Gastro-enteropancreatic Neuroendocrine Tumor
Conditions
Keywords
Lutathera, GEP-NET, NETTER-2, 177Lu-DOTA0-TATE, Lutetium oxodotreotide, Lutetium dotatate, AAA601
Brief summary
The aim of NETTER-2 was to determine if Lutathera in combination with long-acting octreotide prolongs progression free survival (PFS) in gastroenteropancreatic neuroendocrine tumor (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 were eligible, as well as patients previously treated with SSAs in the absence of progression.
Detailed description
The study consisted of a screening phase, a treatment phase, an optional cross-over phase for subjects assigned to the control arm, optional re-treatment phase for subjects assigned to the Lutathera arm, and a follow-up phase. This study compared treatment with Lutathera (7.4 GBq/200 mCi 4 × administrations every 8 weeks ± 1 week; cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting release (LAR) (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment) and high dose octreotide LAR (60 mg every 4 weeks).
Interventions
DRUGLutathera
Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.
DRUG30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)
Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.
DRUG2.5% Lys-Arg sterile amino acid solution
Participants who received Lutathera were administered a concomitant 2.5% Lys-Arg solution for kidney protection, with each Lutathera dose. The 2.5% Lys-Arg solution was administered intravenously for 4 hours (infusion rate: 250 ml/h); the infusion was to start 30 minutes prior to the start of the Lutathera infusion and continue during (30 min) and up to at least 3 hours after the Lutathera infusion.
DRUGHigh dose 60 mg octreotide long-acting repeatable
Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.
Sponsors
Advanced Accelerator Applications
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Central Assessment | from randomization to the first line progression or death due to any cause, up to approx. 42 months | PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per Central Assessment (Key Secondary) | Up to approx. 42 months | ORR is defined as the percentage of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Up to approx. 42 months | TTD is defined as the first deterioration of at least 10 points from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): global health status, diarrhea, fatigue, and pain. The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement). |
| Disease Control Rate (DCR) Per Central Assessment | Up to approx. 42 months | Disease Control Rate is the percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) (centrally assessed according to RECIST 1.1). CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). |
| Duration of Response (DOR) Per Central Assessment | Up to approx. 42 months | Duration of Response defined as time from first complete or partial response to progression or death due to underlying cancer according to RECIST 1.1. |
| Rate of Adverse Events | from FPFV until end of study (about 94 months) | Rate of adverse events scored according to CTCAE grade |
| Rate of Laboratory Toxicities | from FPFV until end of study (about 94 months) | Rate of laboratory toxicities scored according to CTCAE grade |
| Overall Survival (OS) | from FPFV until end of study (about 94 months) | OS is the time from randomization date until day of death due to any cause. |
Countries
Canada, France, Germany, Italy, Netherlands, South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
This study randomized subjects in 38 centers in 9 participating countries. Overall, 222 subjects were planned to be randomized (2:1) to Lutathera arm or control arm.
Participants by arm
| Arm | Count |
|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment. | 151 |
| Octreotide LAR 60 mg (Control Arm) Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase. | 75 |
| Total | 226 |
Baseline characteristics
| Characteristic | Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Octreotide LAR 60 mg (Control Arm) | Total |
|---|---|---|---|
| Age, Continuous | 60.2 years STANDARD_DEVIATION 13.21 | 59.6 years STANDARD_DEVIATION 11.52 | 60.0 years STANDARD_DEVIATION 12.65 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian (Indian & Korean) | 23 Participants | 11 Participants | 34 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Missing | 8 Participants | 12 Participants | 20 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 115 Participants | 50 Participants | 165 Participants |
| Sex: Female, Male Female | 70 Participants | 35 Participants | 105 Participants |
| Sex: Female, Male Male | 81 Participants | 40 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 32 / 147 | 14 / 73 | 3 / 29 | 0 / 8 |
| other Total, other adverse events | 129 / 147 | 65 / 73 | 22 / 29 | 6 / 8 |
| serious Total, serious adverse events | 30 / 147 | 15 / 73 | 2 / 29 | 0 / 8 |
Outcome results
Primary
Progression Free Survival (PFS) Per Central Assessment
PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion.
Time frame: from randomization to the first line progression or death due to any cause, up to approx. 42 months
Population: Full Analysis Set (FAS) comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Progression Free Survival (PFS) Per Central Assessment | 22.8 months |
| Octreotide LAR 60 mg (Control Arm) | Progression Free Survival (PFS) Per Central Assessment | 8.5 months |
p-value: <0.000195% CI: [0.182, 0.418]Log Rank
Secondary
Disease Control Rate (DCR) Per Central Assessment
Disease Control Rate is the percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) (centrally assessed according to RECIST 1.1). CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD).
Time frame: Up to approx. 42 months
Population: FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Disease Control Rate (DCR) Per Central Assessment | 90.7 Percentage of participants |
| Octreotide LAR 60 mg (Control Arm) | Disease Control Rate (DCR) Per Central Assessment | 66.7 Percentage of participants |
Secondary
Duration of Response (DOR) Per Central Assessment
Duration of Response defined as time from first complete or partial response to progression or death due to underlying cancer according to RECIST 1.1.
Time frame: Up to approx. 42 months
Population: FAS comprises all participants to whom study treatment has been assigned by randomization. Only participants who had a response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Duration of Response (DOR) Per Central Assessment | 23.3 months |
| Octreotide LAR 60 mg (Control Arm) | Duration of Response (DOR) Per Central Assessment | NA months |
Secondary
Overall Response Rate (ORR) Per Central Assessment (Key Secondary)
ORR is defined as the percentage of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to approx. 42 months
Population: FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Overall Response Rate (ORR) Per Central Assessment (Key Secondary) | 43.0 Percentage of participants |
| Octreotide LAR 60 mg (Control Arm) | Overall Response Rate (ORR) Per Central Assessment (Key Secondary) | 9.3 Percentage of participants |
p-value: <0.000195% CI: [3.32, 18.4]Stratified One-sided p-value
Secondary
Overall Survival (OS)
OS is the time from randomization date until day of death due to any cause.
Time frame: from FPFV until end of study (about 94 months)
Secondary
Rate of Adverse Events
Rate of adverse events scored according to CTCAE grade
Time frame: from FPFV until end of study (about 94 months)
Secondary
Rate of Laboratory Toxicities
Rate of laboratory toxicities scored according to CTCAE grade
Time frame: from FPFV until end of study (about 94 months)
Secondary
Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)
TTD is defined as the first deterioration of at least 10 points from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): global health status, diarrhea, fatigue, and pain. The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from not at all to very much for most items. Raw scores are linearly transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement).
Time frame: Up to approx. 42 months
Population: FAS comprises all participants to whom study treatment has been assigned by randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Global Health status | 13.2 months |
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Diarrhea | 17.4 months |
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Fatigue | 6.0 months |
| Lutathera® Plus Octreotide LAR 30 mg (Investigational Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Pain | 10.3 months |
| Octreotide LAR 60 mg (Control Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Pain | 8.6 months |
| Octreotide LAR 60 mg (Control Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Global Health status | 8.6 months |
| Octreotide LAR 60 mg (Control Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Fatigue | 6.0 months |
| Octreotide LAR 60 mg (Control Arm) | Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) | Diarrhea | 17.3 months |
Comparison: Global Health Statusp-value: 0.222295% CI: [0.57, 1.283]Log Rank