Study of Everolimus Treatment in Newly-diagnosed Patients With Advanced Gastrointestinal Neuroendocrine Tumors

Phase II Multicenter Single-arm Study Evaluating the Safety and Efficacy of Everolimus as a First-line Treatment in Newly-diagnosed Patients With Advanced GI Neuroendocrine Tumors.

The purpose of this study is to explore the efficacy and safety of everolimus administered as a first-line treatment in newly-diagnosed patients with advanced or inoperable Gastrointestinal (GI) or pancreatic neuroendocrine tumors.

Study Overview

• Status: Terminated
• Conditions: Gastrointestinal Tumors; Pancreatic Neuroendocrine Tumors; Pancreatic Tumors; Gastrointestinal Neuroendocrine Tumors
• Intervention / Treatment: Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 14564
    • 3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
  • Athens, Greece, 18547
    • 2nd Dept of Medical Oncology, Metropolitan Hospital
  • Athens, Greece, 11522
    • 2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital
  • Athens, Greece, 11527
    • 2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio"
  • Athens, Greece, 11525
    • Dept of Medical Oncology, 251 General Airforce Hospital
  • Athens, Greece, 12462
    • 2nd Dept of Internal Medicine, Propaedeutic, University Hospital "Attikon"
  • Athens, Greece, 12462
    • 4th Dept of Internal Medicine, University Hospital "Attiko"
  • Heraklion, Greece, 71110
    • Dept of Medical Oncology, University Hospital of Heraklion
  • Ioannina, Greece, 45110
    • Dept of Medical Oncology, Ioannina University Hospital
  • Patra, Greece, 26504
    • Division of Oncology, Dept of Internal Medicine, University Hospital of Patras
  • Thessaloniki, Greece, 56429
    • Dept of Medical Oncology, Papageorgiou General Hospital
  • Thessaloniki, Greece, 57001
    • Dept of Medical Oncology, Thermi Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, aged ≥ 18 years of age.
2. Newly diagnosed patients with biopsy-proven well or moderately differentiated advanced (metastatic or unresectable) GI or pancreatic neuroendocrine tumor.
3. Measurable disease based on RΕCIST 1.1 using a triphase CT scan or multi-phase MRI scan.
4. Patients with a ki-67 measurement <20% prior to their enrollment to the study.
5. Performance status 0-2 on the WHO scale.
6. Adequate bone marrow function as shown by:ANC ≥ 1.5 x 10^9/L,Platelets ≥ 100 x 10^9/L,Hemoglobin > 9 g/dL.
7. Adequate liver function as shown by:Serum bilirubin ≤ 1.5 x ULN,ALT/SGPT and AST/SGOT ≤ 2.5 x ULN (ή ≤ 5 x ULN in patients with known liver metastases),INR < 1.3 (INR < 3 in patients treated with anticoagulants).
8. Adequate renal function as shown by: serum creatinine ≤ 1.5 x ULN.
9. Fasting serum cholesterol ≤ 300 mg/dL or ≤ 7.75 mmol/L and fasting triglycerides ≤ 2.5 x ULN. Note: In case one or both the above upper limits are exceeded, patient enrollment can only be performed upon proper antilipidemic treatment initiation.
10. Women of childbearing potential, with a negative serum or urine pregnancy test within 48 hours prior to first study treatment administration.
11. Signed informed consent form obtained before any trial related activity, including the screening phase, according to the applicable law and ICH/GCP requirements.
12. Signed informed consent for the use of biological and genetic material

Exclusion Criteria:

1. Patients with poorly differentiated or undifferentiated GI or pancreatic neuroendocrine carcinoma.
2. Previous or concurrent cytotoxic chemotherapy, immunotherapy or radiotherapy.
3. Hepatic artery embolization or cryoablation of hepatic metastasis within 1 month of study enrollment.
4. Prior therapy with mTOR inhibitors (for example sirolimus, temsirolimus, everolimus).
5. Patients receiving chronic treatment with corticosteroid immunosuppressives.
6. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN.

7. Patients who have any severe and/or uncontrolled medical conditions such as:

   • unstable angina pectoris, symptomatic congestive heart failure NYHA class II, III, IV, myocardial infarction ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia (LVEF < 50 %)
   • active or uncontrolled severe infection
   • cirrhosis, chronic active hepatitis, chronic persistent hepatitis or inadequate hepatic function (ALT/SGPT and AST/SGOT > 5 x ULN)
   • inadequate bone marrow (ANC < 1.5 x 10^9/L, platelets < 100 x 10^9/L, hemoglobin ≤ 9 g/dL) or renal failure (serum creatinine > 1.5 x ULN
   • severely impaired lung function (patients needing oxygen support).
8. Active bleeding diathesis or on oral treatment with vitamin K antagonists (apart from low-dose coumadine).
9. Performance status ≥ 3 on the WHO scale.
10. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required.
11. No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or treated in situ cancer of the cervix, or any other cancer from which the patient has been disease free for ≥ 3 years.
12. Patients within 28 days post-major surgery (e.g. intra-thoracic, intrabdominal or intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry. Note: Patients must have recovered from the acute effects of surgery prior to enrollment.
13. Female patients who are pregnant or nursing (lactating).
14. Adults with reproductive potential who are not using effective birth control methods. If barrier contraceptive measures are being used, these must be continued throughout the study by both sexes.
15. Patients participating in another clinical trial or receiving an investigational drug.
16. Patients unwilling or unable to comply with the protocol at the investigator's discretion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Everolimus	Drug: Everolimus; Everolimus 10mg(2x5mg)orally once daily until disease progression, unacceptable toxicity or consent withdrawal; Other Names: Afinitor; RAD001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
15 month PFS (Progression-Free Survival) rate	To determine the rate of PFS patients at 15 months of treatment.	15 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-Free Survival (PFS)	Defined as the time from the date of enrollment to the date of 1st radiologically documented disease progression or disease related death,assessed up to 36 months.
Overall Survival (OS)	Defined as the time from the date of enrollment to the date of death from any cause,assessed up to 36 months.
Evaluation of best response to treatment and the time to best response achievement	Defined as the period from the date of treatment initiation to best response observation date througout the study, assessed up to 15 months.
Assessment of safety	Assessment of adverse events will be performed every 28 days (per cycle) during treatment, assessed up to 16 months.
Association of biologic markers with disease progression	Up to 36 months

Collaborators and Investigators

• Sponsor: Hellenic Cooperative Oncology Group
• Collaborators: Novartis
• Investigators: Study Chair: Anna Koumarianou, Dr, 4th Dept of Internal Medicine, University Hospital "Attikon"

Publications and helpful links

General Publications

• Koumarianou A, Pectasides D, Koliou GA, Dionysopoulos D, Kolomodi D, Poulios C, Skondra M, Sgouros J, Pentheroudakis G, Kaltsas G, Fountzilas G. Efficacy and Safety of First-Line Everolimus Therapy Alone or in Combination with Octreotide in Gastroenteropancreatic Neuroendocrine Tumors. A Hellenic Cooperative Oncology Group (HeCOG) Study. Biology (Basel). 2020 Mar 9;9(3):51. doi: 10.3390/biology9030051.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 6, 2012
• Primary Completion (ACTUAL): January 1, 2017
• Study Completion (ACTUAL): August 6, 2019

Study Registration Dates

• First Submitted: July 13, 2012
• First Submitted That Met QC Criteria: July 23, 2012
• First Posted (ESTIMATE): July 24, 2012

Study Record Updates

• Last Update Posted (ACTUAL): September 3, 2019
• Last Update Submitted That Met QC Criteria: August 30, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: metastatic; advanced; unresectable; well or moderately differentiated
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Endocrine System Diseases; Gastrointestinal Diseases; Stomach Diseases; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Intestinal Diseases; Pancreatic Diseases; Neoplasms; Stomach Neoplasms; Pancreatic Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neuroendocrine Tumors; Intestinal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: HE 67/12; 2011-006160-48 (EUDRACT_NUMBER)