Carcinoid Tumor of the Small Bowel, Neuroendocrine Tumour
Conditions
Keywords
Neuroendocrine tumour, 177Lu-Dota0-Tyr3-octreotate
Brief 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.
Detailed description
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: 1. 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. 2. 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: 1. 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. 2. 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.
Interventions
DRUGOctreotide LAR
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.
Sponsors
Advanced Accelerator Applications
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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 | 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). |
| Rate of Overall Survival (OS) | 12 months, 24 months, 36 months, 48 months, 60 months | Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups. |
| Time to Tumour Progression (TTP) | 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 | 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). |
| Objective Response Rate (ORR) | 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 | 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. |
| Number of Participants With Adverse Events | From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months | 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. |
| Change From Baseline in the EORTC QLQ-C30 Questionnaire | Inclusion (Baseline) (BL), Week 72, Week 120 | 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). |
| Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Inclusion (Baseline) (BL), Week 72, Week 120 | 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. |
| Duration of Response (DoR) | 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 | 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. |
Countries
Belgium, France, Germany, Italy, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 41 sites across 8 countries.
Participants by arm
| Arm | Count |
|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate * 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. | 117 |
| Octreotide LAR * 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. | 114 |
| Total | 231 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Follow-Up Period | Consent withdrawal | 4 | 10 |
| Long-term Follow-Up Period | Death | 69 | 64 |
| Long-term Follow-Up Period | Lost to Follow-up | 2 | 4 |
| Long-term Follow-Up Period | Other | 2 | 2 |
| Treatment Period | Adverse Event | 13 | 10 |
| Treatment Period | Non-compliance | 2 | 0 |
| Treatment Period | Other | 6 | 1 |
| Treatment Period | Physician Decision | 17 | 17 |
| Treatment Period | Progressive Disease | 19 | 64 |
| Treatment Period | Withdrawal by Subject | 10 | 9 |
Baseline characteristics
| Characteristic | Octreotide LAR | Total | 177Lu-DOTA0-Tyr3-Octreotate |
|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.8 | 63.7 years STANDARD_DEVIATION 9.55 | 63.4 years STANDARD_DEVIATION 9.34 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 9 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Applicable | 9 Participants | 21 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 96 Participants | 189 Participants | 93 Participants |
| Sex: Female, Male Female | 60 Participants | 114 Participants | 54 Participants |
| Sex: Female, Male Male | 54 Participants | 117 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 111 | 68 / 112 |
| other Total, other adverse events | 105 / 111 | 90 / 112 |
| serious Total, serious adverse events | 40 / 111 | 31 / 112 |
Outcome results
Primary
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).
Time frame: 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
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Progression Free Survival (PFS) | NA months |
| Octreotide LAR | Progression Free Survival (PFS) | 8.5 months |
p-value: <0.000195% CI: [0.108, 0.289]Log Rank
Secondary
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).
Time frame: Inclusion (Baseline) (BL), Week 72, Week 120
Population: Safety Analysis Set (SAF). Values at Inclusion were taken from last non-missing value prior to randomization (the only scheduled pre-randomization assessment was at the Baseline visit). Calculations at each visit included only participants with scores at the visit and Inclusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Diarrhoea: chg from BL @ wk 120 (n=2,0) | -16.667 Scores on a scale | Standard Deviation 23.5702 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Physical functioning: chg from BL @ wk 120 (n=2,0) | -3.333 Scores on a scale | Standard Deviation 4.714 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Role functioning: chg from BL @ wk 72 (n=33,11) | 5.051 Scores on a scale | Standard Deviation 33.1989 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Social functioning: chg from BL @ wk 72 (n=33,11) | 8.586 Scores on a scale | Standard Deviation 28.9039 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Social functioning: chg from BL @ wk 120 (n=2,0) | 8.333 Scores on a scale | Standard Deviation 35.3553 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Global Health Status/QoL: chg from BL @ wk 72 (n=33,11) | 5.556 Scores on a scale | Standard Deviation 21.4155 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Cognitive functioning: chg from BL @ wk 72 (n=33,11) | 5.556 Scores on a scale | Standard Deviation 15.9571 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Cognitive functioning: chg from BL @ wk 120 (n=2,0) | 16.667 Scores on a scale | Standard Deviation 23.5702 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Global Health Status/QoL: chg from BL @ wk 120 (n=2,0) | -16.667 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Nausea & Vomiting: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Pain: chg from BL @ wk 72 (n=33,11) | -8.586 Scores on a scale | Standard Deviation 22.485 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Physical functioning: chg from BL @ wk 72 (n=33,11) | 3.232 Scores on a scale | Standard Deviation 12.4857 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Dyspnoea: chg from BL @ wk 72 (n=33,11) | -3.030 Scores on a scale | Standard Deviation 22.6134 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Insomnia: chg from BL @ wk 120 (n=2,0) | 33.333 Scores on a scale | Standard Deviation 47.1405 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Appetite loss: chg from BL @ wk 72 (n=33,11) | -8.081 Scores on a scale | Standard Deviation 20.4639 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Appetite loss: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Constipation: chg from BL @ wk 72 (n=33,11) | 0.000 Scores on a scale | Standard Deviation 18.6339 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Constipation: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Diarrhoea: chg from BL @ wk 72 (n=33,11) | -12.121 Scores on a scale | Standard Deviation 36.1499 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Financial difficulties: chg from BL @ wk 72 (n=33,11) | -7.071 Scores on a scale | Standard Deviation 33.0798 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Financial difficulties: chg from BL @ wk 120 (n=2,0) | -16.667 Scores on a scale | Standard Deviation 70.7107 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Fatigue: chg from BL @ wk 72 (n=33,11) | -7.239 Scores on a scale | Standard Deviation 24.7084 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Fatigue: chg from BL @ wk 120 (n=2,0) | 11.111 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Nausea & Vomiting: chg from BL @ wk 72 (n=33,11) | -4.545 Scores on a scale | Standard Deviation 15.1799 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Pain: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 23.5702 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Dyspnoea: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Insomnia: chg from BL @ wk 72 (n=33,11) | 0.000 Scores on a scale | Standard Deviation 26.3523 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Role functioning: chg from BL @ wk 120 (n=2,0) | 8.333 Scores on a scale | Standard Deviation 11.7851 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Emotional functioning: chg from BL @ wk 72 (n=33,11) | 7.744 Scores on a scale | Standard Deviation 22.6602 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Emotional functioning: chg from BL @ wk 120 (n=2,0) | 12.500 Scores on a scale | Standard Deviation 5.8926 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Global Health Status/QoL: chg from BL @ wk 72 (n=33,11) | 1.515 Scores on a scale | Standard Deviation 10.4205 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Dyspnoea: chg from BL @ wk 72 (n=33,11) | 3.030 Scores on a scale | Standard Deviation 27.707 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Fatigue: chg from BL @ wk 72 (n=33,11) | -2.020 Scores on a scale | Standard Deviation 13.8939 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Cognitive functioning: chg from BL @ wk 72 (n=33,11) | 1.515 Scores on a scale | Standard Deviation 13.8535 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Insomnia: chg from BL @ wk 72 (n=33,11) | 6.061 Scores on a scale | Standard Deviation 29.1288 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Nausea & Vomiting: chg from BL @ wk 72 (n=33,11) | -4.545 Scores on a scale | Standard Deviation 7.785 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Pain: chg from BL @ wk 72 (n=33,11) | -3.030 Scores on a scale | Standard Deviation 10.0504 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Social functioning: chg from BL @ wk 72 (n=33,11) | -7.576 Scores on a scale | Standard Deviation 18.8025 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Constipation: chg from BL @ wk 72 (n=33,11) | 0.000 Scores on a scale | Standard Deviation 14.9071 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Physical functioning: chg from BL @ wk 72 (n=33,11) | -4.242 Scores on a scale | Standard Deviation 10.0101 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Role functioning: chg from BL @ wk 72 (n=33,11) | -3.030 Scores on a scale | Standard Deviation 16.3608 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Appetite loss: chg from BL @ wk 72 (n=33,11) | 9.091 Scores on a scale | Standard Deviation 21.5557 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Financial difficulties: chg from BL @ wk 72 (n=33,11) | 6.061 Scores on a scale | Standard Deviation 20.1008 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Emotional functioning: chg from BL @ wk 72 (n=33,11) | 6.061 Scores on a scale | Standard Deviation 17.9083 |
| Octreotide LAR | Change From Baseline in the EORTC QLQ-C30 Questionnaire | Diarrhoea: chg from BL @ wk 72 (n=33,11) | -3.030 Scores on a scale | Standard Deviation 27.707 |
Secondary
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.
Time frame: Inclusion (Baseline) (BL), Week 72, Week 120
Population: Safety Analysis Set (SAF). Values at Inclusion were taken from last non-missing value prior to randomization (the only scheduled pre-randomization assessment was at the Baseline visit). Calculations at each visit included only participants with scores at the visit and Inclusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Diseases rel. worries scale: chg from BL @ wk 72 (n=33,11) | -6.061 Scores on a scale | Standard Deviation 27.9289 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | G.I. scale: chg from BL @ wk 120 (n=2,0) | -13.333 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Muscle/Bone pain symptom: chg from BL @ wk 72 (n=33,10) | -5.051 Scores on a scale | Standard Deviation 33.4594 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Muscle/Bone pain symptom: chg from BL @ wk 120 (n=2,0) | -16.667 Scores on a scale | Standard Deviation 23.5702 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Sexual function: chg from BL @ wk 72 (n=21,7) | 6.349 Scores on a scale | Standard Deviation 40.3031 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Sexual function: chg from BL @ wk 120 (n=2,0) | 50.000 Scores on a scale | Standard Deviation 70.7107 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Information/Communication: chg from BL @ wk 72 (n=33,11) | -4.040 Scores on a scale | Standard Deviation 26.0309 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Information/Communication: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Body image: chg from BL @ wk 72 (n=33,11) | -4.040 Scores on a scale | Standard Deviation 18.1766 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Body image: chg from BL @ wk 120 (n=2,0) | 16.667 Scores on a scale | Standard Deviation 23.5702 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Treatment scale: chg from BL @ wk 72 (n=21,5) | -8.995 Scores on a scale | Standard Deviation 14.9563 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Diseases rel. worries scale: chg from BL @ wk 120 (n=2,0) | 33.333 Scores on a scale | Standard Deviation 31.427 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Treatment scale: chg from BL @ wk 120 (n=1,0) | -16.667 Scores on a scale | — |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Social function scale: chg from BL @ wk 72 (n=33,11) | -7.576 Scores on a scale | Standard Deviation 23.3985 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Social function scale: chg from BL @ wk 120 (n=2,0) | 11.111 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Endocrine scale: chg from BL @ wk 72 (n=33,11) | -8.754 Scores on a scale | Standard Deviation 20.1762 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Endocrine scale: chg from BL @ wk 120 (n=2,0) | 0.000 Scores on a scale | Standard Deviation 0 |
| 177Lu-DOTA0-Tyr3-Octreotate | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | G.I. scale: chg from BL @ wk 72 (n=33,11) | -2.727 Scores on a scale | Standard Deviation 15.3083 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Diseases rel. worries scale: chg from BL @ wk 72 (n=33,11) | 1.010 Scores on a scale | Standard Deviation 33.7765 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Endocrine scale: chg from BL @ wk 72 (n=33,11) | -11.111 Scores on a scale | Standard Deviation 21.0819 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Treatment scale: chg from BL @ wk 72 (n=21,5) | 0.000 Scores on a scale | Standard Deviation 11.1111 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Muscle/Bone pain symptom: chg from BL @ wk 72 (n=33,10) | -16.667 Scores on a scale | Standard Deviation 36.0041 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Information/Communication: chg from BL @ wk 72 (n=33,11) | -12.121 Scores on a scale | Standard Deviation 30.8139 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | G.I. scale: chg from BL @ wk 72 (n=33,11) | 2.424 Scores on a scale | Standard Deviation 10.0101 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Social function scale: chg from BL @ wk 72 (n=33,11) | -7.576 Scores on a scale | Standard Deviation 21.1217 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Body image: chg from BL @ wk 72 (n=33,11) | -3.030 Scores on a scale | Standard Deviation 17.9787 |
| Octreotide LAR | Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) | Sexual function: chg from BL @ wk 72 (n=21,7) | 14.286 Scores on a scale | Standard Deviation 17.8174 |
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS). Only Participants with an Objective Response are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Duration of Response (DoR) | NA Months |
| Octreotide LAR | Duration of Response (DoR) | 1.9 Months |
Secondary
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.
Time frame: From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months
Population: Safety Analysis Set (SAF).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Number of Participants With Adverse Events | Deaths during follow-up period | 66 Participants |
| 177Lu-DOTA0-Tyr3-Octreotate | Number of Participants With Adverse Events | Adverse Events (AEs) | 105 Participants |
| 177Lu-DOTA0-Tyr3-Octreotate | Number of Participants With Adverse Events | Serious Adverse Events (SAEs) | 40 Participants |
| 177Lu-DOTA0-Tyr3-Octreotate | Number of Participants With Adverse Events | Deaths during treatment period | 4 Participants |
| Octreotide LAR | Number of Participants With Adverse Events | Deaths during treatment period | 5 Participants |
| Octreotide LAR | Number of Participants With Adverse Events | Deaths during follow-up period | 63 Participants |
| Octreotide LAR | Number of Participants With Adverse Events | Serious Adverse Events (SAEs) | 31 Participants |
| Octreotide LAR | Number of Participants With Adverse Events | Adverse Events (AEs) | 90 Participants |
Secondary
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.
Time frame: 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
Population: Full Analysis Set (FAS). Only participants with available post-baseline CT scans were considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Objective Response Rate (ORR) | 14.7 Percentage of Participants |
| Octreotide LAR | Objective Response Rate (ORR) | 4.0 Percentage of Participants |
p-value: 0.0141Fisher Exact
Secondary
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).
Time frame: 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
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Overall Survival (OS) | 48.0 Months |
| Octreotide LAR | Overall Survival (OS) | 36.3 Months |
p-value: 0.303995% CI: [0.6, 1.17]Log Rank
Secondary
Rate of Overall Survival (OS)
Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups.
Time frame: 12 months, 24 months, 36 months, 48 months, 60 months
Population: Full Analysis Set (FAS).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Rate of Overall Survival (OS) | 24 months | 76.0 Percentage of Survival Estimates |
| 177Lu-DOTA0-Tyr3-Octreotate | Rate of Overall Survival (OS) | 48 months | 49.5 Percentage of Survival Estimates |
| 177Lu-DOTA0-Tyr3-Octreotate | Rate of Overall Survival (OS) | 36 months | 61.4 Percentage of Survival Estimates |
| 177Lu-DOTA0-Tyr3-Octreotate | Rate of Overall Survival (OS) | 60 months | 37.1 Percentage of Survival Estimates |
| 177Lu-DOTA0-Tyr3-Octreotate | Rate of Overall Survival (OS) | 12 months | 91.0 Percentage of Survival Estimates |
| Octreotide LAR | Rate of Overall Survival (OS) | 60 months | 35.4 Percentage of Survival Estimates |
| Octreotide LAR | Rate of Overall Survival (OS) | 12 months | 79.7 Percentage of Survival Estimates |
| Octreotide LAR | Rate of Overall Survival (OS) | 24 months | 62.7 Percentage of Survival Estimates |
| Octreotide LAR | Rate of Overall Survival (OS) | 36 months | 50.1 Percentage of Survival Estimates |
| Octreotide LAR | Rate of Overall Survival (OS) | 48 months | 41.8 Percentage of Survival Estimates |
p-value: 0.303995% CI: [0.6, 1.17]Log Rank
Secondary
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).
Time frame: 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
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Time to Tumour Progression (TTP) | NA Months |
| Octreotide LAR | Time to Tumour Progression (TTP) | 8.7 Months |
p-value: <0.000195% CI: [0.077, 0.242]Log Rank