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A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours (NETTER-1)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pierrel Research Europe GmbH
Information provided by (Responsible Party):
Advanced Accelerator Applications
ClinicalTrials.gov Identifier:
NCT01578239
First received: April 10, 2012
Last updated: June 7, 2016
Last verified: June 2016
  Purpose

The purpose of this study is to

  • compare Progression Free Survival (PFS) after treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, progressive (as determined by Response Evaluation Criteria in Solid Tumors [RECIST] Criteria), somatostatin receptor positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours).
  • compare the Objective Response Rate (ORR) between the two study arms
  • compare the Overall Survival (OS) between the two study arms
  • compare the Time to Tumour Progression (TTP) between the two study arms
  • evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate
  • evaluate the health related quality of life (QoL) as measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-G.I.NET21 questionnaire
  • explore the correlation of toxicity outcomes and administered radiation doses corrected for body weight and body surface area
  • explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine
  • evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20 patients
  • explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score
  • explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP)

Condition Intervention Phase
Carcinoid Tumor of the Small Bowel
Neuroendocrine Tumour
Drug: Octreotide LAR
Drug: 177Lu-DOTA0-Tyr3-Octreotate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicentre, Stratified, Open, Randomized, Comparator-controlled, Parallel-group Phase III Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours

Resource links provided by NLM:


Further study details as provided by Advanced Accelerator Applications:

Primary Outcome Measures:
  • Progression Free survival (PFS) [ Time Frame: 12+/- 1 weeks ] [ Designated as safety issue: No ]

    Primary efficacy endpoint is PFS as measured by objective tumour response, centrally assessed according to RECIST Criteria.

    CT/MRI tumour assessment in both arms will be performed every 12±1 weeks from the first treatment date.



Secondary Outcome Measures:
  • Safety assessments (Adverse Events, laboratory parameters, cancer related symptoms, Physical Examination, Vital signs, Karnofsky Performance Status, ECG) [ Time Frame: 72 weeks (unless early termination) : All adverse events (AEs) and serious adverse events (SAEs) will be recorded starting from the signing of the informed consent until the last study-related visit in both study arms. ] [ Designated as safety issue: Yes ]

    The following parameters will be monitored:

    • Changes from Baseline in Hematology (WBC, platelets, haemoglobin, MCV), Blood chemistry (BUN, serum creatinine and creatinine clearance, uric acid, albumin, total bilirubin, AP, aspartate aminotransferase [AST/ASAT], alanine aminotransferase [ALT/ALAT], gamma-glutamyl transferase [γ-GT], [Na], [K], lactic dehydrogenase [LDH], glycosylated hemoglobin/hemoglobin A1c [glycoHb], free thyroxine [fT4]) and Urinalysis (RBC/hpf, WBC/hpf, casts/lpf, protein, 5-HIAA),
    • Cancer related symptoms,
    • Physical Examination, including heart rate, blood pressure and weight,
    • Karnofsky Performance Status,
    • ECG intervals.

    All AEs and SAEs reported (spontaneously or not) by the patient will be collected during the study.


  • Long-term safety and efficacy assessment [ Time Frame: Every 6 months for a period of up to 5 years after the end of the study ] [ Designated as safety issue: Yes ]

    Any progressive patient ceases treatment/assessment and proceeds to long-term follow-up assessment.

    Any non-progressive patients continues treatment/assessments until the PFS Primary End-Point, then:

    1. Patients who have 76week or more treatment/assessment stop treatment but continue the long-term follow-up assessments for 5 years overall from the date of randomization of the last randomized.
    2. Remaining randomized patients continue in the fixed 76-week treatment/assessment phase unless progression occurs, then proceed to the long-term follow-up assessment phase for 5 years overall from the date of randomization of the last randomized patient.

    During the long-term follow-up assessment phase, toxicities suspected in relation with the study drug (including haematology, biochemistry, urine analyses), anti-tumour treatment administered after progression/discontinuation, disease status based on local CT/MRI assessment, and OS data will be collected every 6 months.



Other Outcome Measures:
  • Exploratory objectives [ Time Frame: Study Treatment Phase ] [ Designated as safety issue: Yes ]
    • To explore the correlation of toxicity outcomes and administered radioactivity corrected for body weight and body surface area;
    • To explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine;
    • To evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20 patients;
    • To explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score;
    • To explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP):
    • To evaluate the Duration of Response (DoR) in the two study arms;
    • To evaluate the Time to Second Progression (PFS2) in the two study arms


Enrollment: 230
Study Start Date: September 2012
Estimated Study Completion Date: February 2021
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 177Lu-DOTA0-Tyr3-Octreotate
  • 30 mg Octreotide LAR treatment for symptom control will continue until the end of study, unless the patient progresses or dies;
  • Treatment will consist of a cumulative dose of 29.6 gigaBecquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate;
  • Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate;
  • Concomitant amino acids will be given with each administration for kidney protection;
  • 177Lu-DOTA0-Tyr3-Octreotate will be administered at 8±1-week intervals, which can be extended up to 16 weeks to accommodate resolving acute toxicity (see Dose Modifying Toxicity (DMT) below); in case patients experience clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections are allowed.
Drug: Octreotide LAR

In the experimental arm, 30 mg Octreotide LAR treatment will be given to the patients until the end of study for symptom control purpose, unless the patient progresses or dies.

In the active comparator arm, 60 mg Octreotide LAR treatment will be given to the patients every 4 weeks (i.m. injections) until the end of the study, unless the patient progresses or dies.

Other Name: SANDOSTATIN LAR
Drug: 177Lu-DOTA0-Tyr3-Octreotate
Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate will be administered at 8±1-week intervals, which can be extended up to 16 weeks to accommodate resolving acute toxicity;
Active Comparator: Octreotide LAR
  • 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the patient progresses or dies (see Dose Modifying Toxicity (DMT));
  • In case patients experience clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections are allowed.
Drug: Octreotide LAR

In the experimental arm, 30 mg Octreotide LAR treatment will be given to the patients until the end of study for symptom control purpose, unless the patient progresses or dies.

In the active comparator arm, 60 mg Octreotide LAR treatment will be given to the patients every 4 weeks (i.m. injections) until the end of the study, unless the patient progresses or dies.

Other Name: SANDOSTATIN LAR

Detailed Description:

A multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study. In this study, treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) will be compared to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours; these patients should be progressive under Octreotide LAR. In case patients in either arm experience clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections are allowed.

Objective tumour response in both arms will be assessed every 12±1 weeks from the first treatment date according to RECIST Criteria. The baseline CT scan/MRI must not be older than 4 weeks before the projected randomization date.

Patients will be evaluated for safety and tolerability in accordance with the Visit Schedules for the 177Lu-DOTA0-Tyr3-Octreotate arm and the Octreotide LAR arm as indicated in Table 1 and Table 2, respectively.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
  2. Ki67 index ≤ 20% (to be centrally confirmed).
  3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to randomization in the study.
  4. Patients ≥18 years of age.
  5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
  6. Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see §Appendix 2, Section 1 and 2, RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to randomization in the study (to be centrally confirmed). The OctreoScan® should be one that was performed while the patient was on a fixed dose of Octreotide LAR. If a patient has had an OctreoScan® performed while Octreotide LAR treatment-naïve, the patient must have a repeat OctreoScan® performed after 3 months of Octreotide LAR treatments before entering the clinical study to prove that the index lesions or new lesions still meet the criteria for inclusion. It is acceptable to have patients temporarily switched to Octreotide s.c. (up to six weeks) in order to obtain an OctreoScan®, provided they return to the same fixed dose of Octreotide LAR prior to the scan.
  7. The tumour uptake observed in each target lesion (for target/non-target/measurable lesions definition see §Appendix 2, Sections 1 and 2, RECIST Criteria, Version 1.1) using OctreoScan® must be ≥ normal liver uptake observed on planar imaging (to be centrally confirmed) (§Appendices 5 and 6).
  8. Karnofsky Performance Score (KPS)>=60.
  9. Presence of at least 1 measurable site of disease.
  10. [Applicable only for France] All patients included in the trial must be affiliated with a social security regime or be a beneficiary of the same in order to be included in the study.

Exclusion Criteria:

  1. Either serum creatinine >150 µmol/L (>1.7 mg/dL), or creatinine clearance <50 mL/min calculated by the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) <50 mL/min (the measured creatinine clearance / GFR is required only as confirmatory exam).
  2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/mm3).
  3. Total bilirubin >3 x ULN.
  4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
  5. Pregnancy or lactation.
  6. For female patients of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in §Appendix 7.
  7. Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study.
  8. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
  9. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
  10. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
  11. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
  12. Uncontrolled congestive heart failure (NYHA II, III, IV).
  13. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
  14. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake on target lesions observed by OctreoScan® imaging during continued Octreotide LAR treatment is at least as high as normal liver uptake observed by planar imaging.
  15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
  16. Prior external beam radiation therapy to more than 25% of the bone marrow.
  17. Current spontaneous urinary incontinence.
  18. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
  19. Patients who have not provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
  20. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
  21. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days are excluded from participation in this trial.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01578239

  Hide Study Locations
Locations
United States, California
Cedars-Sinai Medical Center Samuel Oschin Cancer Center
Los Angeles, California, United States, 90048
Stanford University Medical Center
Stanford, California, United States, 94304
United States, Florida
H Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Illinois
Robert H. Lurie Comprehensive Cancer Center, Northwestern Univ.
Chicago, Illinois, United States, 60611-3015
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Kettering Medical Center
Kettering, Ohio, United States, 45429
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt University - Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Excel Diagnostics and Nuclear Oncology Center
Houston, Texas, United States, 77042
Austria
Allgemeines Krankenhaus , Universitatsklinik fur Nuclearmedizin
Wien, Austria, 1090
Wilhelminenspital
Wien, Austria, 1171
Belgium
Digestive Oncology, Leuven Cancer Institute
Leuven, Brabant flamand, Belgium, 3000
France
Hôpital Beaujon AP-HP
Paris, Ile de France, France, 92118
Institut Gustave Roussy
Villejuif Cedex, Ile de France, France, 94805
Institut Claudius Regaud
Toulouse, Midi-Pyrénées, France, 31052
Hotel Dieu/CHU Nantes
Nantes, Pays de la Loire, France, 44093
Hôpital la Timone /CHU Marseille
Marseille, Provence-Alpes-Côte d'Azur, France, 13385
Groupement Hospitalier Est
Lyon, Rhône-Alpes, France, 69500
Germany
Klinikum Rechts Isar, Nuclear Medicine
Munich, Bayern, Germany, 81675
Universitätsmedizin Mainz, Medizinische Klinik I Schwerpunkt Endokrinologie
Mainz, Rheinland-Pfalz, Germany, 55131
Zentralklinik Bad Berka
Bad Berka, Thüringen, Germany, 99437
Charité, Virchow-Klinikum, Gastroentrology, Hepatology & Endocrinology
Berlin, Germany, 13353
Italy
Istituto Oncologico Romagnolo per lo Studio dei Tumori
Meldola, Emilia-Romagna, Italy, 47014
IEO Istituto Europeo di Oncologia
Milano, Lombardia, Italy, 20141
Presidio Osp. Di Macerata
Macerata, Marche, Italy, 62100
Azienda Ospedaliero - Universitaria Pisana (Presidio Ospedaliero S. Chiara)
Pisa, Toscana, Italy, 56126
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano, Italy, 20133
Università "Sapienza" di Roma, Facoltà di Medicina e Psicologia, Ospedale S. Andrea-Roma
Roma, Italy, 00189
Portugal
Hospitais da Universidade de Coimbra
Coimbra, Centro, Portugal, 3000-075
Instituto Português de Oncologia
Porto, Norte, Portugal, 4200-072
Spain
University Hospital of Bellvitge
Hospitalet de Llobregat (Barcelona), Cataluña, Spain, 08907
Ramon y Cajal University Hospital
Madrid, Spain, 28034
Hospital universitario La Fe
Valencia, Spain
United Kingdom
University of Oxford
Oxford, South East England, United Kingdom, OX3 7LE
Beatson Oncology Centre
Glasgow, United Kingdom, G12 0YN
"Nuclear Medicine Consultant
Liverpool, United Kingdom
Royal Free Hospital
London, United Kingdom, NW3 2QG
"Institute for Liver Studies
London, United Kingdom, SE5 9RS
Imperial College Healthcare Trust, Hammersmith Hospital
London, United Kingdom, W12 0HS
The Christie NHS foundation Trust
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
Advanced Accelerator Applications
Pierrel Research Europe GmbH
Investigators
Study Director: Paola Santoro, Biologist Advanced Accelerator Applications
  More Information

Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT01578239     History of Changes
Other Study ID Numbers: AAA-III-01  2011-005049-11 
Study First Received: April 10, 2012
Last Updated: June 7, 2016
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Portugal: National Pharmacy and Medicines Institute
Spain: Agencia Española de Medicamentos y Productos Sanitarios
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Advanced Accelerator Applications:
Neuroendocrine tumour
177Lu-Dota0-Tyr3-octreotate

Additional relevant MeSH terms:
Neoplasms
Neuroendocrine Tumors
Carcinoid Tumor
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Octreotide
Somatostatin
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 23, 2016