A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
Condition: Carcinoid Tumor of the Small Bowel; Neuroendocrine Tumour
MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor
Intervention: Octreotide LAR; 177Lu-DOTA0-Tyr3-Octreotate
Intervention description: 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.; 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.
Intervention MeSH terms: Octreotide; Lutetium Lu 177 dotatate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 231.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neuroendocrine tumour; 177Lu-Dota0-Tyr3-octreotate

Summary:

      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.
    

Eligibility 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.