Trial record 1 of 3 for: netter 1 Previous Study Return to List Next Study

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1 1 von :25 A service of the U.S. National Institutes of Health Trial record 1 of 3 for: netter 1 Previous Study Return to List Next Study 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 currently recruiting participants. Verified October 2013 by Advanced Accelerator Applications Sponsor: Advanced Accelerator Applications Collaborator: Pierrel Research Europe GmbH ClinicalTrials.gov Identifier: NCT First received: April 10, 2012 Last updated: October 31, 2013 Last verified: October 2013 History of Changes Information provided by (Responsible Party): Advanced Accelerator Applications Full Text View Tabular View No Study Results Posted Disclaimer How to Read a Study Record 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).

2 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 Drug: 177Lu-DOTA0-Tyr3-Octreotate Phase 3 Study Type: Study Design: Official Title: Interventional Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment 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: MedlinePlus related topics: Cancer Carcinoid Tumors 2 von :25

3 3 von :25 Drug Information available for: Somatostatin Octreotide acetate Octreotide U.S. FDA Resources 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], gammaglutamyl 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 3 years after the end of the study ] [ Designated as safety issue: Yes ] Patient will be contacted every 6 months up to 3 years after the end of the study (phone contacts or visits at Site). Laboratory assessments

4 4 von :25 (haematology, biochemistry, urinalysis), SAEs suspected in relationship to the study drug, progression free survival (local evaluation) and overall survival data will be reported. Estimated Enrollment: 200 Study Start Date: September 2012 Estimated Study Completion Date: December 2017 Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure) Arms 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. 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. Assigned Interventions Drug: Octreotide 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 GBq (800mCi) 177Lu-Dota0-Tyr3-octreotate concomitant aminoacids will be given with each administration for kidney protection 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; Drug: Octreotide 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); Other Name: SANDOSTATIN LAR

5 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: Genders Eligible for Study: Accepts Healthy Volunteers: 18 Years and older Both No Criteria Inclusion Criteria: Presence of inoperable (curative intent) at enrolment time, histologically proven, midgut carcinoid tumour. Ki67 index 20%. 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 enrolment in the study. Patients 18 years of age. Patients must have progressive disease based on RECIST Criteria, Version 1.1 evidenced with CT scans/mri within 3 years from enrolment; previous images must be centrally evaluated to confirm the disease progression under previous therapy:for the purpose of determining disease progression the oldest CT/MRI scan must not be older than 3 years and the most recent scan must not be older than 4 weeks from the projected randomization date. The CT scan/mri scan should be one that was performed while the patient was on a fixed dose of Sandostatin LAR. Confirmed presence of somatostatin receptors on all technically evaluable tumour lesions documented by CT/MRI scans, based on positive OctreoScan imaging within 24 weeks prior to enrolment in the study. The tumour uptake observed using OctreoScan must be normal liver uptake observed on planar imaging. 5 von :25

6 6 von :25 Karnofsky Performance Score (KPS) 60 Presence of at least 1 measurable site of disease. Exclusion Criteria: Serum creatinine >150 µmol/l or 1.7 mg/dl, or a measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) of <50 ml/min. Hb concentration <5.0 mmol/l (<8.0 g/dl); WBC <2x10^9/L (2000/mm3); platelets <75x10^9/L (75x10^3/mm3). Total bilirubin >3 x upper limit of normal (ULN). Serum albumin <3.0 g/dl unless prothrombin time is within the normal range. Pregnancy 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) Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study. Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study. Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mammalian target of rapamycin (mtor)-inhibitors or other investigational therapy within 12 weeks prior to enrolment in the study. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the study. Uncontrolled congestive heart failure (NYHA II, III, IV). Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 x ULN. Any patient who has both OctreoScan positive and negative tumours. 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 observed by OctreoScan imaging during continued Octreotide treatment is at least as high as normal liver uptake observed by planar imaging. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study. Prior external beam radiation therapy to more than 25% of the bone marrow. Urinary incontinence. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated

7 and proven no evidence of recurrence for 5 years. Patients who have not provided a signed an informed consent form to participate in the study, obtained prior to the start of any protocol related activities. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. Contacts and Locations Please refer to this study by its ClinicalTrials.gov identifier: NCT Contacts Contact: Maurizio F Mariani, M.D ext 206 maurizio.mariani@adacap.com Contact: Paola Santoro, Biologist ext 221 paola.santoro@adacap.com Show 51 Study Locations Sponsors and Collaborators Advanced Accelerator Applications Pierrel Research Europe GmbH Investigators Study Director: Paola Santoro, Biologist Advanced Accelerator Applications More Information No publications provided Responsible Party: Advanced Accelerator Applications ClinicalTrials.gov Identifier: NCT History of Changes Other Study ID Numbers: AAA-III-01, Study First Received: April 10, 2012 Last Updated: October 31, von :25

8 8 von :25 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: Carcinoid Tumor Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Adenocarcinoma Carcinoma Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Octreotide Somatostatin Antineoplastic Agents, Hormonal Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Gastrointestinal Agents Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs ClinicalTrials.gov processed this record on December 15, 2013