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Folfoxiri Plus Bev Followed by Reintroduction of Folfoxiri Plus Bev at Progression Versus Folfox Plus Bev Followed by Folfiri Plus Bev in mCRC (TRIBE2)

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ClinicalTrials.gov Identifier: NCT02339116
Recruitment Status : Active, not recruiting
First Posted : January 15, 2015
Last Update Posted : January 16, 2019
Sponsor:
Information provided by (Responsible Party):
Gruppo Oncologico del Nord-Ovest

Tracking Information
First Submitted Date  ICMJE January 12, 2015
First Posted Date  ICMJE January 15, 2015
Last Update Posted Date January 16, 2019
Actual Study Start Date  ICMJE February 26, 2015
Actual Primary Completion Date May 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2015)
Progression Free Survival 2 (PFS2) [ Time Frame: from randomization to the first of the following events: a) death; b) disease progression on any treatment given after 1st progression, up to 18 months after last patient last visit ]
PFS2 will be defined as beginning with randomization and ending with the first of the following events: a) death; b) disease progression on any treatment given after 1st progression. For patients that will not receive any treatment within 3 months after 1st progression, PFS2 will be equal to PFS. The determination of disease progression will be based on investigator-reported measurements. Disease status will be evaluated according to RECIST 1.1 criteria. Censoring rules for PFS2 will be: end of study without PD, loss at follow-up. Curative surgery for metastasis will not result in censoring for PFS2.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02339116 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2015)
  • Progression free survival (PFS) [ Time Frame: from randomization to to the first documentation of objective disease progression or death due to any cause, whichever occurs first, up to 18 months after last patient last visit ]
    Progression free survival (PFS) is defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumor assessments after baseline will have time to event censored on the date of randomization
  • 2nd-Progression free survival (2nd-PFS) [ Time Frame: from the beginning of the second-line treatment to the documentation of objective disease progression or death due to any cause, whichever occurs first, up to 18 months after last patient last visit ]
    2nd-Progression free survival (2nd-PFS) is defined as the time from the beginning of the second-line treatment to the documentation of objective disease progression or death due to any cause, whichever occurs first. 2nd-PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and 2nd-progression free at the time of the analysis.
  • Time to failure of strategy (TFS) [ Time Frame: from randomization to: death; patient requires a new therapeutic agent; PD on treatment with all agents of the initial strategy; PD during a partial or complete treatment holiday and receives no further therapy within 3 months, up to 18 months after LPLV ]
    Time to failure of strategy (TFS) is defined as the time time from randomization to the first of the following events: death; patient requires the addition of a new therapeutic agent (i.e. an agent not included in the original strategy); patient experiences disease progression while being treated with all agents that are components of the initial treatment strategy (except for agents which cannot be used because of persistent toxicity or contraindications); or patient experiences disease progression during a partial or complete treatment holiday from initial treatment strategy and receives no further therapy within 3 months. Subjects who did not have an event as stated above while on study will be censored at the last evaluable radiographic assessment date.
  • Overall survival (OS) [ Time Frame: from randomization to the date of death due to any cause up to 18 months after last patient last visit ]
    Overall survival (OS) is defined as the time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
  • Objective Response Rate [ Time Frame: Every 8 weeks, up to 18 months after last patient last visit ]
    percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during the induction and the maintenance phases of treatment.
  • Toxicity Rate [ Time Frame: At every cycle of treatment up to the second evidence of PD or up to 18 months after LPLV ]
    Toxicity Rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0), during the induction and the maintenance phases of treatment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Folfoxiri Plus Bev Followed by Reintroduction of Folfoxiri Plus Bev at Progression Versus Folfox Plus Bev Followed by Folfiri Plus Bev in mCRC
Official Title  ICMJE FIRST-LINE FOLFOXIRI PLUS BEVACIZUMAB FOLLOWED BY REINTRODUCTION OF FOLFOXIRI PLUS BEVACIZUMAB AT PROGRESSION Versus FOLFOX PLUS BEVACIZUMAB FOLLOWED BY FOLFIRI PLUS BEVACIZUMAB AT PROGRESSION IN FIRST- AND SECOND-LINE TREATMENT OF UNRESECTABLE METASTATIC COLORECTAL CANCER.
Brief Summary

Bev improves the efficacy of first-line chemotherapy in unresectable mCRC. In the phase III TRIBE trial upfront FOLFOXIRI plus bev provided a significant advantage in terms of PFS and RR compared to FOLFIRI plus bev. A trend toward better OS was also evidenced. The second-line treatment was at investigator's choice. A manageable increase in diarrhea, mucositis and neutropenia was reported, while no differences in febrile neutropenia, serious adverse events and toxic deaths were evidenced.

A growing amount of data support the clinical relevance of achieving an early and deep tumor shrinkage.

Phase III TML and BEBYP trials demonstrated that the continuation of bev beyond disease progression combined with a switched chemotherapy regimen provided a significant advantage in terms of OS and PFS.

Based on recent evidences, the partial interruption of the upfront "induction" chemotherapy before disease progression and the prosecution of bev until disease progression as maintenance treatment is a valid strategy in the treatment of mCRC.

On the basis of these considerations, a first-line doublet plus bev followed by a second-line switched doublet (from oxaliplatin to irinotecan and viceversa) plus bev should be considered a standard option for mCRC patients. Only retrospectively collected data are currently available about the efficacy of first-line FOLFOXIRI plus bev followed by second-line rechallenge with FOLFOXIRI plus bev. We therefore designed the present phase III randomized trial of first-line FOLFOXIRI plus bev followed by reintroduction of FOLFOXIRI plus bev at progression versus FOLFOX plus bev followed by FOLFIRI plus bev at progression in first- and second-line treatment of unresectable mCRC patients.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE
  • Drug: fluoruracil
  • Drug: Oxaliplatin
  • Drug: Irinotecan
  • Drug: Bevacizumab
Study Arms  ICMJE
  • Experimental: Folfoxiri/bev --> folfoxiri/bev

    FOLFOXIRI plus bev (to be repeated every 2 weeks for a maximum of 8 cycles):

    Bevacizumab 5 mg/kg iv over 30 minutes, day 1 Irinotecan 165 mg/sqm iv over 60 minutes, day 1 Oxaliplatin 85 mg/sqm iv over 2 hours, day 1 L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 5-fluorouracil 3200 mg/sqm 48 h-continuous infusion, starting on day 1 At the time of disease progression, patients will re-introduce FOLFOXIRI plus bev at the same doses and schedule previously tolerated, for a maximum of 8 cycles. If no progression occurs during FOLFOXIRI plus bev, patients will receive maintenance 5-FU/LV plus bev at the same dose used in the last cycle of the induction treatment.

    Interventions:
    • Drug: fluoruracil
    • Drug: Oxaliplatin
    • Drug: Irinotecan
    • Drug: Bevacizumab
  • Active Comparator: folfox/bev-->folfiri/bev

    mFOLFOX-6 plus bev (to be repeated every 2 weeks for a maximum of 8 cycles) Bevacizumab 5 mg/kg iv over 30 minutes, day 1 Oxaliplatin 85 mg/sqm iv over 2 hours, day 1 L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 5-fluoruracil 400 mg/sqm iv bolus, day 1 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion, starting on day 1

    At the time of disease progression patients will receive FOLFIRI plus bev (to be repeated every 2 weeks for a maximum of 8 cycles):

    Bevacizumab 5 mg/kg iv over 30 minutes, day 1 Irinotecan 180 mg/sqm iv over 2 hours, day 1 L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 5-fluoruracil 400 mg/sqm iv bolus, day 1 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion.

    Interventions:
    • Drug: fluoruracil
    • Drug: Oxaliplatin
    • Drug: Irinotecan
    • Drug: Bevacizumab
Publications * Cremolini C, Marmorino F, Loupakis F, Masi G, Antoniotti C, Salvatore L, Schirripa M, Boni L, Zagonel V, Lonardi S, Aprile G, Tamburini E, Ricci V, Ronzoni M, Pietrantonio F, Valsuani C, Tomasello G, Passardi A, Allegrini G, Di Donato S, Santini D, Falcone A; all the investigators of the Gruppo Oncologico del Nord Ovest. TRIBE-2: a phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group. BMC Cancer. 2017 Jun 9;17(1):408. doi: 10.1186/s12885-017-3360-z.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 14, 2015)
654
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Actual Primary Completion Date May 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Main Inclusion Criteria:

Histologically proven diagnosis of colorectal cancer Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease At least one measurable lesion according to RECIST1.1 criteria Availability of a tumoral sample Male or female of 18-75 years of age ECOG PS < or = 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years Life expectancy of at least 12 weeks Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hgb >9 g/dl Total bilirubin 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) <2.5 x UNL (or <5 x UNL in case of liver metastases) alkaline phosphatase <2.5 x UNL (or <5 x UNL in case of liver metastases) Creatinine clearance >50 mL/min or serum creatinine 1.5 x UNL Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate <1 g of protein/24 hr Will and ability to comply with the protocol Written informed consent to study procedures and to molecular analyses -

Main Exclusion Criteria:

Radiotherapy to any site within 4 weeks before the study Previous adjuvant oxaliplatin-containing chemotherapy Previous treatment with bevacizumab Untreated brain metastases or spinal cord compression or primary brain tumours History or evidence upon physical examination of CNS disease unless adequately treated Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria Serious, non-healing wound, ulcer, or bone fracture Evidence of bleeding diathesis or coagulopathy Uncontrolled hypertension and prior histor of hypertensive crisis or hypertensive encephalopathy Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment Any previous venous thromboembolism > NCI CTCAE Grade 3 History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.

Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes Chronic, daily treatment with high-dose aspirin (>325 mg/day) Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer) Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02339116
Other Study ID Numbers  ICMJE TRIBE2
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gruppo Oncologico del Nord-Ovest
Study Sponsor  ICMJE Gruppo Oncologico del Nord-Ovest
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Alfredo Falcone, MD Azienda Ospedaliero Universitaria Pisana, Pisa Italy
PRS Account Gruppo Oncologico del Nord-Ovest
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP