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

• ClinicalTrials.gov Identifier: NCT03972488
• Recruitment Status: Active, not recruiting
• First Posted: June 3, 2019
• Last Update Posted: May 15, 2024
• Sponsor: Advanced Accelerator Applications
• Information provided by (Responsible Party): Advanced Accelerator Applications

Tracking Information

• First Submitted Date: May 24, 2019
• First Posted Date: June 3, 2019
• Last Update Posted Date: May 15, 2024
• Actual Study Start Date: January 22, 2020
• Actual Primary Completion Date: July 20, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 15, 2021)

Progression Free Survival (PFS) [ Time Frame: through Week 72 until 99 PFS events are reached ]

Time from randomization to the first line progression (centrally assessed according to RECIST 1.1 or death due to any cause)

Original Primary Outcome Measures (submitted: May 31, 2019)

Progression Free Survival (PFS) [ Time Frame: through Week 72 until 99 PFS events are reached ]

Time from randomization to the first line progression (centrally assessed according to RECIST 1.1)

Current Secondary Outcome Measures (submitted: March 13, 2024)

• Objective Response Rate [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  Rate of complete and partial responses (CR, PR) (centrally assessed according to RECIST 1.1)
• Time to Deteriration (TTD) global health status, diarrhea, fatigue, pain (EORTC QLQ-C30) [ Time Frame: every 12 ± 1 week from first treatment date until the end of treatment ]
  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)
• Disease Control Rate (DCR) [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  Rate of complete response (CR), partial response (PR) and stable disease (SD) centrally assessed according to RECIST 1.1.
• Duration of Response (DOR) [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  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
• Rate of Adverse Events [ Time Frame: Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion. ]
  Rate of adverse events scored according to CTCAE grade
• Rate of laboratory toxicities [ Time Frame: Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion. ]
  Rate of laboratory toxicities scored according to CTCAE grade
• Overall Survival (OS) [ Time Frame: up to 4 years from randomization of last patient ]
  OS is the time from randomization date until day of death due to any cause.

Original Secondary Outcome Measures (submitted: May 31, 2019)

• Objective Response Rate [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  Rate of complete and partial responses (CR, PR) (centrally assessed according to RECIST 1.1)
• Time to Decline (TTD) global health status, diarrhea, fatigue, pain (EORTC QLQ-C30) [ Time Frame: every 12 ± 1 week from first treatment date until the end of treatment ]
  TTD by 10 points from baseline in EORTC QLQ-C30 questionnaire: global health status (TTD)-diarrhea (TTD)-fatigue, (TTD)-pain (TTD)
• Time to Decline (TTD) Total Health Status (EORTC QLQ-G.I.NET21) [ Time Frame: every 12 ± 1 week from first treatment date until the end of treatment ]
  TTD by 10 points from baseline in total health status score as measured by EORTC QLQ-G.I.NET21 questionnaire
• Disease Control Rate (DCR) [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  Rate of CR, PR and SD between the two treatment arms (centrally assessed according to RECIST 1.1)
• Duration of Response (DOR) [ Time Frame: week 16 ±1; week 24 ±1 and then every 12 ±1 weeks until Week 72 ]
  time from initially meeting the criteria for response (CR or PR) until the time of progression according to RECIST 1.1
• Rate of Adverse Events [ Time Frame: Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion. ]
  Rate of adverse events between the two treatment arms (scored according to CTCAE grade)
• Rate of laboratory toxicities [ Time Frame: Lutathera: within 2 weeks before infusion and 4 ± 1 weeks after infusion. ]
  Rate of laboratory toxicities between the two treatment arms (scored according to CTCAE grade)
• Time to death [ Time Frame: up to 4 years from end of treatment of last patient ]
  time from randomization date until day of death due to any cause between the two treatment arms

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Gastro-enteropancreatic Neuroendocrine Tumor

Intervention

• Drug: Lutathera
  7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 weeks
• Drug: long-acting octreotide
  30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment
• Drug: 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)
• Other: 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)
• Other: Optional post-progression re-treatment with Lutathera after cross-over
  additional 2-4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)

Study Arms

• Experimental: Lutathera plus long-acting octreotide
  Interventions:

  • Drug: Lutathera
  • Drug: long-acting octreotide
  • Other: Optional post-progression re-treatment with Lutathera
• Active Comparator: high dose long-acting octreotide
  Interventions:

  • Drug: high dose long-acting octreotide
  • Other: Optional post-progression cross-over to Lutathera
  • Other: Optional post-progression re-treatment with Lutathera after cross-over

• Publications *: Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol. 2021 Jul 1;33(4):378-385. doi: 10.1097/CCO.0000000000000740.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 13, 2024): 226
• Original Estimated Enrollment (submitted: May 31, 2019): 222
• Estimated Study Completion Date: October 29, 2027
• Actual Primary Completion Date: July 20, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Italy, Korea, Republic of, Netherlands, Spain, United Kingdom, United States
• Removed Location Countries: Brazil, China

Administrative Information

• NCT Number: NCT03972488
• Other Study ID Numbers: CAAA601A22301; 2019-001562-15 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Advanced Accelerator Applications
• Original Responsible Party: Same as current
• Current Study Sponsor: Advanced Accelerator Applications
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Advanced Accelerator Applications
• Verification Date: May 2024