Clinical trial NCT00720512: Second-Line Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer Who Have Received First-Line Chemotherapy and Bevacizumab
Official title: AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
adenocarcinoma of the rectum
recurrent colon cancer
recurrent rectal cancer
stage IV colon cancer
stage IV rectal cancer
stage III rectal cancer
stage III colon cancer
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
First posted: 2008-07-22
Enrollment: 184
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: RATIONALE: Drugs used in chemotherapy, such as irinotecan, oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether combination chemotherapy is more effective with or without bevacizumab in treating metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying second-line combination chemotherapy to see how well it works compared with or without bevacizumab in treating patients with metastatic colorectal cancer who have received first-line chemotherapy and bevacizumab.

Detailed description: OBJECTIVES:

Primary

* To compare the progression-free survival of second-line chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer who have received first-line chemotherapy with bevacizumab.

Secondary

* To compare the overall survival, response rate, and safety profile of second-line chemotherapy of these regimens in these patients.
* To conduct pharmacogenomics assessment of candidate variants in the VEGF gene and evaluate their association with progression-free survival and other study outcomes.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, ECOG performance status (0 vs 1-2), disease-free interval from the last administration of first-line chemotherapy for metastatic disease (≤ 3 months vs \> 3 months), and type of second-line chemotherapy (irinotecan hydrochloride, leucovorin calcium, and fluorouracil \[FOLFIRI\] vs oxaliplatin, leucovorin calcium, and fluorouracil \[mFOLFOX-6\]). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over 1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil IV over 46 hours continuously beginning on day 1.
* Arm II: Patients receive combination chemotherapy as in arm I and bevacizumab IV on day 1.

Treatment in both arms repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Existing formalin-fixed paraffin-embedded tumor tissue samples are assessed for pharmacogenomics and markers predictive of response, resistance to, or toxicity from bevacizumab. Samples are analyzed via RT-PCR, array comparative genomic hybridization, fluorescence in situ hybridization, sequencing of candidate genes, and immunohistochemistry.

After completion of study treatment, patients are followed for 1 year.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed colorectal adenocarcinoma

  * Metastatic or unresectable disease
* Progressive disease based on the following criteria:

  * Progression during or after first-line chemotherapy for metastatic disease, including any of the following:

    * Fluoropyrimidine-based monotherapy with bevacizumab
    * Fluoropyrimidine and irinotecan hydrochloride-based doublet with bevacizumab
    * Fluoropyrimidine and oxaliplatin-based doublet with bevacizumab
  * Progression after more than 3 months from the last administration of first-line chemotherapy for metastatic disease with a fluoropyrimidine, irinotecan hydrochloride, and oxaliplatin triplet (FOLFOXIRI) with bevacizumab to which the patient had previously responded
* Measurable disease, as assessed by RECIST criteria
* No prior or concurrent CNS metastasis

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Life expectancy \> 3 months
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 9 g/dL
* INR ≤ 1.5 times upper limit of normal (ULN)
* aPTT ≤ 1.5 ULN
* Serum bilirubin ≤ 1.5 times ULN
* AST and ALT ≤ 2.5 times ULN (\< 5 times ULN if liver metastases present)
* Alkaline phosphatase ≤ 2.5 times ULN (\< 5 times ULN if liver metastases present)
* Serum creatinine ≤ 1.5 times ULN
* Proteinuria \< 2+ OR protein ≤ 1g by 24-hour urine
* Not pregnant or nursing
* Fertile patients must use effective contraception
* No bowel obstruction or subobstruction
* No history of inflammatory enteropathy
* No prior extensive intestinal resection (i.e., \> hemicolectomy or extensive small intestine resection with chronic diarrhea)
* No symptomatic peripheral neuropathy \> grade 2
* No active uncontrolled infection
* No active disseminated intravascular coagulation
* No prior or concurrent malignancy, except for curatively treated basal cell and squamous cell carcinoma of the skin, or in situ carcinoma of the cervix
* No clinically significant cardiovascular disease, including any of the following:

  * Cerebrovascular accident within the past 6 months
  * Myocardial infarction within the past 6 months
  * Unstable angina
  * NYHA class II-IV chronic heart failure
  * Uncontrolled arrhythmia
* No uncontrolled hypertension
* No thromboembolic or hemorrhagic events within the past 6 months
* No evidence of bleeding diathesis or coagulopathy
* No serious, non healing wound/ulcer or serious bone fracture
* No significant traumatic injury within the past 28 days

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 6 weeks since prior radiotherapy
* At least 4 weeks since prior surgery
* No prior first-line chemotherapy for metastatic disease without bevacizumab
* No prior cetuximab or other investigational agents
* More than 28 days since prior open biopsy
* More than 28 days since prior and no concurrent major surgical procedure
* No concurrent therapeutic anticoagulation, antiplatelet agents, or NSAID with anti-platelet activity

  * Acetylsalicylic acid ≤ 325 mg/day allowed

Primary outcomes:
measure: Progression-free survival
timeFrame: last progression of the last patient
Secondary outcomes:
measure: Overall survival
timeFrame: the end of the stady
measure: Response rate
timeFrame: last visit of the last patient
measure: Safety
timeFrame: the end of the study
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: Universita Politecnica Delle Marche
city: Arezzo
country: Italy
facility: Azienda Usl 8 Arezzo
city: Biella
country: Italy
facility: Ospedale degli Infermi - ASL 12
city: Brindisi
country: Italy
facility: A. Perrino Hospital
city: Caltanissetta
country: Italy
facility: Azienda Ospedaliera S. Elia
city: Cuneo
country: Italy
facility: Ospedale Santa Croce
city: Empoli
country: Italy
facility: Ospedale San Giuseppe
city: Fabriano
country: Italy
facility: Ospedale E. Profili
city: Fano
country: Italy
facility: Ospedale Civile S. Croce
city: Florence
country: Italy
facility: Azienda Ospedaliera di Firenze
city: Florence
country: Italy
facility: Azienda Ospedaliero Careggi
city: Genoa
country: Italy
facility: Istituto Nazionale per la Ricerca sul Cancro
city: La Spezia
country: Italy
facility: Ospendale S. Andrea EST
city: Lecce
country: Italy
facility: Azienda Ospedaliera Vito Fazzi
city: Lido di Camaiore
country: Italy
facility: Azienda USL12 Versilia
city: Lucca
country: Italy
facility: Ospedale Campo Di Marte Lucca
city: Novara
country: Italy
facility: Azienda Ospedaliera Maggiore Della Carita
city: Pisa
country: Italy
facility: Azienda Ospedaliera Pisana
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Siena
country: Italy
facility: Dipartimento Oncologico
Study officials:
affiliation: Presidio Ospedaliero di Livorno
name: Alfredo Falcone, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-730. doi: 10.1093/annonc/mdv012. Epub 2015 Jan 18.