E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lung Neuroendocrine Tumours |
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E.1.1.1 | Medical condition in easily understood language |
Lung neuroendocrine tumours |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052399 |
E.1.2 | Term | Neuroendocrine tumour |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the antitumour efficacy of LAN monotherapy plus BSC every 28 days versus placebo plus BSC, in terms of progression free survival (PFS), measured by central review using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in subjects with unresectable and/or metastatic well differentiated, typical or atypical lung neuroendocrine tumours. |
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E.2.2 | Secondary objectives of the trial |
To compare the objective response rate (ORR) of LAN monotherapy plus BSC every 28 days versus placebo plus BSC, as assessed by RECIST v 1.1 criteria (proportion of subjects with a best overall response of partial response (PR) or complete response (CR)), • To compare the overall survival (OS) of subjects randomised to LAN monotherapy plus BSC every 28 days versus subjects randomised to placebo plus BSC, • To compare time to treatment failure (Kaplan Meier estimates) of LAN monotherapy plus BSC every 28 days versus placebo plus BSC, • To compare the changes from Baseline in the biomarker chromogranin A (CgA), • To compare the proportion of subjects with a decrease of CgA≥30% at week 8 in the population of subjects with an elevated CgA (≥2 x ULN) at Baseline, • To describe the change in Quality of Life (QoL) from baseline, as assessed by the EORTC QLQ-C30 questionnaire, (2 more, see synopsis) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
(1) Provision of written informed consent prior to any study related procedures, (2) Subjects aged ≥ 18 years, (3) Have metastatic and/or unresectable pathologically confirmed well-differentiated, typical or atypical neuroendocrine tumour of the lung, (4) Histologic evidence of well differentiated NETs of the lung (typical and atypical according to the WHO criteria evaluated locally), (5) Has a mitotic index <2 mitoses/2 mm2 for typical carcinoid (TC) and <10 mitoses/2 mm2 and/or foci of necrosis for atypical carcinoid (AC), (6) At least one measurable lesion of the disease on imaging (CT or MRI; RECIST v1.1)), (7) Positive somatostatin receptor imaging (SRI) (Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: uptake greater than liver background);), (8) ECOG performance status 0-1, (9) Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required., (10) Female subjects who are at risk of becoming pregnant must agree to use an effective method of contraception such as double barrier contraception, an injectable, combined oral contraceptive or an intrauterine device (IUD). The subject must agree to use the contraception during the whole period of the study and for eight months after the last study drug administration. Non childbearing potential is defined as being postmenopausal for at least 1 year, or permanently sterilized at least 3 months before study entry, (11) Male subjects must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception (see above),). The subject must agree to use the contraception during the whole period of the study and for eight months after the last study drug administration, (12) Signed HIPAA authorization where required, (13) Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the study site for the follow-up evaluation as specified in the protocol. |
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E.4 | Principal exclusion criteria |
(1) Poorly differentiated or high grade carcinoma, or subjects with neuroendocrine tumours not of lung origin are excluded, (2) Subjects with Multiple endocrine neoplasia type 1 (MEN 1), (3) Has been treated with an SSA at any time prior to randomization, except if that treatment was for less than 15 days (e.g. peri-operatively) of short acting SSA or one dose of long acting SSA and the treatment was received more than 6 weeks prior to randomization, (4) Has been treated with Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization, (5) Has been treated for Lung NET with chemotherapy* within 4 weeks of randomization (whatever the number of cycles), (6) Has been treated with more than two lines of chemotherapy* for Lung NET, * cytotoxic chemotherapy or molecular targeted therapy or interferon. (7) Treated with surgery within 6 weeks prior to randomization, (8) Previous local therapy (e.g. chemo-embolization, bland, or radioembolization) is allowed if completed > 6 weeks prior to randomization. For subjects who received local therapy prior to randomization, there must be documented growth of measurable disease within the embolization field prior to study, (9) Symptomatic subjects requiring SSA for symptom management (please also note the exclusion criteria 3), (10) Subjects with known ectopic production of adrenocorticotropic hormone (ACTH) or other hormonal secreting subjects allowed – ONLY if symptoms adequately controlled without SSAs, (11) Subjects on concomitant Growth Hormone (GH) antagonist, cyclosporine or bromocriptine (12) Inadequate bone marrow function as per investigator's judgement (13) Severe renal insufficiency as defined by a calculated creatinine clearance <30 mL/min, (14) Total bilirubin >2x ULN, AST, ALT or Alk Ph >5xN, lipase, amylase >2xN, (15) Serum albumin <3.0 g/dL unless prothrombin time is within the normal range, (16) Known hypersensitivity to the study drug, (17) Present cholecystitis, (18) Uncontrolled congestive heart failure (19) Glycosylated hemoglobin (HbA1c) > 8.5%, (20) Abnormal findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, would compromise the subject's safety or the outcome of the study, (21) 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, (22) Pregnant or lactating women or those of childbearing potential age and not practicing a medically acceptable method for birth control, (23) Subjects who have participated in any therapeutic clinical study/received any investigational agent within 30 days of randomization. (24) Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study (25) Uncontrolled hypothyroidism (26) Has been previously screened (i.e. informed consent signed) in this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS), assessed by central review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomization to disease progression or death from any causes |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to study protocol |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints • ORR: best overall response of CR or PR measured by RECIST v1.1 criteria, every 12 weeks until the Post Treatment/Early Withdrawal Visit, • OS, defined as the time from randomization to death from any causes, • Time to treatment failure, defined as the time from randomization to disease progression [defined as the minimum (time to event according to central review, time to event according to local review)] using RECIST v1.1, death, consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of carcinoid syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue octreotide and/or LAR SSA), or initiation of anticancer treatment, • Mean changes from Baseline in biomarker CgA at Week 8, Week 12 and every 12 weeks thereafter until the Post DB and in the OL Extension Treatment Phase, • Proportion of subjects with decrease in CgA ≥30% at Week 8, in the population of subjects with an elevated CgA (≥2 x ULN) at Baseline, • Change in QoL, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) questionnaire from Baseline to Week 12, every 12 weeks and at the Post Treatment /Early Withdrawal Visit and in OL Extension Treatment and Follow-up Phases., • Time to QoL deterioration, defined by a decrease from baseline in EORTC QLQ-C30 score of at least10 points., • Mean changes from Baseline in urinary 5-HIAA levels at Week 8, and every 12 weeks thereafter, and at the Post Treatment/Early Withdrawal Visit and in OL Extension Treatment and Follow-up Phases in subjects with elevated urinary 5-HIAA (≥2 x ULN) at Baseline., • PK of LAN. Safety and tolerability assessments throughout the study: • Adverse Events (AEs) grouped by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term, and graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. • Clinical evaluations (medical and surgical history and physical evaluations, including biochemistry/hematology, ECG, anti-Lanreotide antibodies) • Gallbladder echography, if biological and/or clinical inflammatory symptoms appear during the course of the study. Exploratory Endpoints • CBR: best overall response of CR, PR or SD measured by RECIST v1.1 criteria every 12 weeks until the Post Treatment/Early Withdrawal Visit, • Factors (at Baseline) associated with PFS, as assessed by central review, will include but will not be limited to mitotic count, CgA level, number of metastatic organs and hepatic and intrathoracic tumour load |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to study protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life and Patient satisfaction |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |