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

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ClinicalTrials.gov Identifier: NCT03972488
Recruitment Status : Not yet recruiting
First Posted : June 3, 2019
Last Update Posted : June 3, 2019
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

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.

Condition or disease Intervention/treatment Phase
Gastro-enteropancreatic Neuroendocrine Tumor Drug: Lutathera Drug: long-acting octreotide Drug: high dose long-acting octreotide Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 222 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : August 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2025


Arm Intervention/treatment
Experimental: Lutathera plus long-acting octreotide 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

Active Comparator: high dose long-acting octreotide Drug: high dose long-acting octreotide
60 mg every 4 weeks




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. 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

  4. 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)

  5. 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

  6. 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)

  7. 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)

  8. 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



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC) PET/CT imaging or [68Ga]-DOTA-TATE PET/CT imaging (e.g. NETSPOT) or Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan SPECT/CT).
  • The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
  • 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 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 administered for more than 1 month and within 12 weeks prior to randomization in the study.
  • Any previous radioembolization, chemoembolization and radiofrequency ablation
  • 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 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, preferably via gated equilibrium radionuclide ventriculography. 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 a fasting blood glucose > 2 ULN
  • 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, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
  • 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.
  • Patients with known intolerance or hypersensitivity to any somatostatin analogs
  • Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03972488


Contacts
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Contact: Paola Santoro, PhD +1 781 354 7273 paola.santoro@adacap.com

Sponsors and Collaborators
Advanced Accelerator Applications
Investigators
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Study Director: Study Director Advanced Accelerator Applications

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Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT03972488     History of Changes
Other Study ID Numbers: CAAA601A22301
First Posted: June 3, 2019    Key Record Dates
Last Update Posted: June 3, 2019
Last Verified: May 2019

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

Additional relevant MeSH terms:
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Neuroendocrine Tumors
Intestinal Neoplasms
Pancreatic Neoplasms
Stomach Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Pancreatic Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Endocrine System Diseases
Stomach Diseases
Octreotide
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents