Gastroenteropancreatic Neuroendocrine Tumors, Paraganglioma, Pheochromocytoma
Conditions
Keywords
GEP-NET, PPGL, adolescents, pediatric, Lutathera, Lutetium [177Lu] oxodotreotide, Lutetium Lu 177 dotatate, Peptide Receptor Radionuclide Therapy, PRRT
Brief summary
This is a multicenter, open-label, single-arm study to evaluate the safety and dosimetry of Lutathera in adolescent patients 12 to \<18 years old with somatostatin receptor positive GEP-NETs and PPGLs. The study will enroll at least 8 patients in the GEP-NET cohort and as many adolescents with PPGL as possible in the exploratory PPGL cohort.
Detailed description
The study schedule for each patient consists of the screening period (up to 2 weeks) followed by the treatment period (4 treatment administrations at 8-week interval), and the follow-up period (10 years). The treatment period will consist of 4 Lutathera treatments administered at 8-week intervals. Lutathera administration will occur on Week 1 Day 1 of each cycle. Each patient will receive a total of 4 doses of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8 weeks; cumulative dose: 29.6 GBq/800 mCi). An infusion of 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each Lutathera dose for renal protection according to the approved Lutathera local prescribing information. An antiemetic will be administered prior to infusion of the AA solution for prevention of infusion-related nausea and vomiting. The dosimetry and PK assessments will be performed during the first week after the 1st Lutathera dose, i.e. one time during the study treatment period for each patient. The dosimetry analysis will allow for estimation from the 1st Lutathera administration of the cumulative absorbed radiation dose from 4 Lutathera doses and also for taking a decision on the next dose levels. In the exceptional circumstances when dosimetry cannot be performed in a particular patient after the first Lutathera dose, it should be completed as soon as feasible upon a later dose. In order to minimize risk for each study subject, an accelerated analysis of dosimetry and safety data will be performed for each patient in the study, to enable the Investigator to take a decision for the subsequent Lutathera doses. The results of dosimetry assessments (imaging and blood dosimetry) will be provided to the investigators for their evaluation prior to administration of subsequent therapeutic cycles in each patient. A total follow-up period of 10 years (120 months) after the last Lutathera dose will take place for each patient who received at least one dose of Lutathera. This follow-up period will be comprised of a short-term follow-up of 6 months to evaluate cumulative Lutathera toxicities, followed by a long-term follow up of another 114 months. An external Data and Safety Monitoring Board (DSMB) will also operate in the study to evaluate accumulating safety and dosimetry data, to ensure the safety of adolescents enrolled in the study, and to provide recommendations to investigators as well as to the clinical team in charge of conducting the study.
Interventions
Radiopharmaceutical solution for infusion (7.4 GBq of Lutathera per 30 ml vial)
Sponsors
Advanced Accelerator Applications
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. GEP-NET cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven, G1 or G2 (Ki-67 index =\< 20%), well differentiated GEP-NET. or PPGL cohort: presence of metastasized or locally advanced, inoperable (curative intent), histologically proven PPGL. 2. Patients from 12 to \< 18 years of age at the time of enrollment. 3. Expression of somatostatin receptors confirmed by a somatostatin receptor imaging (SRI) modality within 3 months prior to enrollment, with tumor uptake observed in the target lesions more or equal to the normal liver uptake. 4. Performance status as determined by Karnofsky score \>= 50 or Lansky Play-Performance Scale score \>= 50. 5. Parent's ability to understand and the willingness to sign a written informed consent document for adolescents as determined by local regulations. Adolescents will sign assent along with parental/legal guardian consent or will co-sign consent with parent/legal guardian in accordance with local regulation, prior to participation in the study. Key
Exclusion criteria
1. Laboratory parameters: 1. Estimated creatinine clearance calculated by the Cockroft-Gault method \< 70 mL/min 2. Hb concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<2x109/L; platelets \<75x109/L. 3. Total bilirubin \>3 x ULN for age. 4. Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range. 2. Established or suspected pregnancy. 3. Breastfeeding female patients unless they accept to discontinue breastfeeding from the 1st dose until 3 months after the last administration of study drug. 4. Female patients of child-bearing potential, unless they are using highly effective methods of contraception during treatment and for 6 months after the last dose of Lutathera. 5. Sexually active male patients, unless they agree to remain abstinent or be willing to use effective methods of contraception. 6. Patients for whom in the opinion of the investigator other therapeutic options are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics. 7. Current spontaneous urinary incontinence. 8. 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. 9. Hypersensitivity to the study drug active substance or to any of the excipients. 10. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study. 11. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded. 12. Patients who received any investigational agent within the last 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absorbed Radiation Doses in Target Organ | Up to 8 days after the first Lutetium [Lu 177] dotatate dose | Absorbed radiation doses in target organ (e.g. kidney and bone marrow) was evaluated when all Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) and Pheochromocytoma and paraganglioma (PPGLs) as a pooled cohort patients had completed the 1st treatment of Lutathera and completed the dosimetry assessment. |
| Incidence of Adverse Events (AEs) and Lab Toxicities After 1st Lutathera Administration | during first cycle of Lutetium [Lu 177] dotatate treatment (Cycle = 56 days) | Safety in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was evaluated through the incidence of AEs and laboratory abnormalities after the first Lutathera dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up | From first Lutetium [Lu 177] dotatate dose to 6 months after last dose, approx. 12 months | Cumulative safety of Lutathera in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was assessed through the incidence of adverse events (AEs) and laboratory toxicities until 6 months after the last Lutathera dose. |
| Incidence of Adverse Events (AEs) During the Long Term Follow-up | Up to 5 years after the last Lutetium [Lu 177] dotatate dose | Long-term safety of Lutathera in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was evaluated through the incidence of AEs and laboratory abnormalities during the 5-year follow-up after the last Lutathera dose. |
| Calculated Probability of Exceeding the Kidney and Bone Marrow External Beam Radiation Therapy (EBRT) Threshold | After 4 cycles of 7.4 GBq/200 mCi; each cycle is 8+/-1 weeks | A comparative assessment of dosimetry for organs at risk specifically kidneys and bone marrow, was performed between adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study to confirm the probability of exceeding 29 Gy (kidneys) \& 2 Gy (bone marrow) thresholds. |
| Pharmacokinetics (PK) Parameter: AUClast - Based on Blood Radioactivity Concentration Data | Up to 72 hours after the first Lutetium [Lu 177] dotatate dose | A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model. |
| Pharmacokinetics (PK) Parameter: Cmax - Based on Blood Radioactivity Concentration Data | Up to 72 hours after the first Lutetium [Lu 177] dotatate dose | A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model. |
| Pharmacokinetics (PK) Parameter: Tmax - Based on Blood Radioactivity Concentration Data | Up to 72 hours after the first Lutetium [Lu 177] dotatate dose | A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model. |
Countries
France, Poland, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
At the data cut-off (DCO) date (12-Mar-2024) for this primary analysis 11 participants were enrolled across 7 centers.
Pre-assignment details
The study schedule for each participant consisted of the screening period (up to 2 weeks) followed by the treatment period and the follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| GEP-NET All eligible participants with Gastroenteropancreatic neuroendocrine tumor (GEP-NET) received at least one dose of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8+/-1 weeks; cumulative dose: 29.6 GBq/800 mCi), with a concomitant administration of 2.5% Lysine - Arginine amino acid solution. | 4 |
| PPGL All eligible participants with Pheochromocytoma and paraganglioma (PPGL) received at least one dose of Lutathera (7.4 GBq/200 mCi x 4 administrations every 8+/-1 weeks; cumulative dose: 29.6 GBq/800 mCi), with a concomitant administration of 2.5% Lysine - Arginine amino acid solution. | 7 |
| Total | 11 |
Baseline characteristics
| Characteristic | GEP-NET | PPGL | Total |
|---|---|---|---|
| Age, Continuous | 15.5 years STANDARD_DEVIATION 0.58 | 14.9 years STANDARD_DEVIATION 1.77 | 15.1 years STANDARD_DEVIATION 1.45 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 7 | 0 / 11 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 11 / 11 |
| serious Total, serious adverse events | 1 / 4 | 1 / 7 | 2 / 11 |
Outcome results
Primary
Absorbed Radiation Doses in Target Organ
Absorbed radiation doses in target organ (e.g. kidney and bone marrow) was evaluated when all Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) and Pheochromocytoma and paraganglioma (PPGLs) as a pooled cohort patients had completed the 1st treatment of Lutathera and completed the dosimetry assessment.
Time frame: Up to 8 days after the first Lutetium [Lu 177] dotatate dose
Population: Dosimetry Analysis Set (DAS): The DAS consisted of all participants who had at least one valid (i.e., not flagged for exclusion by the dosimetrist) dosimetry measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GEP-NET | Absorbed Radiation Doses in Target Organ | Red Marrow (Blood) | 0.024 Gy/GBq | Standard Deviation 0.0035 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Spleen | 0.63 Gy/GBq | Standard Deviation 0.39 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Pituitary | 1.2 Gy/GBq | Standard Deviation 0.43 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Urinary Bladder Wall | 0.50 Gy/GBq | Standard Deviation 0.034 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Red Marrow (Image) | 0.043 Gy/GBq | Standard Deviation 0.018 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Total Body | 0.040 Gy/GBq | Standard Deviation 0.013 |
| GEP-NET | Absorbed Radiation Doses in Target Organ | Kidney | 0.71 Gy/GBq | Standard Deviation 0.25 |
| PPGL | Absorbed Radiation Doses in Target Organ | Total Body | 0.041 Gy/GBq | Standard Deviation 0.0073 |
| PPGL | Absorbed Radiation Doses in Target Organ | Kidney | 0.82 Gy/GBq | Standard Deviation 0.32 |
| PPGL | Absorbed Radiation Doses in Target Organ | Pituitary | 1.0 Gy/GBq | Standard Deviation 0.45 |
| PPGL | Absorbed Radiation Doses in Target Organ | Red Marrow (Blood) | 0.028 Gy/GBq | Standard Deviation 0.0052 |
| PPGL | Absorbed Radiation Doses in Target Organ | Red Marrow (Image) | 0.067 Gy/GBq | Standard Deviation 0.028 |
| PPGL | Absorbed Radiation Doses in Target Organ | Spleen | 0.82 Gy/GBq | Standard Deviation 0.17 |
| PPGL | Absorbed Radiation Doses in Target Organ | Urinary Bladder Wall | 0.59 Gy/GBq | Standard Deviation 0.096 |
Primary
Incidence of Adverse Events (AEs) and Lab Toxicities After 1st Lutathera Administration
Safety in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was evaluated through the incidence of AEs and laboratory abnormalities after the first Lutathera dose.
Time frame: during first cycle of Lutetium [Lu 177] dotatate treatment (Cycle = 56 days)
Population: Safety Set: The Safety Set included all participants that received at least one dose of Lutathera.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GEP-NET | Incidence of Adverse Events (AEs) and Lab Toxicities After 1st Lutathera Administration | 4 Participants |
| PPGL | Incidence of Adverse Events (AEs) and Lab Toxicities After 1st Lutathera Administration | 6 Participants |
Secondary
Calculated Probability of Exceeding the Kidney and Bone Marrow External Beam Radiation Therapy (EBRT) Threshold
A comparative assessment of dosimetry for organs at risk specifically kidneys and bone marrow, was performed between adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study to confirm the probability of exceeding 29 Gy (kidneys) & 2 Gy (bone marrow) thresholds.
Time frame: After 4 cycles of 7.4 GBq/200 mCi; each cycle is 8+/-1 weeks
Population: Dosimetry Analysis Set (DAS) consisted of all participants who had at least one valid dosimetry measurement. Original NETTER-P protocol intended to conduct separate analyses for the GEP-NET and the PPGL populations. However, the protocol was amended to allow combined analyses for dosimetry across the two patient indications. The number of patients was equal 10, since data from one patient was excluded from the dosimetry modeling analysis, due to technical issues during image acquisitions.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GEP-NET | Calculated Probability of Exceeding the Kidney and Bone Marrow External Beam Radiation Therapy (EBRT) Threshold | Observed: Kidney (Probability (%) >29 Gy) | 20.0 probability |
| GEP-NET | Calculated Probability of Exceeding the Kidney and Bone Marrow External Beam Radiation Therapy (EBRT) Threshold | Observed: Bone Marrow (Probability (%) >2 Gy) | 0.0 probability |
Secondary
Incidence of Adverse Events (AEs) During the Long Term Follow-up
Long-term safety of Lutathera in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was evaluated through the incidence of AEs and laboratory abnormalities during the 5-year follow-up after the last Lutathera dose.
Time frame: Up to 5 years after the last Lutetium [Lu 177] dotatate dose
Secondary
Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up
Cumulative safety of Lutathera in adolescents with SSTR-positive GEP-NETs and PPGLs as a pooled cohort was assessed through the incidence of adverse events (AEs) and laboratory toxicities until 6 months after the last Lutathera dose.
Time frame: From first Lutetium [Lu 177] dotatate dose to 6 months after last dose, approx. 12 months
Population: Safety Set: The Safety Set included all participants that received at least one dose of Lutathera.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GEP-NET | Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up | AEs during Lutathera treatment | 4 Participants |
| GEP-NET | Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up | AEs during short-term follow-up | 1 Participants |
| PPGL | Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up | AEs during Lutathera treatment | 7 Participants |
| PPGL | Incidence of Adverse Events (AEs) During Treatment and Short-term Follow-up | AEs during short-term follow-up | 3 Participants |
Secondary
Pharmacokinetics (PK) Parameter: AUClast - Based on Blood Radioactivity Concentration Data
A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model.
Time frame: Up to 72 hours after the first Lutetium [Lu 177] dotatate dose
Population: The PK Analysis Set (PKAS) consisted of all participants who had at least one valid (i.e., not flagged for exclusion) PK measurement. Original NETTER-P protocol intended to conduct separate analyses for the GEP-NET and the PPGL populations. However, the protocol was amended to allow combined analyses for PK across the two patient indications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GEP-NET | Pharmacokinetics (PK) Parameter: AUClast - Based on Blood Radioactivity Concentration Data | Observed | 41 ng.h/mL | Geometric Coefficient of Variation 24.15 |
| GEP-NET | Pharmacokinetics (PK) Parameter: AUClast - Based on Blood Radioactivity Concentration Data | Predicted | 32.34 ng.h/mL | Geometric Coefficient of Variation 10.43 |
Secondary
Pharmacokinetics (PK) Parameter: Cmax - Based on Blood Radioactivity Concentration Data
A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model.
Time frame: Up to 72 hours after the first Lutetium [Lu 177] dotatate dose
Population: The PK Analysis Set (PKAS) consisted of all participants who had at least one valid (i.e., not flagged for exclusion) PK measurement. Original NETTER-P protocol intended to conduct separate analyses for the GEP-NET and the PPGL populations. However, the protocol was amended to allow combined analyses for PK across the two patient indications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GEP-NET | Pharmacokinetics (PK) Parameter: Cmax - Based on Blood Radioactivity Concentration Data | Observed | 11.17 ng/mL | Geometric Coefficient of Variation 33.04 |
| GEP-NET | Pharmacokinetics (PK) Parameter: Cmax - Based on Blood Radioactivity Concentration Data | Predicted | 10.31 ng/mL | Geometric Coefficient of Variation 5.22 |
Secondary
Pharmacokinetics (PK) Parameter: Tmax - Based on Blood Radioactivity Concentration Data
A comparative assessment of PK will be performed between Observed and Predicted adolescent patients with GEP-NETs and PPGLs as a pooled cohort and adult patients using the extrapolation model developed for the clinical study. The observed PK metrics were calculated using non-compartmental analysis (NCA), the predicted PK metrics were derived based on the adolescent population pharmacokinetics (popPK) model.
Time frame: Up to 72 hours after the first Lutetium [Lu 177] dotatate dose
Population: The PK Analysis Set (PKAS) consisted of all participants who had at least one valid (i.e., not flagged for exclusion) PK measurement. Original NETTER-P protocol intended to conduct separate analyses for the GEP-NET and the PPGL populations. However, the protocol was amended to allow combined analyses for PK across the two patient indications.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| GEP-NET | Pharmacokinetics (PK) Parameter: Tmax - Based on Blood Radioactivity Concentration Data | Observed | 0.58 hr |
| GEP-NET | Pharmacokinetics (PK) Parameter: Tmax - Based on Blood Radioactivity Concentration Data | Predicted | 0.5 hr |