: 1 cycle). | Drug | B |
Primary outcome
progression free survival (PFS)
Time frame: 5 years
6 secondary outcomes
Overall survival (OS)
Time frame: 5 years
Response rate (RR)
Time frame: 5 years
Radical Resection (R0) surgery rate
Time frame: 5 years
CTC count basal and correlate to PFS, OS, RR
Time frame: 5 years
Adverse events
Time frame: 5 years
Correlation of molecular status of bio markers related to the cellular and tumoral reproduction and/or mode of action and clinical anti-tumour activity outcome ( PFS, OS, RR)
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2019.
- Derived from this study: PubMed 40259317Valladares-Ayerbes M, Toledano-Fonseca M, Grana B, Jimenez-Fonseca P, Pulido-Cortijo G, Gil S, Sastre J, Salud A, Rivera F, Salgado M, Garcia-Alfonso P, Lopez Lopez R, Guillen-Ponce C, Rodriguez-Ariza A, Vieitez JM, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). Associations of blood RNA biomarkers and circulating tumour cells in patients with previously untreated metastatic colorectal cancer. BMC Cancer. 2025 Apr 21;25(1):743. doi: 10.1186/s12885-025-14098-9.
- Derived from this study: PubMed 36944559Jimenez-Fonseca P, Sastre J, Garcia-Alfonso P, Gomez-Espana MA, Salud A, Gil S, Rivera F, Reina JJ, Quintero G, Valladares-Ayerbes M, Safont MJ, La Casta A, Robles-Diaz L, Garcia-Paredes B, Lopez Lopez R, Guillot M, Gallego J, Alonso-Orduna V, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNU-1 and Phase II VISNU-2 Randomized Trials. Clin Colorectal Cancer. 2023 Jun;22(2):222-230. doi: 10.1016/j.clcc.2023.02.004. Epub 2023 Feb 21.
- Derived from this study: PubMed 32278676Sastre J, Orden V, Martinez A, Bando I, Balbin M, Bellosillo B, Palanca S, Peligros Gomez MI, Mediero B, Llovet P, Moral VM, Vieitez JM, Garcia-Alfonso P, Calle SG, Ortiz-Morales MJ, Salud A, Quintero G, Lopez C, Diaz-Rubio E, Aranda E; Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD). Association Between Baseline Circulating Tumor Cells, Molecular Tumor Profiling, and Clinical Characteristics in a Large Cohort of Chemo-naive Metastatic Colorectal Cancer Patients Prospectively Collected. Clin Colorectal Cancer. 2020 Sep;19(3):e110-e116. doi: 10.1016/j.clcc.2020.02.014. Epub 2020 Mar 6.
- Related InfoLink 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.
Eduardo Díaz-Rubio, MD-PhD study chair
Hospital San Carlos, Madrid
Enrique Aranda, MD-PhD study chair
Hospital Reina Sofía
Javier Sastre, MD-PhD study chair
Hospital San Carlos, Madrid
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 FOLFIRI + bevacizumab and FOLFIRI + cetuximab in people with Colorectal Cancer Metastatic, run by Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) at 1 site in Spain.
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 11 inclusion and 30 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 11 Apr 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 Spain. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
progression free survival (PFS) (time frame: 5 years). 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 NCT01640444, which also lists 3 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 11 Apr 2019.