Study to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE in patients with Grade 1 and Grade 2 advanced GEP-NET (NETTER-3)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

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

8 Sep 2025 → ongoing

Decision date (initial)

2025-07-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-518325-15-00

WHO UTN

U1111-1320-4743

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate that [177Lu]Lu-DOTA-TATE plus octreotide LAR is superior to active comparator in delaying the time-to-first occurrence of progression or death (PFS) as first line treatment.

Secondary objectives 10

1. To demonstrate that [177Lu]Lu-DOTA-TATE plus octreotide LAR is superior to active comparator in delaying time to deterioration (TTD) of Quality of Life (QoL)
2. To evaluate the efficacy of [177Lu]Lu-DOTA-TATE plus octreotide LAR, compared to active comparator, in terms of PFS.
3. To evaluate the efficacy of [177Lu]Lu-DOTA-TATE plus octreotide LAR, compared to active comparator, in terms of objective response
4. To evaluate the efficacy of [177Lu]Lu-DOTA-TATE plus octreotide LAR, compared to active comparator, in keeping the disease under control
5. To evaluate the efficacy of [177Lu]Lu-DOTA-TATE plus octreotide LAR, compared to active comparator, in terms of duration of response (DOR).
6. To evaluate the safety and tolerability of [177Lu]Lu-DOTA-TATE plus octreotide LAR compared to active comparator.
7. To evaluate the effect of [177Lu]Lu-DOTA-TATE plus octreotide LAR compared to active comparator, on overall survival (OS).
8. To evaluate the effect of [177Lu]Lu-DOTA-TATE plus octreotide LAR, compared to active comparator, on QoL as assessed by EORTC QLQ-G.I.NET21 and EORTC QLQ-C30 (domains not included as key secondary objectives) and EQ-5D-5L.
9. To evaluate the dosimetry of [177Lu]Lu-DOTA-TATE at selected cycles in a subset of participants.
10. To evaluate the pharmacokinetics (PK) of [177Lu]Lu-DOTA-TATE at selected cycles in a subset of participants.

Conditions and MedDRA coding

Gastroenteropancreatic neuroendocrine tumor (GEP-NET)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Presence of metastasized or locally advanced, unresectable (curative intent), histologically proven, well differentiated G1 or G2 (Ki-67 <10%) GEP-NET diagnosed within 6 months prior to screening.
2. Participants with high disease burden in the Investigator's opinion. Following criteria should be used as the guiding principle for determining high disease burden: • Primary tumor or a metastatic lesion > 4 cm • More than one tumor or metastatic lesions measuring > 2 cm • Elevated alkaline phosphatase > 2.5 X upper limit of normal (ULN) • Presence of bone metastasis • Presence of peritoneal metastasis • Symptoms due to tumor volume such as pain, fatigue, weight loss, anorexia etc. • Symptoms due to hormone excess requiring active management Additionally, participants who, in the Investigator's opinion, have high disease burden due to their disease characteristics not specified above could also be considered eligible. The clinical characteristics of the disease must be clearly recorded in the electronic case report form.
3. Participants ≥ 12 years of age. For Germany, Hungary, The Netherlands and Poland, only adult participants ≥ 18 years of age will be enrolled.
4. Radioligand imaging (RLI) SSTR uptake on all target lesions (defined by RECIST v1.1 criteria) at least as high as normal liver uptake, assessed within 3 months prior to randomization. Any of the RLI modalities such as, [68Ga]Ga-DOTA-TOC PET/CT or PET/MRI, [68Ga]Ga-DOTA-TATE PET/CT or PET/MRI, [64Cu]Cu-DOTA-TATE PET/CT or PET/MRI, somatostatin receptor scintigraphy (SRS) (planar and/or SPECT/CT) with [111In]In-pentetreotide, or SRS (planar and/or SPECT/CT) with [99mTc]Tc-octreotide, can be used as per local practice.
5. Adequate bone marrow and organ function as defined by the following laboratory values prior to receiving the first study treatment: a. White blood cells (WBCs) ≥ 2 x 109/L* b. Platelet count ≥ 75 x 109/L* c. Hemoglobin ≥ 8 g/dL* d. Creatinine clearance > 40 mL/min calculated by the Cockcroft Gault method e. Total bilirubin ≤ 3 x ULN f. Potassium within normal limits. Potassium level of up to 6.0 millimoles per liter (mmol/L) is acceptable at study entry if associated with creatinine clearance withinr normal limits calculated using Cockcroft-Gault formula. Mild decrease (grade 1) below lower limit of normal (LLN) is acceptable at study entry if considered not clinically significant by Investigator. See details regarding potassium assessment and Lysine – Arginine amino acid solution administration in Section 8.4.4. *No platelet transfusion packed red cell transfusion, or granulocyte-colony stimulating factor (G-CSF) will be allowed during screening after ICF signature. Transfusion for the sole purpose of making a participant eligible for the study inclusion is not allowed.
6. ECOG performance status 0-1.
7. Presence of at least 1 measurable site of disease

Exclusion criteria 10

1. Prior administration of a therapeutic radiopharmaceutical for GEP-NET at any time prior to randomization in the study.
2. Any previous therapy with interferons, mTOR-inhibitors, chemotherapy or other systemic therapies (except SSAs; please refer to exclusion criteria # 3 for further details) of GEP-NET. If as per Investigator opinion a participant is a candidate for such therapies, such participant must not be enrolled.
3. Participant who received more than 4 cycles of prior SSA (e.g., octreotide LAR) are not eligible. In addition, any participant receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before the administration of [177Lu]Lu-DOTA-TATE, or any participant receiving treatment with SSAs, which cannot be interrupted for at least 4 weeks before the administration of [177Lu]Lu-DOTA-TATE.
4. Documented RECIST v1.1 progression during previous SSA treatments for the current GEP-NET at any time prior to randomization.
5. Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET
6. Any major surgery within 12 weeks prior to randomization in the study.
7. Known brain metastases.
8. Participant with known intolerance to CT scans with i.v. contrast due to allergic reaction or renal insufficiency. If such a participant can be imaged with MRI, then the participant would not be excluded.
9. Hypersensitivity to any somatostatin analogues, to the Investigational Medicinal Products (IMPs) active substance or to any of the excipients.
10. Active severe urinary incontinence, severe voiding dysfunction, or urinary obstruction requiring an indwelling/condom catheter that, in the judgment of the Investigator, could prevent adhering to radiation safety instructions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS, defined as the time from randomization to the first occurrence of progression (centrally assessed by Blinded Independent Review Committee (BIRC) according to RECIST v1.1) or death due to any cause

Secondary endpoints 10

1. Time to deterioration (by an absolute change of at least 15%), defined as the time from randomization to the first occurrence of deterioration compared to baseline scores or death from any cause for each of the following domains (tested separately) of EORTC QLQ-GI.NET21 [gastrointestinal scale (GI scale)] and EORTC QLQ-C30 questionnaires (fatigue, diarrhea, and global health scale).
2. PFS, defined as the time from randomization to the first occurrence of progression (Investigator assessed according to RECIST v1.1) or death due to any cause.
3. Objective response rate (ORR): Rate of participants with best overall response (BOR) of partial response (PR) or complete response (CR) as per RECIST v1.1 (both Investigator and centrally assessed by BIRC).
4. Disease control rate (DCR): Rate of participants with BOR of PR, CR or stable disease (SD) as per RECIST v1.1 (both Investigator and centrally assessed by BIRC).
5. DOR: The time from initially meeting the criteria for response (CR or PR) until the time of progression according to RECIST v1.1 or death due to underlying disease only.
6. Incidence and severity of adverse events (AEs) and serious adverse event (SAEs), changes in laboratory values, vital signs and ECGs. Tolerability: Dose interruptions, discontinuations, and reductions.
7. OS: Time from the randomization date until the date of death due to any cause.
8. • TTD (using the same definition as for key secondary endpoints) for EORTC QLQ-G.I.NET21 and EORTC QLQ-C30 domains not included among key secondary endpoints • Absolute change from baseline in EORTC QLQ-G.I.NET21 and EORTC QLQ-C30 domains. • Absolute change from baseline in the EQ-5D-5L index at each timepoint.
9. Absorbed radiation dose in selected organs, tumor lesions and total body.
10. PK parameters (Area Under Curve (AUC), clearance, distribution volume, half-life) from [177Lu]Lu-DOTA-TATE blood radioactivity data.

Investigational products

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

Test 4

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 11

Locations

7 EU/EEA countries · 40 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 87 files

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

Application history

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