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

Study Overview
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Brief Summary
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This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutathera plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in participants with metastasized or locally advanced, inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment.

Detailed Description
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After the screening period, participants who signed the ICF and were eligible for the study in accordance with the entry criteria were randomly assigned to treatment either Lutathera or Octreotide LAR. Participant randomization was performed according to a centralized permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups, stratified by tumor uptake score and by the length of time that a participant was on a constant dose of Octreotide (=< 6 versus > 6 months). Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed: Any participants with progressive disease (confirmed by central review of CT/MRI scans) ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety. All non-progressive participants continued treatment/assessments until the PFS primary endpoint was met (i.e. 74 evaluable and centrally confirmed disease progressions or death events). Once the Primary End-Point was reached: Participants who received more than 76 weeks of treatment/assessment, stopped the study treatment (however somatostatin analogues could be received as subsequent treatment as per Investigator's discretion) but continued the long-term follow-up assessment for 5 years overall from the date of randomization of the last participant randomized. The remaining randomized participants continued in the fixed 76-week treatment/assessment period unless progression occurred, then continued the long-term follow-up assessments for 5 years overall from the date of randomization of the last participant.

Official Title
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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

Conditions
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Carcinoid Tumor of the Small Bowel, Neuroendocrine Tumour

Intervention / Treatment
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* Drug: Octreotide LAR
* Drug: 177Lu-DOTA0-Tyr3-Octreotate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed). Ki67 index ≤ 20% (to be centrally confirmed). 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. Patients ≥18 years of age. 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. 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. 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). Karnofsky Performance Score (KPS)>=60. Presence of at least 1 measurable site of disease. [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: 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). Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/mm3). Total bilirubin >3 x ULN. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range. Pregnancy or lactation. 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. Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study. 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. Uncontrolled congestive heart failure (NYHA II, III, IV). Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN. 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. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study. Prior external beam radiation therapy to more than 25% of the bone marrow. Current spontaneous urinary incontinence. 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DOTA0-Tyr3-Octreotate<br>30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). Concomitant amino acids were given with each administration for kidney protection. 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed. | Drug: Octreotide LAR<br>* In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died. In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.<br>* Other names: SANDOSTATIN LAR, Octreotide;Drug: 177Lu-DOTA0-Tyr3-Octreotate<br>* Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.<br>* Other names: Lutathera;|
| Active Comparator: Octreotide LAR<br>60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed. | Drug: Octreotide LAR<br>* In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died. In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.<br>* Other names: SANDOSTATIN LAR, Octreotide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression Free Survival (PFS) was defined as the time from randomization to documented centrally assessed disease progression, as evaluated by the Independent Review Committee (IRC), or death due to any cause. If a participant had no centrally assessed progression and had not died at the time of the primary endpoint analysis, the participant was regarded as censored in the context of a time to event analysis at the date of last evaluable tumor assessment. Disease progression was determined by objective tumor response status using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1). | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate (ORR) was calculated as the proportion of patients with tumour size reduction (sum of partial responses (PR) and complete responses (CR)) according to RECIST 1.1. | From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months | 
| Overall Survival (OS) | Overall Survival (OS) was defined as the time from the date of randomization to the date of death due to any cause or the date of last contact (censored observation) prior to the date of the data cut-off, and during the entire study period (i.e. the treatment period plus follow-up). | From date of randomization until date of death from any cause up to final safety cut-off date reached on 18Jan2021, assessed up to approximately 100 months | 
| Rate of Overall Survival (OS) | Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups. | 12 months, 24 months, 36 months, 48 months, 60 months | 
| Time to Tumour Progression (TTP) | Time to Tumour Progression (TTP) was defined as the time from randomization to progression centrally assessed. It included patients who dropped out due to toxicity, but omitted patients who died without measured progression (censored to last follow-up date or death date). | From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months | 
| Duration of Response (DoR) | The Duration of Response (DoR) was defined as the time from initially meeting the criteria for response (CR or PR) until the time of progression by RECIST 1.1. | From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months | 
| Number of Participants With Adverse Events | The distribution of adverse events was done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths, through the monitoring of relevant clinical and laboratory safety parameters. | From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months | 
| Change From Baseline in the EORTC QLQ-C30 Questionnaire | 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 transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement). | Inclusion (Baseline) (BL), Week 72, Week 120 | 
| Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | 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. | Inclusion (Baseline) (BL), Week 72, Week 120 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroendocrine tumour, 177Lu-Dota0-Tyr3-octreotate