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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Gastro-enteropancreatic Neuroendocrine Tumor

Intervention / Treatment
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* Drug: Lutathera
* Drug: long-acting octreotide
* Drug: high dose long-acting octreotide
* Other: Optional post-progression re-treatment with Lutathera
* Other: Optional post-progression cross-over to Lutathera


Participation Criteria
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Eligibility Criteria
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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 6 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

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lutathera plus long-acting octreotide<br> | Drug: Lutathera<br>* 7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 weeks<br>Drug: long-acting octreotide<br>* 30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment<br>Other: Optional post-progression re-treatment with Lutathera<br>* additional 2-4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)<br>|
| Active Comparator: high dose long-acting octreotide<br> | Drug: high dose long-acting octreotide<br>* 60 mg every 4 weeks<br>Other: Optional post-progression cross-over to Lutathera<br>* maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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