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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)

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ClinicalTrials.gov Identifier: NCT01578239
Recruitment Status : Completed
First Posted : April 16, 2012
Results First Posted : October 2, 2017
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

Brief Summary:

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

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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 231 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : September 30, 2012
Actual Primary Completion Date : July 31, 2015
Actual Study Completion Date : January 14, 2021


Arm Intervention/treatment
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, Octreotide

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;
Other Name: Lutathera

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, Octreotide




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: after 74 centrally confirmed cases disease progression or death ]
    Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CT/MRI tumour assessment in both arms are performed every 12±1 weeks from the first treatment date.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis) ]
    Objective Response Rate (ORR) is calculated as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1.

  2. Overall Survival (OS) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis) ]
    Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.

  3. Time to Tumour Progression (TTP) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis)vidence of tumor progression, assessed for approximately 5 years ]
    Time to Tumour Progression (TTP) is defined as the time from randomization to progression centrally assessed. It includes patients who dropped out due to toxicity, but omits patients who died without measured progression (censored to last follow-up date or death date).

  4. Duration of Response (DoR) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis) ]
    The Duration of Response (DoR) is defined as the time from initially meeting the criteria for response (CR or PR) until the time of progression by RECIST.

  5. Number of Participants With Treatment Emergent Adverse Events [ Time Frame: From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis) ]
    The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

  6. EORTC QLQ-C30 Questionnaire [ Time Frame: From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis) ]
    The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly converted to a 0-100 scale with higher scores reflecting higher levels of function and higher levels of symptom burden.

  7. EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) [ Time Frame: From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis) ]
    The Quality of Life GI Neuroendocrine Tumor survey (QLQ GINET21) contains a total of 21 items: four single-item assessments relating to muscle and/or bone pain (MBP), body image (BI), information (INF) and sexual functioning (SX), together with 17 items organized into five proposed scales: endocrine symptoms (ED; three items), GI symptoms (GI; five items), treatment-related symptoms (TR; three items), social functioning (SF) and disease-related worries (DRW; three items). The response format of the questionnaire is a four-point Likert scale. Responses are linearly transformed to a 0-100 scale using EORTC guidelines, with higher scores reflecting more severe symptoms.



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
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.

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 ClinicalTrials.gov identifier (NCT number): NCT01578239


Locations
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Sponsors and Collaborators
Advanced Accelerator Applications
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT01578239    
Other Study ID Numbers: AAA-III-01
2011-005049-11 ( EudraCT Number )
CAAA601A12301 ( Other Identifier: Novartis )
First Posted: April 16, 2012    Key Record Dates
Results First Posted: October 2, 2017
Last Update Posted: March 24, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Advanced Accelerator Applications:
Neuroendocrine tumour
177Lu-Dota0-Tyr3-octreotate
Additional relevant MeSH terms:
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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
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents