Post-Authorization Safety Study (PASS) of LysaKare® in Adult Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) Patients

A Multicenter, Open-label Post Authorization Safety Study to Evaluate the Effect of LysaKare® Infusion on Serum Potassium Levels in GEP-NET Patients Eligible for Lutathera® Treatment

The purpose of the study was to evaluate the effect of arginine/lysine solution administration on serum potassium levels. A systematic assessment of serum potassium levels was performed during infusion and up to 24 hours post start of infusion compared to baseline.

Study Overview

• Status: Completed
• Conditions: Gastroenteropancreatic Neuroendocrine Tumors
• Intervention / Treatment: Drug: arginine/lysine

Detailed Description

The study schedule for each patient consisted of a screening period followed by an infusion day with an optional overnight in-clinic stay, and a follow up call 48h post infusion.

Screening Phase:

At screening, patient eligibility was determined according to inclusion and exclusion criteria, with evaluation of patient's vital signs, ECG and laboratory parameters. The duration of screening could be as short as one day but could not exceed 7 days. Patients who showed potassium level > 6.0 mmol/L (> 5.5 mmol/L for Poland only) at screening could have their potassium level corrected and could be re-screened afterwards.

Treatment Phase:

Eligible patients were admitted to the in-clinic unit and dosed with arginine/lysine solution for infusion of 1,000 mL, which was administered intravenously over a period of 4 hours. Before the infusion (at 0 h time point), a set of baseline tests were performed. During and after the infusion, patient condition was monitored for evaluation of any adverse events. Only patients with a potassium level of ≤ 6 mmol/L at screening (> 5.5 mmol/L for Poland only) were allowed to be dosed. Potassium testing on the infusion day was performed at 0h (before the infusion), and at 2h, 4h, 6h, 8h, 12h, and 24h after the start of infusion. Vital signs and ECGs were taken as specified in the assessment schedule. All patients were monitored closely for signs and symptoms of hyperkalemia, e.g. dyspnoea, weakness, numbness, chest pain and cardiac manifestations (conduction abnormalities and cardiac arrhythmias). Other common adverse reactions during arginine/lysine solution administration are nausea and vomiting. Before the start of arginine/lysine solution infusion, an intravenous bolus of an anti-emetic was given. The choice of anti-emetic drugs was at the discretion of the physician.

Follow-up Phase:

All patients were called for a safety follow-up in 48 hours after dosing. Patients were not scheduled to receive repeat dosing with arginine/lysine solution as concomitant medication with Lutathera® within 7 days of the arginine/lysine solution infusion in the study.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • MI
    • Milan, MI, Italy, 20141
      • Istituto Europeo di Oncologia
• Netherlands
  • GD
    • Rotterdam, GD, Netherlands, 3015
      • Erasmus University Medical Center
• Poland
  • Warsaw, Poland, 02-351
    • Gammed-Centrum Diagnostyczno-Lecznicze
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • University Hospitals Birmingham NHS Foundation Trust
  • Coventry, United Kingdom, CV2 2DX
    • University Hospitals Coventry & Warwickshire NHS Trust
  • Guildford, United Kingdom, GU2 7XX
    • Royal Surrey Country Hospital
  • Liverpool, United Kingdom, L7 8YA
    • Liverpool Royal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs), who are eligible for the treatment with Lutathera as per Lutathera label indication.
• Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related procedures.

Exclusion Criteria:

• Pre-existing hyperkalemia (>6.0 mmol/L at screening) if not adequately corrected before starting the LysaKare (arginine/lysine) infusion. For Poland only, pre-existing hyperkalemia (> 5.5 mmol/L at screening) if not adequately corrected before starting the LysaKare (arginine/lysine) infusion.
• Instances when Lutathera is not recommended per the Lutathera Summary of Product Characteristics (SmPC).
• Pregnancy or lactation, positive pregnancy test at screening or pre-dose based on the contraindication for Lutathera.
• Any significant medical or social condition which may interfere with the subject's ability to comply with the study visit schedule or the study assessments.
• Patients who have received any investigational agent within the last 30 days.
• Patients that have received a dose of Lutathera prior to the screening visit or are scheduled for Peptide Receptor Repeat (PRRT) treatment within 7 days of the study infusion of arginine/lysine solution.
• Other protocol-defined exclusion criteria may apply.

Exclusion Criteria (Poland Only):

- Pre-existing hyperkalemia (> 5.5 mmol/L at screening) if not adequately corrected before starting the arginine/lysine solution infusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GEP-NET; One dose of arginine/lysine solution administered intravenously over a 4-hour period	Drug: arginine/lysine; 1000 milliliters (mL) administered at a constant rate of 250 mL per hour; Other Names: LysaKare

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Serum Potassium Levels Over 24 Hours	Serum potassium levels at each collection time point will be measured at local laboratories of study sites using validated methods. The potassium concentration results will be summarized descriptively and will include mean change, maximum change, time to the maximum change, and the overall dynamics of the potassium concentration curve during and after the arginine/lysine infusion.	Day 0/Infusion Day (Hour 0, Hour 2, Hour 4, Hour 6, Hour 8, Hour 12, Hour 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment Adverse Events (AEs) & Serious Adverse Events (SAEs)	Safety measured by the percentage of participants with treatment emergent adverse events (starting from the signing of the ICF until the end of the follow-up call (48 hours after infusion).	Day 0/Infusion Day up to 48 hours post infusion
Number of Participants With Notable Changes in Vital Signs	Safety measured by the notable post-baseline changes in vital signs: (systolic blood pressure, diastolic blood pressure, pulse rate & weight) compared to baseline.	Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
Number of Participants With Notable Changes in Electrocardiogram (ECG)	Safety measured by the notable post-baseline changes in ECG values compared to baseline PR, QRS, QT, QTcF, and RR intervals were obtained from 12-lead ECGs for each subject during the study	Day 0/Infusion Day (0, 4, 8 and 24 hours)
Number of Participants With Notable Changes in Hematology Parameters	Safety measured by the notable post-baseline changes in Hematology parameters compared to baseline as represented by Shift tables based on common toxicity criteria (CTC) grades. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline.	Day 0/Infusion Day (0 and 24 hours)
Number of Participants With Notable Changes in Chemistry Parameters	Safety measured by the notable post-baseline changes in Chemistry parameters compared to baseline. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline. Key shifts were in the following parameters: creatinine, lactate dehydrogenase and creatinine clearance.	Day 0/Infusion Day (0 and 24 hours)
Number of Participants With Notable Changes in Electrolyte Parameters	Safety measured by the notable post-baseline changes in Electrolyte parameters compared to baseline. Each participant was counted only for the worst grade observed post-baseline. Notable change is the shift to higher grades from baseline.	Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
Mean Change From Baseline in Blood Gas Parameter, pH, Over 24 Hours	Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: pH.	Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
Mean Change From Baseline in Blood Gas Parameter, Lactic Acid, Over 24 Hours	Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: Lactic Acid	Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)
Mean Change From Baseline in Blood Gas Parameter, Partial Pressure Carbon Dioxide, Over 24 Hours	Safety measured by the mean changes in blood gas compared to baseline. Blood gas parameter: Partial Pressure Carbon Dioxide.	Day 0/Infusion Day (0, 2, 4, 6, 8, 12 and 24 hours)

Collaborators and Investigators

• Sponsor: Advanced Accelerator Applications
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2021
• Primary Completion (Actual): November 18, 2023
• Study Completion (Actual): November 18, 2023

Study Registration Dates

• First Submitted: August 20, 2020
• First Submitted That Met QC Criteria: August 20, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 23, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Neuroendocrine tumors; Lutathera; Lutetium Lu 177 dotatate; amino acid; NETs; PRRT; GEP-NET; carcinoid tumors; Peptide Receptor Radionuclide Therapy; LysaKare; arginine/lysine; Lutetium Lu 177 oxodotreotide
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Stomach Neoplasms; Pancreatic Neoplasms; Neuroendocrine Tumors; Intestinal Neoplasms
• Other Study ID Numbers: CAAA001A12401; 2019-004073-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No