Clinical trial NCT02271464: Maintenance Bevacizumab Only or Bevacizumab Plus Metronomic Chemotherapy in Advanced Colorectal Cancer
Official title: Phase II Randomized Study of Maintenance Treatment With Bevacizumab or Bevacizumab Plus Metronomic Chemotherapy After First-line Induction FOLFOXIRI Plus Bevacizumab for Metastatic Colorectal Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Metastatic colorectal cancer
Ist line therapy
metronimic therapy
bevacizumab
Lead sponsor: Azienda Ospedaliero, Universitaria Pisana
Sponsor class: OTHER
First posted: 2014-10-22
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study consist of 4-months induction first-line chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab followed by maintenance with bevacizumab or bevacizumab plus metronomic chemotherapy (with capecitabine and cyclophosphamide) in mCRC patients.

The main objective of this study is to preliminarily evaluate the potential effects of the combination of a metronomic chemotherapy with capecitabine and cyclophosphamide to maintenance bevacizumab on pharmacodynamic and clinical parameters among mCRC patients.


Eligibility criteria: Inclusion Criteria:

* Histologically proven diagnosis of colorectal cancer.
* Not resectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
* At least one measurable lesion according to RECIST criteria.
* Male or female of 18-75 years of age.
* ECOG PS \< 2 if aged \< 71 years, ECOG PS = 0 if aged 71-75 years;
* Life expectancy of at least 12 weeks.
* Previous adjuvant chemotherapy containing oxaliplatin is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse;
* Previous adjuvant chemotherapy with fluoropyrimidine monotherapy is allowed if more than 6 months have 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 institutional 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, 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.
* Written informed consent to treatment and translational analyses.

Exclusion Criteria:

* Radiotherapy to any site within 4 weeks before the study.
* 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.
* 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.
* 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.
* Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of 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.
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study (barrier contraceptive measure or oral contraception).

Primary outcomes:
measure: progression-free survival (PFS)
timeFrame: up to 4 years
Secondary outcomes:
measure: Best overall response rate (ORR)
timeFrame: up to 4 years
measure: Duration of response
timeFrame: up to 4 years
measure: Resection rate
timeFrame: up to 4 years
measure: Time to strategy failure (TSF)
timeFrame: up to 4 years
measure: Time to 2nd progressive disease
timeFrame: up to 4 years
measure: Overall survival (OS)
timeFrame: up to 4 years
measure: Toxicity rate
timeFrame: up to 4 years
measure: Overall toxicity rate
timeFrame: up to 4 years
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Istituto Ospedaliero Fondazione Poliambulanza Di Brescia
city: Brescia
country: Italy
facility: Pres.Ospedaliero Spedali Civili Brescia
city: Cremona
country: Italy
facility: Istituti Ospitalieri Di Cremona
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce E Carle Di Cuneo
city: Ferrara
country: Italy
facility: A.O. Universitaria Arcispedale S.Anna Di Ferrara
city: Frosinone
country: Italy
facility: Ausl Di Frosinone -
city: Genova
country: Italy
facility: E.O. Ospedali Galliera
city: Legnago
country: Italy
facility: Ospedale Per Acuti Mater Salutis Di Legnago
city: Lucca
country: Italy
facility: Oncologia AUSL 2 Lucca
city: Milano
country: Italy
facility: Irccs Fondazione Centro S. Raffaele Del Monte Tabor
city: Napoli
country: Italy
facility: A.O. Universitaria Federico Ii Di Napoli
city: Padova
country: Italy
facility: Irccs Istituto Oncologico Veneto (Iov)
city: Pisa
country: Italy
facility: Polo Oncologico Area Vasta Nord Ovest
city: Pontedera
country: Italy
facility: Ausl 5 Di Pisa
city: Prato
country: Italy
facility: Ospedale Mesericordia E Dolce
city: Reggio Emilia
country: Italy
facility: Ospedale S. Maria Nuova
city: Roma
country: Italy
facility: Ospedale San Giovanni Calibita Fatebenefratelli
city: Roma
country: Italy
facility: Ospedale San Pietro Fatebenefratelli Di Roma
city: Roma
country: Italy
facility: Campus Biomedico
city: Udine
country: Italy
facility: A.O. Universitaria S. Maria Della Misericordia
Study officials:
affiliation: Polo Oncologico Area Vasta Nord Ovest
name: Alfredo Falcone, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cremolini C, Marmorino F, Bergamo F, Aprile G, Salvatore L, Masi G, Dell'Aquila E, Antoniotti C, Murgioni S, Allegrini G, Borelli B, Gemma D, Casagrande M, Granetto C, Delfanti S, Di Donato S, Schirripa M, Sensi E, Tonini G, Lonardi S, Fontanini G, Boni L, Falcone A. Phase II randomised study of maintenance treatment with bevacizumab or bevacizumab plus metronomic chemotherapy after first-line induction with FOLFOXIRI plus Bevacizumab for metastatic colorectal cancer patients: the MOMA trial. Eur J Cancer. 2019 Mar;109:175-182. doi: 10.1016/j.ejca.2018.12.028. Epub 2019 Feb 5.
citation: van Dijk E, Biesma HD, Cordes M, Smeets D, Neerincx M, Das S, Eijk PP, Murphy V, Barat A, Bacon O, Prehn JHM, Betge J, Gaiser T, Fender B, Meijer GA, McNamara DA, Klinger R, Koopman M, Ebert MPA, Kay EW, Hennessey BT, Verheul HMW, Gallagher WM, O'Connor DP, Punt CJA, Loupakis F, Lambrechts D, Byrne AT, van Grieken NCT, Ylstra B. Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab. J Clin Oncol. 2018 Jul 10;36(20):2052-2060. doi: 10.1200/JCO.2017.77.1782. Epub 2018 May 24.
citation: Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi G, Moretto R R, Pietrantonio F, Marmorino F, Zucchelli G, Tomasello G, Tonini G, Allegrini G, Granetto C, Ferrari L, Urbani L, Cillo U, Pilati P, Sensi E, Pellegrinelli A, Milione M, Fontanini G, Falcone A. Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer. 2017 Mar;73:74-84. doi: 10.1016/j.ejca.2016.10.028. Epub 2016 Dec 13.