Clinical trial NCT01648465: Study of Everolimus Treatment in Newly-diagnosed Patients With Advanced Gastrointestinal Neuroendocrine Tumors
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Gastrointestinal Tumors
Pancreatic Tumors
Gastrointestinal Neuroendocrine Tumors
Pancreatic Neuroendocrine Tumors
Keywords: metastatic
unresectable
well or moderately differentiated
advanced
Lead sponsor: Hellenic Cooperative Oncology Group
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2012-07-24
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 15 month PFS (Progression-Free Survival) rate
timeFrame: 15 months
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: 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.
measure: Overall Survival (OS)
timeFrame: Defined as the time from the date of enrollment to the date of death from any cause,assessed up to 36 months.
measure: Evaluation of best response to treatment and the time to best response achievement
timeFrame: Defined as the period from the date of treatment initiation to best response observation date througout the study, assessed up to 15 months.
measure: Assessment of safety
timeFrame: Assessment of adverse events will be performed every 28 days (per cycle) during treatment, assessed up to 16 months.
measure: Association of biologic markers with disease progression
timeFrame: Up to 36 months
Other outcomes:
Locations:
city: Athens
country: Greece
facility: 2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital
city: Athens
country: Greece
facility: Dept of Medical Oncology, 251 General Airforce Hospital
city: Athens
country: Greece
facility: 2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio"
city: Athens
country: Greece
facility: 2nd Dept of Internal Medicine, Propaedeutic, University Hospital "Attikon"
city: Athens
country: Greece
facility: 4th Dept of Internal Medicine, University Hospital "Attiko"
city: Athens
country: Greece
facility: 3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
city: Athens
country: Greece
facility: 2nd Dept of Medical Oncology, Metropolitan Hospital
city: Heraklion
country: Greece
facility: Dept of Medical Oncology, University Hospital of Heraklion
city: Ioannina
country: Greece
facility: Dept of Medical Oncology, Ioannina University Hospital
city: Patra
country: Greece
facility: Division of Oncology, Dept of Internal Medicine, University Hospital of Patras
city: Thessaloniki
country: Greece
facility: Dept of Medical Oncology, Papageorgiou General Hospital
city: Thessaloniki
country: Greece
facility: Dept of Medical Oncology, Thermi Clinic
Study officials:
affiliation: 4th Dept of Internal Medicine, University Hospital "Attikon"
name: Anna Koumarianou, Dr
role: STUDY_CHAIR
References:
citation: 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.