Maintenance Bevacizumab Only or Bevacizumab Plus Metronomic Chemotherapy in Advanced Colorectal Cancer

NCT ID: NCT02271464

Last Updated: 2017-12-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 232 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-31
• Study Completion Date: 2017-09-30

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.

Conditions

Metastatic Colorectal Cancer

Keywords

Metastatic colorectal cancer; Ist line therapy; metronimic therapy; bevacizumab

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Maintenance:BEVACIZUMAB

Induction: FOLFOXIRI; Manteinance: Bevacizumab

Group Type: EXPERIMENTAL

Maintenance:BEVACIZUMAB

Intervention Type: DRUG

Patients will be randomly assigned to receive induction chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab:

• BEVACIZUMAB 5 mg/kg over 30 minutes, day 1
• IRINOTECAN 165 mg/sqm IV over 1-h, day 1
• OXALIPLATIN 85 mg/sqm IV over 2-h, day 1
• L-LEUCOVORIN 200 mg/sqm IV over 2-h, day 1
• 5-FLUOROURACIL 3200 mg/sqm IV 48-h continuous infusion, starting on day 1

with cycles repeated every 2 weeks for 4 months (8 cycles), followed after 2 weeks by (if no progression occurs):

• BEVACIZUMAB 7.5 mg/kg over 30 minutes, day 1 (every three weeks)

Maintenance:BEVACIZUMAB+CAPECITABINE+CYCLOPHOSPHAMIDE

Induction: FOLFOXIRI; Maintenance:BEVACIZUMAB+CAPECITABINE+CYCLOPHOSPHAMIDE(Metronomic Chemotherapy)

Group Type: EXPERIMENTAL

Maintenance:BEVACIZUMAB+CAPECITABINE+CYCLOPHOSPHAMIDE

Intervention Type: DRUG

Patients will be randomly assigned to receive induction chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab:

• BEVACIZUMAB 5 mg/kg over 30 minutes, day 1
• IRINOTECAN 165 mg/sqm IV over 1-h, day 1
• OXALIPLATIN 85 mg/sqm IV over 2-h, day 1
• L-LEUCOVORIN 200 mg/sqm IV over 2-h, day 1
• 5-FLUOROURACIL 3200 mg/sqm IV 48-h continuous infusion, starting on day 1

with cycles repeated every 2 weeks for 4 months (8 cycles), followed after 2 weeks by (if no progression occurs):

• BEVACIZUMAB 7.5 mg/kg over 30 minutes, day 1 (every three weeks),
• CAPECITABINE 500 mg/tid orally, continuously,
• CYCLOPHOSPHAMIDE 50 mg/day orally, continuously.

Interventions

Maintenance:BEVACIZUMAB

Patients will be randomly assigned to receive induction chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab:

• BEVACIZUMAB 5 mg/kg over 30 minutes, day 1
• IRINOTECAN 165 mg/sqm IV over 1-h, day 1
• OXALIPLATIN 85 mg/sqm IV over 2-h, day 1
• L-LEUCOVORIN 200 mg/sqm IV over 2-h, day 1
• 5-FLUOROURACIL 3200 mg/sqm IV 48-h continuous infusion, starting on day 1

with cycles repeated every 2 weeks for 4 months (8 cycles), followed after 2 weeks by (if no progression occurs):

• BEVACIZUMAB 7.5 mg/kg over 30 minutes, day 1 (every three weeks)

Intervention Type: DRUG

Maintenance:BEVACIZUMAB+CAPECITABINE+CYCLOPHOSPHAMIDE

Patients will be randomly assigned to receive induction chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab:

• BEVACIZUMAB 5 mg/kg over 30 minutes, day 1
• IRINOTECAN 165 mg/sqm IV over 1-h, day 1
• OXALIPLATIN 85 mg/sqm IV over 2-h, day 1
• L-LEUCOVORIN 200 mg/sqm IV over 2-h, day 1
• 5-FLUOROURACIL 3200 mg/sqm IV 48-h continuous infusion, starting on day 1

with cycles repeated every 2 weeks for 4 months (8 cycles), followed after 2 weeks by (if no progression occurs):

• BEVACIZUMAB 7.5 mg/kg over 30 minutes, day 1 (every three weeks),
• CAPECITABINE 500 mg/tid orally, continuously,
• CYCLOPHOSPHAMIDE 50 mg/day orally, continuously.

Intervention Type: DRUG

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Azienda Ospedaliero, Universitaria Pisana

OTHER

Sponsor Role: lead

Responsible Party

Alfredo Falcone

Prof.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Alfredo Falcone, MD

Role: PRINCIPAL_INVESTIGATOR

Polo Oncologico Area Vasta Nord Ovest

Locations

Istituto Ospedaliero Fondazione Poliambulanza Di Brescia

Brescia, , Italy

Pres.Ospedaliero Spedali Civili Brescia

Brescia, , Italy

Istituti Ospitalieri Di Cremona

Cremona, , Italy

Azienda Ospedaliera S. Croce E Carle Di Cuneo

Cuneo, , Italy

A.O. Universitaria Arcispedale S.Anna Di Ferrara

Ferrara, , Italy

Ausl Di Frosinone -

Frosinone, , Italy

E.O. Ospedali Galliera

Genova, , Italy

Ospedale Per Acuti Mater Salutis Di Legnago

Legnago, , Italy

Oncologia AUSL 2 Lucca

Lucca, , Italy

Irccs Fondazione Centro S. Raffaele Del Monte Tabor

Milan, , Italy

A.O. Universitaria Federico Ii Di Napoli

Napoli, , Italy

Irccs Istituto Oncologico Veneto (Iov)

Padua, , Italy

Polo Oncologico Area Vasta Nord Ovest

Pisa, , Italy

Ausl 5 Di Pisa

Pontedera, , Italy

Ospedale Mesericordia E Dolce

Prato, , Italy

Ospedale S. Maria Nuova

Reggio Emilia, , Italy

Ospedale San Giovanni Calibita Fatebenefratelli

Roma, , Italy

Ospedale San Pietro Fatebenefratelli Di Roma

Roma, , Italy

Campus Biomedico

Roma, , Italy

A.O. Universitaria S. Maria Della Misericordia

Udine, , Italy

Countries

Italy

References

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.

Reference Type: DERIVED

PMID: 30735919 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29792754 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27986363 (View on PubMed)

Other Identifiers

2011-006332-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MOMA261111

Identifier Type: -

Identifier Source: org_study_id