Development of safe and effective platform for administration of lutetium-177 dotatoc peptide receptor radionuclide therapy for neuroendocrine tumours or other tumours highly expressing somatostatin receptors

Abstract

To provide a method of administering peptide receptor radionuclide therapy for neuroendocrine tumours while minimizing gastrointestinal adverse side effects and reducing kidney function deterioration.SOLUTION: The present invention emphasizes on the use of lutetium-177 (177 Lu)-DOTATOC as a radiotherapeutic agent and arginine as the sole kidney protective agent, and intravenous infusion of the 177 Lu-DOTATOC and arginine through separate infusion lines onto different peripheral veins on opposite hands, in which the subject receiving the method of administration according to the present invention exhibits significantly and effectively reduced development of any gastrointestinal adverse events, enabling safe protection of kidneys from treatment-related injury.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to an improved method of peptide receptor radionuclide therapy (PRRT) administration with significantly reduced gastrointestinal side effects compared to other existing peptide receptor radionuclide therapy (PRRT) administrations.

Background Art

[0002] Neuroendocrine tumors (NETs) are relatively rare tumors, often underdiagnosed or misdiagnosed, usually occurring throughout the gastrointestinal tract, most commonly in the pancreas, stomach, small intestine, and rectum, but rarely also in sites such as the lungs and head and neck. These tumors arise from neuroendocrine cells specialized to have the characteristics of both nerve cells and hormone-producing cells.

[0003] Worldwide, the incidence of such malignant tumors is increasing. Although not officially registered in the Hong Kong Cancer Registry, it is estimated that approximately 100 new cases are diagnosed each year in the seven public cancer hospitals in Hong Kong. More than three quarters of these patients have progressive disease that is inoperable at the time of diagnosis, and therefore mainly palliative treatment is carried out.

[0004] Recently, peptide receptor radionuclide therapy (PRRT) has become a new hope for NETs that do not respond to first-line systemic therapy. PRRT is based on the use of radiolabeled peptides to deliver radioactive particles directly to tumor cells, and somatostatin analogs that utilize the overexpression of somatostatin receptors on the surface of neuroendocrine tumor cells are frequently selected. By targeting and selectively delivering in this way, collateral damage to surrounding healthy tissues and cells can be minimized. In particular, lutetium 177 ( 177 Lu, a pure beta-emitting radionuclide) binds to the somatostatin receptors on NET tumor cells by intravenous administration when bound to the somatostatin analogs DOTATATE or DOTATOC, and kills the surrounding tumor cells by internal radiotherapy.

[0005] In the first and largest Phase III randomized comparative trial (NETTER-1) comparing 177Lu-DOTATATE with octreotide LAR alone in 229 patients, progression-free survival (65.2% vs 10.8% at 20 months, P<0.001) and a likely significant extension of QOL were shown.

[0006] During PRRT, radiolabeled 177 Lu-DOTATATE is also taken up by cells of the proximal renal tubules of the kidney. This uptake into the renal tubules can expose the kidneys to excessive radiation, potentially resulting in sequelae such as radiation nephropathy and chronic renal insufficiency. Administration of basic amino acids, mainly lysine and arginine, may reduce the uptake of peptides in the proximal tubules via the megalin-cubilin receptor complex. Basic amino acids are thought to competitively bind to proximal tubule cells and prevent the uptake of radionuclides. Another strong rationale for amino acid administration is that after amino acid administration, renal blood flow and glomerular filtration rate (GFR) increase for several hours, facilitating more rapid excretion of radionuclides from the kidneys.

[0007] However, many patients enrolled in NETTER-1 developed common gastrointestinal side effects, most likely due to amino acid infusions that were intravenously co-administered from 30 minutes before 177Lu-DOTATATE injection for at least 4 hours, either an amino acid solution (Aminosyn II 10% with 21.0 g of lysine and 20.4 g of arginine in 2 L of solution) or Vamin-18 (with 18 g of lysine and 22.6 g of arginine in 2 L of solution). The most common side effects reported in this study were nausea (59%), vomiting (47%), abdominal pain (26%), diarrhea (29%), and abdominal distension (13%). In particular, grade 3 or 4 adverse events occurred in up to 7% of patients.

[0008] Currently, 177Lu-DOTATATE is commercially available as Lutathera (registered trademark), which is owned, manufactured, and sold by Novartis, a leading global pharmaceutical company. The amino acids lysine and arginine (in the form of L-lysine hydrochloride and L-arginine hydrochloride solution) are commercially available as LysaKare, which is owned and provided by Advanced Accelerator Applications, acquired by Novartis in 2017. Unfortunately, since both LysaKare and Lutathera (registered trademark) are owned, manufactured, and sold by Novartis, LysaKare cannot be obtained alone without Lutathera (registered trademark). In other words, if a patient wants to receive PRRT for NET, there is no option other than Lutathera (registered trademark). Therefore, there is a need for an effective NET treatment method with fewer side effects. The present invention addresses this need.

Summary of the Invention

[0009] Here, a method is provided that replaces the combined administration of the aforementioned LysaKare and Lutathera (registered trademark), thereby minimizing gastrointestinal side effects in a subject and providing effective kidney protection.

[0010] DOTATOC (Figure 1) is structurally and chemically similar to DOTATATE (Figure 2) and can also be used for the treatment of NET. The inventors, with the support of the Li Ka Shing Foundation LoveCanHelp Project and the Li Ka Shing Faculty of Medicine, The University of Hong Kong, have provided PRRT clinical services in the form of Lu-DOTATOC to eligible patients with inoperable NET since November 2020. 177 From November 2020 to March 2023, a total of 15 patients with inoperable metastatic NET 177Twenty cycles of PPRT were performed using Lu-DOTATOC. Since LysaKare cannot be obtained and purchased separately without using Lutathera (registered trademark), the inventors have invented a new kidney protection method using only arginine (Amargine, manufactured by VeritonPharma, containing 4.5 to 6 grams of L-arginine hydrochloride in a 10 mL injection) as a kidney protectant. The inventors 177 Specifically designed a new method of administering 5 grams of arginine reconstituted with 500 mL of 10% dextrose solution 30 minutes before the start of Lu-DOTATOC infusion (in the range of 20 minutes to 1 hour). This is to administer a total of 20 grams with 2000 mL of 10% dextrose solution over 4 hours (in the range of 3 to 5 hours), and then, for kidney protection, an additional 2000 mL of physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) is intravenously administered over 16 hours (in the range of 15 to 17 hours).

[0011] In the NETTER-1 study, gastrointestinal adverse events related to amino acid infusion may be related to the fact that both amino acids (LysaKare) and 177 Lu-DOTATATE (Lutathera, registered trademark) were injected into the same peripheral vein of the same limb of the same body, even though they were administered from separate infusion lines. It is hypothesized that mixing LysaKare and Lutathera (registered trademark) in the same peripheral vein may commonly cause gastrointestinal adverse events. The present invention addresses this problem.

[0012] According to a first aspect of the present invention, there is provided a method for treating NET by PRRT that reduces gastrointestinal side effects while preventing a decline in renal function in a subject. This method includes performing a first intravenous infusion, which is carried out over 4 hours (in the range of 3 to 5 hours) with 20 grams of L-arginine hydrochloride in 2000 mL of 10% dextrose solution. Thereafter, 2000 mL of physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) is intravenously administered over a further 16 hours (in the range of 15 to 17 hours). Each infusion rate is controlled by an infusion pump.

[0013] The first infusion and the second infusion are each performed at a different peripheral vein on the opposite hand via a different infusion line. By this administration route, the serum renal function of the subject can be maintained at a level of 44.2 - 132.6 μmol / L (or equivalent to 0.5 - 1.5 mg / dL) at 1 year after administration, and the change in creatinine clearance from the start of administration to 1 year after administration can be less than 5%. From the start of administration to 1 year after administration, no gastrointestinal side effects occurred in all subjects.

[0014] In an embodiment of the first aspect, a second intravenous infusion of 7.4 GBq ± 10% (200 mCi ± 10%) of 177 Lu-DOTATOC in 8 mL (which may be in the range of 7 to 10 mL) of physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) is started approximately 30 minutes (in the range of 20 minutes to 1 hour) after the first intravenous infusion.

[0015] In an embodiment of the first aspect, a second intravenous infusion of 7.4 GBq ± 10% (200 mCi ± 10%) of 177 Lu-DOTATOC in 8 mL (which may be in the range of 7 to 10 mL) of physiological saline (0.9% sodium chloride or 308 mOsm / L sodium chloride solution) is started approximately 30 minutes (in the range of 20 minutes to 1 hour) after the first intravenous infusion.

[0016] In other embodiments, gastrointestinal adverse events include, but are not limited to, nausea, vomiting, dyspepsia, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain, and abdominal distension.

[0017] In yet another embodiment, the method further comprises premedication with ondansetron, dexamethasone, and esomeprazole, which is administered 20 - 40 minutes before the first and second infusions.

[0018] In still another embodiment, the method further comprises intravenous infusion of physiological saline (0.9% sodium chloride or 308 mOsm / L sodium chloride solution) over 16 hours (in the range of 15 - 17 hours) after the second infusion.

Brief Description of the Drawings

[0019] Embodiments of the present invention will be described in detail below with reference to the drawings.

[0020] Figure 1 shows the chemical structure of DOTADOC.

[0021] Figure 2 shows the chemical structure of DOTATATE.

[0022] Figure 3 shows the infusion of Lu - DOTATOC and arginine and normal saline via two separate venous lines in two different hands. The intravenous infusion of arginine (right) 177 is started approximately 30 minutes before the start of the infusion of Lu - DOTATOC (left), but the two intravenous infusions are performed simultaneously. 177

Modes for Carrying Out the Invention

[0023] To avoid or minimize gastrointestinal adverse events associated with amino acid infusion in PRRT of a subject, for a subject patient, arginine infusion and 177Administer Lu-DOTATOC separately (i.e., inject saline after injecting arginine into one peripheral vein and inject 177 Lu-DOTATOC into the opposite peripheral vein, or vice versa) (Figure 3).

[0024] In one aspect, a first injection of an amino acid that reduces the nephrotoxicity caused by the radionuclide in the second injection is administered to the subject. Examples of amino acids include lysine and arginine, which are thought to reduce the risk of kidney damage by reducing the radiation absorbed by the kidneys by radionuclide therapy. This is because these amino acids compete with radiopharmaceuticals for reabsorption in the proximal renal tubules of the kidneys.

[0025] In the present invention, 4.5 to 6 grams of an amino acid such as arginine or lysine in solution is used. The solution may be based on a known intravenous fluid such as a dextrose-based solution. Furthermore, plasma volume expanders such as gelofusine may be used as the intravenous solution base because they may help reduce the radiation dose to the kidneys by reducing the uptake of the radiopharmaceutical by the kidneys.

[0026] Radionuclide agent 177 Lu-DOTATOC is administered from a peripheral vein of the body opposite to the vein into which the amino acid is administered. Usually, the second injection is performed within a short period after the amino acid injection. By this administration route, the radionuclide does not mix with the amino acid therapy. This separate administration may significantly avoid gastrointestinal side effects.

[0027] In a series of tests, a first intravenous injection of 20 grams of arginine added to 2000 mL of 10% dextrose solution, followed by administration of saline, and 30 minutes (ranging from 20 minutes to 1 hour) after the first intravenous injection, 8 mL of saline (ranging from 7 mL to 10 mL) containing 7.4 GBq ± 10% (200 mCi ± 10%) of 177A second intravenous injection with Lu-DOTATOC is administered. It is important that the two injections are performed from separate peripheral veins on the opposite side of the body, such as the hands, via separate drip lines. The second injection is carried out over 30 minutes (in the range of 20 - 40 minutes).

[0028] According to the results based on the present invention, in accordance with the method disclosed in the present invention 177 It was shown that there were no patients who showed a decrease in renal function or the occurrence of gastrointestinal adverse events before, during, or after the injection of Lu-DOTATOC.

[0029] These patients were examined twice a week for the first month, monthly in the second and third months, and then every three months for serum renal function tests, complete blood counts, liver function tests, lactate dehydrogenase, uric acid, and thyroid function tests. The serum renal function of all patients was within the normal reference range of 44.2 - 132.6 μmol / L (or equivalent to 0.5 - 1.5 mg / dL), and the creatinine clearance did not change by more than 5% one year after PRRT.

[0030] Furthermore, one year after PRRT, there were no patients who developed gastrointestinal adverse events including, but not limited to, nausea, vomiting, dyspepsia, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain, abdominal distension, etc.

[0031] 177 Thirty minutes before the start of the Lu-DOTATOC injection, a pre-medication of ondansetron 8 mg, dexamethasone 8 mg, and esomeprazole 40 mg was administered by bolus injection.

[0032] After the completion of the arginine injection, the subjects are also given intensive intravenous rehydration with physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) over 16 hours (in the range of 15 - 17 hours).

[0033] Referring to FIGS. 1 and 2, the DOTATOC used in the present invention differs from DOTATATE (used in Lutathera®) in that DOTATOC incorporates the synthetic somatostatin analog octreotide containing the amino acid phenylalanine, while DOTATATE incorporates another analog octreotate containing the amino acid tyrosine. DOTATATE has high specificity and affinity for somatostatin receptor subtype 2 (SSTR) and shows high efficacy in gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs) with high expression of SSTR2. However, due to the chemical structure of DOTATOC, a broader receptor affinity targeting SSTR2, SSTR3, and SSTR5 is enabled.

[0034] The present invention 177 In addition to separately injecting Lu-DOTATOC and the amino acid into different peripheral veins on the opposite side, it also differs from the combination of LysaKare-Lutathera® regarding the selection of the amino acid as a renal protective agent. LysaKare employs both lysine and arginine as renal protective agents, while in the present invention, only arginine in the form of L-arginine hydrochloride is used as the renal protective agent.

[0035] Examples

[0036] Recommended Workflow for PRRT Management

[0037] The following is a proposed workflow for administering PRRT according to the method of the present invention.

[0038] 1. Management before and during PRRT injection: - Admit the patient to an isolation ward equipped with radiation protection and shielding devices at 8:00 am on the day of PRRT - Permit diet within the allowable range - Intake / output chart (ask the patient to record the intake and urine volume) - Check the electrocardiogram (ECG) - At admission, measure blood pressure, body temperature, and blood oxygen saturation (SaO 2Check - At the time of admission, check the complete blood count (CBC), liver function tests, renal function tests (LRFT), bone profile, uric acid, lactate dehydrogenase (LDH), and thyroid function tests (TFT). - Order intravenous arginine 5×4 in 500 ml of 10% dextrose solution. - Order ondansetron 8 mg intravenous injection (or other types of 5-HT3 antagonists at an equivalent dose), dexamethasone 8 mg intravenous injection, and esomeprazole 40 mg intravenous injection (or other types of proton pump inhibitors at an equivalent dose). - Set up two heparin blocks (HBs) with three-way stopcocks (a 1×20-gauge vascular catheter for PRRT injection, a 1×20-gauge vascular catheter for arginine + D10 injection and / or rescue drug injection). - Start intravenous infusion of 500 ml of physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) over 6 hours via one heparin block with a three-way stopcock. - Instruct the patient to fast except for medications at 1 pm on the day of PRRT. - Request the patient to empty the bladder / intestines before the injection of ondansetron (or other types of 5-HT3 antagonists), dexamethasone, esomeprazole (or other types of proton pump inhibitors), and arginine, and before PRRT. - Inject ondansetron 8 mg (or other types of 5-HT3 antagonists at an equivalent dose) 30 minutes before PRRT injection (to minimize nausea / vomiting after PRRT). - Inject dexamethasone 8 mg 30 minutes before PRRT injection (to minimize worsening of pain after PRRT). - Inject esomeprazole 40 mg (or an equivalent dose of other types of proton pump inhibitors) after the dexamethasone injection. - Inject 5 grams of arginine per pint of 500 ml of dextrose solution intravenously at a rate of 4 pints over 1 hour per pint, then administer 500 ml of physiological saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) intravenously at a rate of 4 pints every 4 hours. - At 4 hours (i.e., 6 PM) of PRRT, investigate the patient's radiation dose level. - At 6 PM, permit the patient to resume eating.

[0039] 2. Equipment required for PRRT injection: - Two three-way stopcocks for tube connection - Two 20-ml syringe with a cork borer for priming the tube and flushing with physiological saline - Two extension tubes (1500 mm in length) to connect the PRRT-containing syringe, the NS bag, and the patient - Two sets of sterilized long forceps for handling the NS tube - 4 pints of 500 ml of 10% dextrose + arginine injection, 4.5 - 6 grams per hour for 4 hours - 100 ml of physiological saline for washing after PRRT injection, one dose - Four vials of 10-ml physiological saline for washing - Two red stopcocks after physiological saline washing - Latex gloves

[0040] 3. (Optional) Emergency medications prescribed as needed during hospital isolation: - For nausea and vomiting, administer intravenous ondansetron 8 mg (or other 5-HT3 antagonists at an equivalent dose) every 12 hours. - For nausea and vomiting, administer intravenous metoclopramide 10 mg every 8 hours. - For recurrence of pain, administer oral paracetamol 1000 mg every 6 hours. - For recurrence of pain, administer oral tramadol 50 mg every 6 hours.

[0041] 4. Procedures before and during PRRT injection: - Prime all tubes with physiological saline solution - Prepare a protective Perspex shield box - Connect one primed tube to one heparin block with a three-way stopcock and a bag containing 250 ml of physiological saline solution - Set the infusion pump speed to 16 - 20 mL / h (to infuse the whole PRRT over 30 minutes, in the range of 20 - 40 minutes) - Insert the PRRT syringe into the infusion pump and lock the syringe - Securely connect the three-way stopcock primed with physiological saline solution to the PRRT syringe - Ensure that the three-way stopcock is in the correct position to facilitate the flow of PRRT to the patient - Press the start button of the infusion pump to initiate PRRT infusion - Continue arginine infusion simultaneously with PRRT injection - Request the patient to report any symptoms during PRRT injection - After PRRT injection, use forceps to remove the physiological saline tube and place it in the shield box - Use long forceps to handle the tube after PRRT injection

[0042] 5. Management after PRRT injection: - Perform a single photon emission computed tomography (SPECT) or computed tomography (CT) scan the day after PRRT - Examine the patient at 12:00 noon the day after PRRT and consider discharging the patient if the radiation level is less than 20 μSv / h

[0043] The above description of the present invention is provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations will be apparent to those skilled in the art.

[0044] Embodiments are selected and described in order to best explain the principles of the invention and its actual applications, so that those skilled in the art can understand the invention with various modifications suitable for various embodiments and possible specific applications.

Claims

1. 1. A peptide receptor radionuclide therapy system for use in treating neuroendocrine tumors in a subject with reduced gastrointestinal side effects and reduced renal function, comprising: a first infusion dose of an L-arginine salt solution; linked to an effective amount of a peptide configured to bind to a somatostatin receptor on a neuroendocrine tumor for administration via a separate infusion line after said first infusion dose. １７７ a second injected dose of Lu; It consists of: administration of the first and second doses maintains the subject's serum renal function at a level of 44.2-132.6 μmol / L (or equivalently, 0.5-1.5 mg / dL) one year after administration; administration of the first and second doses results in a change in the patient's creatinine clearance of less than 5% from baseline to one year after administration; Peptide receptor radionuclide therapy systems.

2. 2. The peptide receptor radionuclide therapy system of claim 1, wherein said first injection dose comprises 20 grams of L-arginine hydrochloride in 2000 mL of 10% dextrose solution.

3. The second injection dose is 7.4 GBq ± 10% in 7-10 mL of saline (0.9% sodium chloride). １７７ 2. The peptide receptor radionuclide therapy system of claim 1, comprising Lu-DOTATOC (200 mCi±10%).

4. 10. The peptide receptor radionuclide therapy system of claim 1, wherein said gastrointestinal side effects include nausea, vomiting, dyspepsia, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain, abdominal bloating, and the like.

5. 1. An intravenous infusion kit for use in treating a neuroendocrine tumor in a subject with reduced gastrointestinal side effects and reduced renal function, comprising: a first infusion dose of an L-arginine salt solution; and administering after said first infusion dose, said compound linked to an effective amount of a peptide configured to bind to a somatostatin receptor on a neuroendocrine tumor. １７７ a second infusion dose of Lu; A package insert containing instructions, the instructions comprising: administering the first infusion dose over a first period of time through a peripheral vein in one hand; administering the second infusion dose through another contralateral peripheral vein for a second period of time after the start of the first period of time; and a package insert containing: An intravenous infusion kit comprising:

6. said first infusion dose comprising 20 grams of L-arginine hydrochloride in 2000 mL of a 10% dextrose solution; said first period of time being between 20 and 40 minutes; The second injection dose is 7.4 GBq ± 10% in 7-10 mL of saline (0.9% sodium chloride). １７７ Lu-DOTATOC (200 mCi ± 10%) the second time period is 20-40 minutes, and the second time period begins 20-60 minutes after the start of administration of the first infusion dose; 6. The intravenous infusion kit of claim 5.

7. a 5-HT3 antagonist; Dexamethasone; Proton pump inhibitors, Further comprising a premedication comprising 6. The intravenous infusion kit of claim 5.

8. The intravenous infusion kit of claim 7, wherein the 5-HT3 antagonist is ondansetron.

9. 8. The intravenous infusion kit of claim 7, wherein the proton pump inhibitor is esomeprazole.

10. L-arginine hydrochloride and １７７ 8. The intravenous infusion kit of claim 7, further comprising a package insert containing instructions for administering said premedication as needed 20 to 40 minutes prior to intravenous infusion of Lu-DOTATOC.

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