A phase III multi-center, randomized, open-label study to evaluate the efficacy and safety of Lutathera in combination with best supportive care octreotide long-acting (30 mg), when given as a 1st line treatment in GEPNET patients with high proliferation rate tumors (G2 and G3), in comparison to treatment with high dose (60 mg) octreotide long-acting

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Advanced Accelerator Applications

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Nov 2019 → ongoing

Decision date (initial)

2024-06-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Advanced Accelerator Applications

External identifiers

EU CT number

2023-507443-10-00

EudraCT number

2019-001562-15

ClinicalTrials.gov

NCT03972488

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Efficacy

To demonstrate that Lutathera is superior to active comparator in delaying the time-to-first occurrence of progression or death (PFS) as first line treatment.

Secondary objectives 6

1. To demonstrate the superiority of Lutathera, compared to active comparator, in terms of objective response.
2. To demonstrate the superiority of Lutathera, compared to active comparator, in terms of time to deterioration in selected QoL items/scales
3. To evaluate the efficacy of Lutathera, compared to active comparator, in keeping the disease under control
4. To evaluate the efficacy of Lutathera, compared to active comparator, in terms of duration of response
5. To evaluate the safety and tolerability of Lutathera
6. To evaluate the effect of Lutathera on overall survival

Conditions and MedDRA coding

Patients with somatostatin receptor positive, well-differentiated G2 and G3, advanced GEP NETs

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
2. Ki67 index ≥10 and ≤ 55%
3. Patients ≥15 years of age and a body weight of >40 kg at screening
4. Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging, [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]- pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions)
5. The tumor uptake observed in the target lesions must be > normal liver uptake
6. Karnofsky Performance Score (KPS) ≥60
7. Presence of at least 1 measurable site of disease
8. Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities

Exclusion criteria 25

1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x10^9/L (2000/mm^3); platelets <75x10^9/L (75x10^3/mm^3)
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. A) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study treatment period (including cross- over and re-treatment, if applicable) and for 7 months after study drug discontinuation. B) Sexually active male patients, unless they agree to remain abstinent (refrain from heterosexual intercourse) or be willing to use condoms and highly effective methods of contraception with female partners of childbearing potential or pregnant female partners during the treatment period (including cross-over and re-treatment, if applicable) and for 4 months after study drug discontinuation. In addition, male patients must refrain from donating sperm during this same period
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study
8. Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization
9. Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study
11. Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET
12. Any surgery within 12 weeks prior to randomization in the study
13. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be >40% before randomization
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome
16. Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment
18. Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (eg octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera
19. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study
20. Prior external beam radiation therapy to more than 25% of the bone marrow
21. Current spontaneous urinary incontinence
22. 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
23. 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
24. Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients
25. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 day

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS): Time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause

Secondary endpoints 2

1. ORR: Rate of patients with best overall response of partial response (PR) or complete response (CR) (centrally assessed according to RECIST 1.1)
2. Time to decline (TTD) by 10 points from baseline in the following scores measured by the EORTC QLQ-C30 questionnaire: global health status, diarrhea, fatigue and pain

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Advanced Accelerator Applications

Sponsor organisation

Advanced Accelerator Applications

Address

8 Rue Henri Sainte Claire Deville

City

Rueil-Malmaison

Postcode

92500

Country

France

Scientific contact point

Organisation

Advanced Accelerator Applications

Contact name

Regulatory Affairs Team

Public contact point

Organisation

Advanced Accelerator Applications

Contact name

Regulatory Affairs Team

Third parties 4

Locations

5 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 45 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications