Overview

This trial is active, not recruiting.

Conditions carcinoid tumor of the small bowel, neuroendocrine tumour
Treatments octreotide lar, 177lu-dota0-tyr3-octreotate
Phase phase 3
Sponsor Advanced Accelerator Applications
Collaborator Pierrel Research Europe GmbH
Start date September 2012
End date July 2015
Trial size 230 participants
Trial identifier NCT01578239, 2011-005049-11, AAA-III-01

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

- 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)

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
octreotide lar SANDOSTATIN 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.
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)
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.
octreotide lar SANDOSTATIN 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.

Primary Outcomes

Measure
Progression Free survival (PFS)
time frame: 12+/- 1 weeks

Secondary Outcomes

Measure
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.
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

Eligibility Criteria

Male or female participants at least 18 years old.

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.

Additional Information

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
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.
Trial information was received from ClinicalTrials.gov and was last updated in June 2016.
Information provided to ClinicalTrials.gov by Advanced Accelerator Applications.
Location data was received from the National Cancer Institute and was last updated in June 2016.