Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET

Gastro-enteropancreatic Neuroendocrine Tumor Clinical Trial

— NETTER-2  

Official title:

A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03972488
• Other study ID #: CAAA601A22301
• Secondary ID: 2019-001562-15
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 22, 2020
• Est. completion date: October 29, 2027

Study information

• Verified date: May 2024
• Source: Advanced Accelerator Applications
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of NETTER-2 is to determine if Lutathera in combination with long-acting octreotide prolongs PFS in GEP-NET patients with high proliferation rate tumors (G2 and G3), when given as a first line treatment compared to treatment with high dose (60 mg) long-acting octreotide. Somatostatin analog (SSA) naive patients are eligible, as well as patients previously treated with SSAs in the absence of progression.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 226
• Est. completion date: October 29, 2027
• Est. primary completion date: July 20, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

Inclusion Criteria:

• 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.

• Ki67 index =10 and = 55%

• Patients = 15 years of age and a body weight of > 40 kg at screening

• 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) imaging.

• The tumor uptake observed in the target lesions must be > normal liver uptake.

• Karnofsky Performance Score (KPS) = 60

• Presence of at least 1 measurable site of disease

• 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:

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method

• Hb concentration < 5.0 mmol/L (<8.0 g/dL); WBC < 2x10E9/L (2000/mm3); platelets < 75x10E9/L (75x10E3/mm3)

• Total bilirubin > 3 x ULN

• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range

• Pregnancy or lactation

• 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

• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.

• Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization

• Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics

• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies for GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.

• Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET

• Any surgery within 12 weeks prior to randomization in the study

• 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.

• 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.

• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome

• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%

• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment

• 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 (e.g. octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera.

• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.

• Prior external beam radiation therapy to more than 25% of the bone marrow.

• Current spontaneous urinary incontinence

• 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

• Patient with known incompatibility to CT Scans with IV contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.

• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.

• Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days

Related Conditions & MeSH terms

• Gastro-enteropancreatic Neuroendocrine Tumor
• Neuroendocrine Tumors

Intervention

Drug:
• Lutathera
7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 weeks
• long-acting octreotide
30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment
• high dose long-acting octreotide
60 mg every 4 weeks

Other:
• Optional post-progression re-treatment with Lutathera
additional 2-4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)
• Optional post-progression cross-over to Lutathera
maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks)
• Optional post-progression re-treatment with Lutathera after cross-over
additional 2-4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)

Locations

Country	Name	City	State
Canada	London Health Sciences Centre, University of Western Ontario - Oncology	London
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto
Canada	BC Cancer Agency	Vancouver
France	CHU Paris Nord-Val de Seine	Clichy
France	Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot	Lyon
France	Institut du Cancer de Montpellier - Oncology	Montpellier
France	CHU-Hôtel Dieu Service de Médecine Nucléaire	Nantes
France	Institut Gustave Roussy	Villejuif
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsklinikum Essen - Klinik für Nuklearmedizin	Essen
Italy	A.O.di Bologna Policl.S.Orsola	Bologna
Italy	University of Genova - Oncology	Genova
Italy	Istituto Oncologico Romagnolo	Meldola
Italy	Fondazione Irccs Istituto Nazionale Tumori	Milano
Italy	Ieo, Irccs	Milano
Italy	IRCCS fondazione Pascale - Oncology	Napoli
Italy	Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology	Reggio Emilia
Italy	Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology	Roma
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-Si
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Seoul National University Hospital - Department of Internal Medicine	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System - Medical Oncology	Seoul
Netherlands	Erasmus Medisch Centrum	Rotterdam
Netherlands	UMC Utrecht - Oncology	Utrecht
Spain	Hospital Universitario Vall d'Hebrón	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitari i Politecnic La Fe	Valencia
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Guys And St Thomas Hospital	London
United Kingdom	Kings College Hospital - Oncology	London
United Kingdom	Royal Free Hospital, London	London
United Kingdom	Weston Park Hospital	Sheffield
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics - Oncology	Iowa City	Iowa
United States	University of Kentucky UK Markey Cancer Center	Lexington	Kentucky
United States	Yale Cancer Center	New Haven	Connecticut
United States	Mayo Clinic - Oncology	Rochester	Minnesota
United States	USF - H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Advanced Accelerator Applications

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	through Week 72 until 99 PFS events are reached
Secondary	Objective Response Rate	Rate of complete and partial responses (CR, PR) (centrally assessed according to RECIST 1.1)	week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72
Secondary	Time to Deteriration (TTD) global health status, diarrhea, fatigue, pain (EORTC QLQ-C30)	TTD is defined as the first deterioration of at least 10 points from baseline in EORTC QLQ-C30 questionnaire: global health status (TTD)-diarrhea (TTD)-fatigue, (TTD)-pain (TTD)	every 12 ± 1 week from first treatment date until the end of treatment
Secondary	Disease Control Rate (DCR)	Rate of complete response (CR), partial response (PR) and stable disease (SD) centrally assessed according to RECIST 1.1.	week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72
Secondary	Duration of Response (DOR)	Time from initially meeting the criteria for response (CR or PR) until the time of progression according to RECIST 1.1 or death due to underlying disease	week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72
Secondary	Rate of Adverse Events	Rate of adverse events scored according to CTCAE grade	Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion.
Secondary	Rate of laboratory toxicities	Rate of laboratory toxicities scored according to CTCAE grade	Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion.
Secondary	Overall Survival (OS)	OS is the time from randomization date until day of death due to any cause.	up to 4 years from randomization of last patient