Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Neuroendocrine Tumors (XELBEVOCT)

Phase II Study of the Combination of Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Inoperable Well-Differentiated Neuroendocrine Tumors

Well differentiated neuroendocrine (NE) carcinomas have low proliferative activity and conventional chemotherapy is not recommended. Metronomic chemotherapy, i.e. the frequent administration of cytotoxic drugs at low doses, has demonstrated antiangiogenetic properties. Since well differentiated NE carcinomas are highly vascular, there is a rationale for testing metronomic chemotherapy and antiangiogenetic drugs. This is a national, multicenter, phase II study.

Study Overview

• Status: Unknown
• Conditions: Neuroendocrine Carcinomas
• Intervention / Treatment: Drug: bevacizumab + octreotide LAR + capecitabine

Detailed Description

Metastatic or locally advanced well differentiated neuroendocrine carcinoma will be treated with a combination of bevacizumab (5 mg/kg) plus octreotide LAR (long- acting release) 20/30 mg plus capecitabine administered on a metronomic schedule (2000 mg/day).

Patients with stable disease, complete or partial response will continue treatment until progressive disease or unacceptable toxicity.

Primary endpoint: the response to treatment, evaluated according to the RECIST criteria.

Secondary endpoint: - toxicity, graded according to the NCI-CTG criteria;

• symptomatic response: evaluated according to the changes in both the frequency and intensity of symptoms;
• biochemical response: evaluated considering the changes in the tumor marker levels (circulating Chromogranin A);
• relationship between vascular endothelial growth factor (VEGF) polymorphisms and response to treatment;
• time to progression and survival: measured from the date of treatment start to the date of progression and the date of last follow-up or death, respectively.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Maria P Brizzi, MD, PhD; Phone Number: 007 +39, 011-9026; Email: mariapia.brizzi@email.it

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • Elisabetta Nobili
    • Contact: Elisabetta Nobili, MD; Phone Number: 680 051 6363; Email: elisabetta.nobili3@unibo.it
    • Principal Investigator: Guido Biasco, MD, PhD
  • Milan, Italy, 20121
    • Completed
    • Nicola Fazio
  • Turin, Italy, 10126
    • Completed
    • Enrica Milanesi
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • Completed
      • Lucia Tozzi
  • Turin
    • Orbassano, Turin, Italy, 10043
      • Recruiting
      • Anna Ferrero
      • Contact: Anna Ferrero, MD; Phone Number: 526 +39 011 9026; Email: anna.ferrero80@libero.it
      • Sub-Investigator: Maria P Brizzi, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically diagnosis of well-differentiated neuroendocrine carcinoma
• Inoperable disease
• Age > 18
• ECOG Performance Status 0-2
• Life expectancy of at least 12 weeks
• Measurable and/or evaluable lesions according to RECIST criteria
• Radiological documentation of disease progression
• Adequate bone marrow reserve
• Adequate hepatic and renal function
• Urine dipstick of proteinuria < 2+
• Written informed consent
• Comply with the protocol procedures

Exclusion criteria:

• Serious non-healing wound or ulcer
• Evidence of bleeding diathesis or coagulopathy
• Uncontrolled hypertension
• Clinically significant 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 ongoing treatment with anticoagulants for therapeutic purposes
• Chronic, daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration
• Patients with severe renal impairment (creatinine clearance below 30 ml/min)
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal 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
• Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drugs: bevacizumab + octreotide LAR + capecitabine; bevacizumab + octreotide + metronomic capecitabine	Drug: bevacizumab + octreotide LAR + capecitabine; long acting octreotide acetate at a dose of 20 or 30 mg administered intramuscularly every 4 weeks; Bevacizumab at a dose of 5 mg/kg every 2 weeks; orally capecitabine administered at a dose of 2000 mg/daily; Other Names: Avastin; Sandostatin LAR; Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
time to progression	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	All adverse events encountered during the clinical study will be reported. The intensity of clinical adverse events will be graded according to the NCI Common Toxicity Criteria (CTC) version 3.0 grading system.	two years
Time to Treatment Failure (TTF)	TTF is the time from first day of treatment to the first occurrence of any adverse events with withdrew prematurely the treatment.	two years
Overall survival (OS)	Overall survival (OS) will be computed as the time between the first day of treatment and the date of death or the last date the patient was known to be alive.	48 months

Collaborators and Investigators

• Sponsor: University of Turin, Italy
• Investigators: Study Director: Alfredo Berruti, MD, PhD, Medical oncology, Department of Clinical and Biological Sciences, University of Turin

Publications and helpful links

General Publications

• Brizzi MP, Berruti A, Ferrero A, Milanesi E, Volante M, Castiglione F, Birocco N, Bombaci S, Perroni D, Ferretti B, Alabiso O, Ciuffreda L, Bertetto O, Papotti M, Dogliotti L. Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte oncology network. BMC Cancer. 2009 Nov 3;9:388. doi: 10.1186/1471-2407-9-388.
• Berruti A, Fazio N, Ferrero A, Brizzi MP, Volante M, Nobili E, Tozzi L, Bodei L, Torta M, D'Avolio A, Priola AM, Birocco N, Amoroso V, Biasco G, Papotti M, Dogliotti L. Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. BMC Cancer. 2014 Mar 14;14:184. doi: 10.1186/1471-2407-14-184.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Anticipated): May 1, 2009
• Study Completion (Anticipated): December 1, 2010

Study Registration Dates

• First Submitted: September 9, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (Estimate): September 16, 2010

Study Record Updates

• Last Update Posted (Estimate): September 16, 2010
• Last Update Submitted That Met QC Criteria: September 15, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: bevacizumab; neuroendocrine tumors; somatostatin analogue; metronomic capecitabine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Capecitabine; Bevacizumab; Octreotide
• Other Study ID Numbers: EudraCT 2006-004748-22