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The MetNET-2 Trial (MetNET-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02823691
Recruitment Status : Recruiting
First Posted : July 6, 2016
Last Update Posted : July 6, 2016
Information provided by (Responsible Party):
Melani Cecilia, National Cancer Institute, Milan

Brief Summary:

This is a Pilot, One-arm, Open-label, Prospective Study to evaluate Safety of Lanreotide 120 mg ATG in combination with Metformin in patients with advanced progressive GI or lung carcinoids.

The patient population will include patients with a histologically documented diagnosis of Well differentiated NET, G1-G2 according to the last WHO Classification criteria for GI and lung NET carcinoids.

Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Drug: Lanreotide and Metformin Early Phase 1

Detailed Description:

This study is strategically positioned in the medical treatment safety and efficacy context, that is Lanreotide can be safely and effectively used in combination with other agents, like Metformin.

Aim of this study is to verify the safety of a concomitant administration of Lanreotide 120 mg ATG with Metformin in advanced, progressing gastro-intestinal or lung carcinoids patients, by accurately monitor patients from a tolerability point of view during all study long.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety of Lanreotide 120 mg ATG in Combination With Metformin in Patients With Progressive Advanced Well-differentiated Gastro-intestinal (GI) or Lung Carcinoids: A Pilot, One-arm, Open-label, Prospective Study: the MetNET-2 Trial
Study Start Date : April 2016
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022

Arm Intervention/treatment
Experimental: Lanreotide and Metformin

Dose and Treatment Regimen:

LANREOTIDE ATG 120 mg/28 days (equivalent to 1 cycle), deep subcutaneous injection (SC) in combination with METFORMIN 2550 mg daily (maximum dose), oral administration (OS).

Metformin starting dose 850 mg/day to be increased up to 1700 mg/day at day 14, 2550 mg/day at day 28, (maximum dose), if well tolerated.

Drug: Lanreotide and Metformin
Lanreotide and Metformin
Other Name: Ipstyl and Metformin

Primary Outcome Measures :
  1. incidence of SAEs and AEs [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. time to progression (TTP) to Lanreotide ATG 120 mg in combination with Metformin [ Time Frame: 3 years ]
    This is a pilot study. This endpoints should be considered an exploratory evaluation

  2. symptomatic responses to Lanreotide ATG 120 mg in combination with Metformin in symptomatic patients [ Time Frame: 1 year ]
    Answers will be based on a 5 point Likert scale (1=completely satisfied, 2= rather satisfied, 3= unchanged, 4= rather dissatisfied, 5= completely dissatisfied).

  3. biochemical responses to Lanreotide ATG 120 mg in combination with Metformin [ Time Frame: 1 year ]
    Biochemical progression will be evaluated testing Chromogranin A, NSE, 5-HIAA (only if functioning tumours) at each 4th month

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Adult patients (male or female, age > 18 years)
  • Patient with advanced disease, not resectable. The evaluation of unresectable disease will be performed by surgeon of multidisciplinary Milan ENETS Center of Excellence tumour board of Fondazione IRCCS Istituto Nazionale dei Tumori Milano.
  • Patients with a histologically documented diagnosis of advanced well differentiated (G1 and G2) GI or lung carcinoids, defined according to the last WHO Classification criteria for NET
  • Tumor tissue available for analysis
  • Measurable disease and disease progression in the 6 months before study inclusion (according to RECIST vs 1.1), documented and appropriate imaging
  • Patient who has received prior treatment with surgery or chemotherapy or somatostatin analogues or m-TOR inhibitors or other systemic antineoplastic/target therapies
  • Functioning or non-functioning NETs
  • Type-2 Diabetic or normoglycaemic patient
  • Documented Octreoscan/PET Ga68 uptake/IHC stain of SSTR2 receptor, within 6 months before study entry
  • Basal blood tests:
  • Counts of neutrophils in absolute value> 1.5 x 103 / L
  • Platelet count> 100 x 103 / L
  • Hemoglobin> 9 g/dl
  • Total Bilirubin <1.5 times the upper limit of normal
  • AST, ALT <2.5 times the upper limit of normal
  • Alkaline phosphatase <2.5 times the upper limit of normal
  • Values of serum creatinine <1.5 mg / dl. - CCr ≥ 60 mL / min
  • ECOG performance status ≤ 2
  • Life expectancy > 12 months
  • Written informed consent
  • Female subjects of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for at least 60 days after participation in the study. Acceptable methods of contraception include double barrier method [i.e. condom and occlusive cap (diaphragm or cervical/vault caps)] spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.
  • Male subjects with female partners of childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 60 days after participation in the study.

Exclusion Criteria

  • Surgery performed within 28 days prior to the beginning of study treatment
  • Brain metastasis or spinal cord compression
  • Type-1 Diabetes
  • Clinically significant cardiovascular disease, such as cardiovascular accidents occurred in less than 6 months, unstable angina, congestive heart failure grade greater than or equal to II (according to the classification of the New York Heart Association NYHA) series cardiac arrhythmias that require treatment
  • Uncontrolled high blood pressure, atrial fibrillation
  • Cardio-vascular, lung, kidney or hepatic disorders not treated/controlled
  • Cirrhosis, acute hepatitis or chronic active hepatitis
  • Metabolic disorders, clinical examination or laboratory investigations which contraindicate the use of drugs to study, or patients at high risk of complications from the treatment
  • Active or uncontrolled severe infections
  • Patients with a condition of metabolic acidosis, acute or chronic, including ketoacitosi
  • History of POTUS (alcohol abuse), or habitual intake of alcohol (≥ 3 glasses of alcoholic drinks / day) sufficient to cause hepatotoxicity
  • Severe states of dehydration
  • Prolonged fasting
  • History of immunosuppression, including positive HIV test
  • Previous or concomitant oncological pathology, except: basal cell skin cancer, in situ, as long as every other cancer patient disease-free for at least 5 years
  • Serious neurological or psychiatric disorders
  • Pregnancy or lactation
  • Patients that do not use appropriate methods of contraception as specified in the inclusion criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02823691

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Contact: Sara Pusceddu, MD +390223903251

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NationalCIMilan Recruiting
Milan, Italy, 20133
Contact: Sara Pusceddu, MD    +390223903251   
Sponsors and Collaborators
Melani Cecilia
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Principal Investigator: Sara Pusceddu, MD

Publications of Results:
Other Publications:
Vlotides G et Al: anticancer effects of metformin on neuroendocrine tumor cell in vitro. 10 the ENETs Annual conference Barcelona 5-8 March 2013
CLARINET Abstract E17-7103, Amsterdam EJC, vol 49 (3), 2013
Machin, D., Campbell, M., Fayers, P., and Pinol, A. 1997. Sample Size Tables for Clinical Studies, 2nd edition. Blackwell Science. Malden, MA.
Cohen J. (1988) Statistical Power Analysis fo the Behavioural Sciences, Lawrence Erbaum Associates, Hillsdale, New Jersey.
NCSS (Number Cruncher Statistical System) Versione 8.0.2012.
Hintze, J. (2011). PASS (Power Analysis and Sample Size System) 11. NCSS, LLC. Kaysville, Utah, USA.
Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. New York
Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. Third Edition. John Wiley & Sons. New York.
Lachin, John M. 2000. Biostatistical Methods. John Wiley & Sons. New York.
- Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New Jersey
Vlotides G et al. "In Vitro Anticancer Effect of Metformin in Neuroendocrine Tumour Cells" Abstract B9; 10th Annual ENETS Conference, 6-8 March 2013, Barcelona
Marciello F. et al. "Role of Metformin on Recurrence-Free-Survival (RFS) in Neuroendocrine Tumors (NETs)" Abstract M4; 11th Annual ENETS Conference, 5-7 March 2014, Barcelona
S. Pusceddu, et al. "Metformin impact on progression-free survival in advanced pancreatic well-differentiated neuroendocrine tumors (pWDNETs). Retrospective evaluation in diabetic patients receiving Everolimus plus Octreotide LAR treatment" 1146Tip - 39th ESMO Congress, Madrid - Annals of Oncology, Vol 25, Suppl 4, 2014
F.G.M. De Braud, et al. "Activity and safety of Everolimus in combination with Octreotide LAR and Metformin in patients with advanced pancreatic well-differentiated Neuroendocrine Tumors (pWDNETs): a single-center, open-label, phase II, proof-of-concept study (MetNET1 trial)"; 1163Tip - 39th ESMO Congress, Madrid - Annals of Oncology, Vol 25, Suppl 4, 2014
Custodio A et al. "Prognostic Role of Diabetes Mellitus (DM) and Metformin (MET) Therapy in Patients (pts) with Advanced G1-G2 Neuroendocrine Tumors (NETs) Treated with Everolimus (EVE)" - abstract L7, ENETS 2015
Custodio A et al. "Everolimus (EVE)-Induced Hyperglycemia (HG) in Patients (pts) with Advanced G1-G2 Neuroendocrine Tumors (NETs): Clinical Relevance and Predictive Value" - abstract L8, ENETS 2015
Colao AM et al. "Metformin-Based Oral Antidiabetic Therapy Is Effective at Controlling Hyperglycemia Associated with Pasireotide in Patients with Acromegaly" - abstract PP09-2 - ENDO 2015

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Responsible Party: Melani Cecilia, MD, National Cancer Institute, Milan Identifier: NCT02823691    
Other Study ID Numbers: NationalCIMilan
First Posted: July 6, 2016    Key Record Dates
Last Update Posted: July 6, 2016
Last Verified: June 2016
Keywords provided by Melani Cecilia, National Cancer Institute, Milan:
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents
Hormones, Hormone Substitutes, and Hormone Antagonists