Study to Evaluate the Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Patients With Grade 1 and Grade 2 Advanced GEP-NET

Official title

A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Patients Newly Diagnosed With Grade 1 and Grade 2 (Ki-67 <10%) Advanced GEP-NET With High Disease Burden (NETTER-3)

Overview

The purpose of the current study is to evaluate the efficacy and safety of \[177Lu\]Lu-DOTA-TATE plus octreotide long-acting release (LAR) versus octreotide LAR alone in newly diagnosed patients with somatostatin receptor positive (SSTR+), well differentiated Grade1 and Grade 2 (G1 and G2) (Ki-67 \<10%) advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high disease burden

Detailed description

The study consists of a screening phase, a treatment phase and a follow-up phase. This study compares treatment with \[177Lu\]Lu-DOTA-TATE plus octreotide LAR and octreotide LAR only.

Interventions

• Radiation [177Lu]Lu-DOTA-TATE
  \[177Lu\]Lu-DOTA-TATE will be administered 4 times during treatment period with frequency of every 8 weeks (Q8W)
• Drug Octreotide LAR
  Octreotide LAR will be administered Q8W when co-administered with \[177Lu\]Lu-DOTA-TATE in the investigational arm followed by Q4W. In the control arm Octreotide LAR will be administered Q4W.

Primary outcome measures

• Progression Free Survival (PFS) centrally assessed by Blinded Independent Review Committee (BIRC) [Time frame: After observing approximately 88 PFS events as per BIRC assessments, expected after approximately 33 months from study start]

Secondary outcome measures (12)

• Time to Deterioration (TDD) (Key Secondary) [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Progression Free Survival (PFS) [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Objective Response Rate (ORR) [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Disease Control Rate (DCR) [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Duration of Response (DOR) [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Overall Survival (OS) [Time frame: Until 60 month from randomization]
• Time to Deterioration (TDD) [Time frame: At the time of primary PFS analysis after observing approximately 88 PFS events per BIRC assessment]
• Absolute change from baseline in EORTC QLQ-G.I.NET21 domain [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Absolute change from baseline in the EQ-5D-5L index at each time point [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Absolute change from baseline in EORTC QLQ-C30 domain [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start.]
• Dosimetry [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]
• Pharmacokinetic (PK) parameter: Area Under Curve (AUC) from [177Lu]Lu-DOTA-TATE blood radioactivity data [Time frame: After observing approximately 88 PFS events as per BIRC assessment, expected after approximately 33 months from study start]

Eligibility criteria

Inclusion criteria

• Presence of metastasized or locally advanced, unresectable (curative intent), histologically proven, well differentiated Grade 1 or Grade 2 (Ki-67 <10%) gastroenteropancreatic neuroendocrine tumor (GEP-NET) diagnosed within 6 months prior to screening.
• 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.
• Participants ≥ 12 years of age.
• RLI somatostatin receptor (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 as available (some examples are listed below) can be used as per local practice:

• \[68Ga\]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
• SRS (planar and/or SPECT/CT) with \[99mTc\]Tc-octreotide.
• Adequate bone marrow and organ function as defined by the following laboratory values prior to receiving the first study treatment:

• White blood cell (WBC) count ≥ 2 x 109/L
• Platelet count ≥ 75 x 109/L
• Hemoglobin (Hb) ≥ 8 g/dL
• Creatinine clearance > 40 mL/min calculated by the Cockcroft Gault method
• Total bilirubin ≤ 3 x ULN
• 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 within 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.
• ECOG performance status 0-1.
• Presence of at least 1 measurable site of disease.

Exclusion criteria

• Prior administration of a therapeutic radiopharmaceutical for GEP-NET at any time prior to randomization in the study.
• Any previous therapy with interferons, mTOR-inhibitors, chemotherapy or other systemic therapies except somatostatin analogues (SSAs) of GEP-NET. If as per Investigator's opinion a participant is candidate for such therapies, such participant must not be enrolled.
• Participant who received more than 4 cycles of prior SSAs (e.g., octreotide long-acting release) 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.
• Documented RECIST v1.1 progression during previous SSA treatments for the current GEP-NET at any time prior to randomization.
• Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET.
• Any major surgery within 12 weeks prior to randomization in the study.
• Known brain metastases.
• Participant with known intolerance to CT scans with intravenous (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.
• Hypersensitivity to any somatostatin analogues, to the Investigational Medicinal Products (IMPs) active substance or to any of the excipients.
• 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.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 19 centers

• Mayo Clinic Arizona — Scottsdale
• Highlands Oncology Group — Fayetteville
• Rocky Mountain Cancer Centers — Denver
• Hartford Hospital — Hartford
• Yale New Haven Hospital — New Haven
• Mayo Clinic Jacksonville — Jacksonville
• Winship Cancer Institute — Atlanta
• St Elizabeth Healthcare — Edgewood
• … and 11 more centers

Italy · 8 centers

• Novartis Investigative Site — Cona
• Novartis Investigative Site — Genova
• Novartis Investigative Site — Milan
• Novartis Investigative Site — Rozzano
• Novartis Investigative Site — Pisa
• Novartis Investigative Site — Roma
• Novartis Investigative Site — Roma
• Novartis Investigative Site — Milan

Spain · 7 centers

• Novartis Investigative Site — L'Hospitalet de Llobregat
• Novartis Investigative Site — Oviedo
• Novartis Investigative Site — Barcelona
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Salamanca

France · 6 centers

• Novartis Investigative Site — Bron
• Novartis Investigative Site — Clichy
• Novartis Investigative Site — Montpellier
• Novartis Investigative Site — Nantes
• Novartis Investigative Site — Pessac
• Novartis Investigative Site — Toulouse

Poland · 6 centers

• Novartis Investigative Site — Gdansk
• Novartis Investigative Site — Gliwice
• Novartis Investigative Site — Krakow
• Novartis Investigative Site — Poznan
• Novartis Investigative Site — Warsaw
• Novartis Investigative Site — Warsaw

Canada · 4 centers

• Novartis Investigative Site — Edmonton
• Novartis Investigative Site — London
• Novartis Investigative Site — Toronto
• Novartis Investigative Site — Montreal

China · 4 centers

• Novartis Investigative Site — Beijing
• Novartis Investigative Site — Beijing
• Novartis Investigative Site — Beijing
• Novartis Investigative Site — Shanghai

Germany · 3 centers

• Novartis Investigative Site — Erlangen
• Novartis Investigative Site — Essen
• Novartis Investigative Site — München

South Korea · 3 centers

• Novartis Investigative Site — Seoul
• Novartis Investigative Site — Seoul
• Novartis Investigative Site — Seoul

Hungary · 2 centers

• Novartis Investigative Site — Budapest
• Novartis Investigative Site — Szeged

Netherlands · 2 centers

• Novartis Investigative Site — Rotterdam
• Novartis Investigative Site — Utrecht

United Kingdom · 1 center

• Novartis Investigative Site — London

Identifiers

NCT: NCT06784752 · CAAA601A62301 · 2024-518325-15-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗