Development of safe and effective platform for lutetium-177-DOTATOC peptide receptor radionuclide treatment of neuroendocrine tumors or other tumors with high expression of somatostatin receptors

Abstract

Provided herein are platforms for the treatment of neuroendocrine neoplasms by administering peptide receptor radionuclide therapies while causing minimal adverse side effects of the gastrointestinal tract and slowing renal dysfunction. According to the invention, the lutetium-177-DOTATOC is used as a radiotherapy agent, the arginine is used as a unique kidney protective agent, and the lutetium-177-DOTATOC and the arginine are respectively subjected to intravenous infusion into peripheral veins on different hands of a subject through individual infusion pipelines. After a subject receives the use method provided by the invention, the incidence rate of any adverse side effects of gastrointestinal tracts is remarkably reduced, and the kidney is also effectively protected.

Description

Technical Field

[0001] The present invention relates to an improved peptide receptor radionuclide therapy (PRRT) administration method that significantly reduces gastrointestinal side effects compared to other existing PRRT administration methods. Background Art

[0002] Neuroendocrine tumors (NETs) are relatively rare tumors that are therefore underdiagnosed and easily misdiagnosed. They typically arise along the entire gastrointestinal tract, most commonly in the pancreas, stomach, small intestine, rectum, and less commonly in the lungs, head, and neck areas. These tumors arise from neuroendocrine cells, which are specialized and have characteristics of both nerve cells and hormone-producing cells.

[0003] The incidence of this malignancy is increasing worldwide. Although the disease is not officially registered in the Hong Kong Cancer Registry, it is estimated that about 100 new cases are diagnosed each year in Hong Kong's seven public cancer hospitals. More than three-quarters of these patients are diagnosed at an advanced stage and are not suitable for surgery, so palliative treatment is the main treatment.

[0004] Recently, peptide receptor radionuclide therapy (PRRT) has emerged as a new hope for first-line systemic treatment of refractory NETs. PRRT works by delivering radioactive particles directly to tumor cells using radiolabeled peptides, of which somatostatin analogs are a common choice, taking advantage of the overexpression of somatostatin receptors on the surface of neuroendocrine tumor cells. This targeted and selective delivery can minimize collateral damage to surrounding healthy tissues and cells. In particular, when lutetium-177 (a pure beta-emitting radioisotope) is combined with DOTATATE or DOTATOC (two somatostatin analogs), it will bind to somatostatin receptors on NET tumor cells via intravenous injection, thereby emitting internal radiation therapy to kill surrounding tumor cells.

[0005] The first and largest phase III randomized controlled trial (NETTER-1) enrolled 229 patients and compared lutetium-177-DOTATATE with octreotide LAR administered alone and demonstrated significantly longer progression-free survival in patients receiving lutetium-177-DOTATATE (65.2% vs. 10.8% at 20 months, P < 0.001), as well as improved quality of life.

[0006] During PRRT, radiolabeled lutetium-177-DOTATATE is also taken up by cells in the renal proximal tubules. This tubular uptake may result in overexposure of the kidneys to radiation and may lead to sequelae such as radiation-induced kidney injury and chronic renal failure. Administration of basic amino acids (primarily lysine and arginine) can lead to a decrease in the uptake of peptides mediated by the megalin-cubilin protein receptor complex in the proximal tubules. It is hypothesized that the basic amino acids competitively bind to the proximal tubular cells and prevent the uptake of the radionuclide. Another strong rationale for the administration of amino acids is that renal blood flow and glomerular filtration rate (GFR) increase within hours of amino acid administration, which helps the radionuclide to be excreted more quickly from the kidneys.

[0007] However, many patients enrolled in NETTER-1 experienced common gastrointestinal adverse reactions, most likely attributable to the amino acid infusion, which was administered simultaneously intravenously for at least 4 hours as an amino acid solution (Aminosyn II 10% (21.0 g lysine and 20.4 g arginine in 2 L solution) or VAMIN-18 (18 g lysine and 22.6 g arginine in 2 L solution)), starting 30 minutes before the infusion of lutetium-177-DOTATATE. Nausea (59%), vomiting (47%), abdominal pain (26%), diarrhea (29%), and abdominal distension (13%) were the most common side effects reported in this NETTER-1 study. In particular, up to 7% of patients experienced grade 3 or 4 adverse side effects.

[0008] Currently, Lutetium-177-DOTATATE is is marketed under the trade name of Lysine, which is owned, manufactured and distributed by Novartis (a leading global pharmaceutical company), while the amino acids lysine and arginine (in the form of L-lysine hydrochloride and L-arginine hydrochloride solutions) are marketed under the trade name LysaKare, which is owned and supplied by Advanced Accelerator Applications, which was acquired by Novartis in 2017. Unfortunately, without In other words, if a patient is willing to receive PRRT for NET, then There is no other alternative. 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] Provided herein are methods for administering the above-described LysaKare and An alternative approach to combination therapy, thereby minimizing adverse gastrointestinal side effects and providing effective renal protection to the subjects.

[0010] DOTATOC(Figure 1 ) is structurally and chemically similar to DOTATATE( Figure 2 ), which can also be used to treat NET. Since November 2020, the inventors have provided clinical services of PRRT in the form of Lu-177-DOTATOC for eligible inoperable NET patients with the support of the Li Ka Shing Foundation's "Love Can Help" medical program and the Li Ka Shing Faculty of Medicine of the University of Hong Kong. From November 2020 to March 2023, a total of 15 patients received 20 Lu-177-DOTATOC PPRT for inoperable and metastatic NET. Since it is not possible to purchase and buy LysaKare separately, the inventors have invented a new method for kidney protection, which uses only arginine (Amargine, 10mL injection contains 4.5-6g of L-arginine hydrochloride, from Veriton Pharma) as a kidney protective agent. The inventors have specially designed a new method to give 5g of arginine dissolved in 500mL of 10% glucose solution 30 minutes (range 20 minutes to 1 hour) before the start of lutetium-177-DOTATOC infusion, and then inject 20g of lutetium-177-DOTATOC dissolved in 2000mL of 10% glucose solution within 4 hours (range 3 to 5 hours), and then further intravenous rehydration with 2000mL of normal saline (0.9% sodium chloride, or 308mOsm / L sodium chloride solution) within the next 16 hours (range 15 to 17 hours) to protect the kidneys.

[0011] In the NETTER-1 study, it was hypothesized that adverse gastrointestinal side effects associated with amino acid infusion may also be associated with the combination of amino acids (LysaKare) and lutetium-177-DOTATATE. Infusions into the same peripheral vein on the same limb are related, even though they are infused through separate infusion lines. LysaKare and Mixing in the same peripheral vein may lead to frequent occurrence of adverse gastrointestinal side effects. The present invention solves this problem.

[0012] According to a first aspect of the present invention, there is provided a method for treating NET with PRRT, wherein the adverse gastrointestinal side effects caused by the PRRT are significantly reduced, while also preventing the deterioration of renal function in the subject, comprising performing a first intravenous infusion, wherein the infusion comprises 20 g of L-arginine hydrochloride dissolved in 2000 mL of a 10% glucose solution for 4 hours (range 3 to 5 hours), followed by further intravenous rehydration with 2000 mL of a saline solution (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) for the next 16 hours (range 15 to 17 hours). The respective infusion rates are controlled by an infusion pump.

[0013] The first and second infusions were administered through separate infusion lines and in separate peripheral veins on different hands. This route of administration maintained the subjects' serum renal function at a level of 44.2–132.6 μmol / L (or equivalent to 0.5–1.5 mg / dL) after one year of administration; the subjects' creatinine clearance changed by less than 5% from the start of administration to one year after administration. No adverse gastrointestinal side effects were observed in all subjects from the start of administration to one year after administration.

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

[0015] In another embodiment, a second intravenous infusion comprising 7.4 GBq ± 10% (200 mCi ± 10%) lutetium-177-DOTATOC dissolved in 8 mL (range can be from 7 to 10 mL) of normal saline solution (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) is infused into the subject starting approximately 30 minutes (range 20 minutes to 40 minutes) after the first intravenous infusion, and the infusion rate is controlled by an infusion pump.

[0016] In other embodiments, gastrointestinal adverse side effects include, but are not limited to, nausea, vomiting, indigestion, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain, and bloating.

[0017] In yet another embodiment, the method further comprises premedication with ondansetron, dexamethasone, esomeprazole, etc., wherein the premedication is administered 20 to 40 minutes prior to the first and second infusions.

[0018] In yet another embodiment, the method further comprises intravenously infusing normal saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) over a period of 16 hours (range 15 to 17 hours) following the second infusion. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The embodiments of the present invention are described in more detail below with reference to the accompanying drawings, wherein:

[0020] Figure 1 Display the chemical structure of DOTATOC;

[0021] Figure 2 Display the chemical structure of DOTATATE;

[0022] Figure 3Depicted is the infusion of Lutetium-177-DOTATOC and Arginine and a saline infusion through two separate IV lines in two different hands. The IV infusion of Arginine (right) begins approximately 30 minutes earlier than the IV infusion of Lutetium-177-DOTATOC (left); however, both IV infusions will be performed simultaneously. DETAILED DESCRIPTION

[0023] In order to avoid or minimize the adverse gastrointestinal side effects associated with amino acid infusion in PRRT in a subject, the present invention provides a novel administration method by administering an arginine infusion agent and lutetium-177-DOTATOC to a subject patient (i.e., arginine infusion followed by saline infusion on a peripheral vein in one hand and lutetium-177-DOTATOC infusion on another peripheral vein in the other hand, or vice versa) using two infusion lines into two separate peripheral veins. Figure 3 ).

[0024] In one aspect, an amino acid that can mitigate the nephrotoxicity caused by the radionuclide in the second infusion is administered to the subject via the first infusion. Examples of amino acids include lysine and arginine, which appear to mitigate the risk of kidney damage by reducing the radiation absorbed by the kidney from radionuclide therapy. This is due to competition between these amino acids and the radiopharmaceutical for reabsorption in the renal proximal tubules.

[0025] In the present invention, 4.5-6 grams of an amino acid, such as arginine or lysine, in solution is used. The solution can be a known intravenous liquid base, such as a glucose-based solution. Other plasma volume expanders, such as girovcin, can be used as an intravenous solution base because it can help reduce the radiation dose to the kidney by reducing the renal uptake of the radiopharmaceutical.

[0026] The radionuclide agent Lutetium-177-DOTATOC is administered through a peripheral vein on the opposite side of the body from the vein where the amino acids are administered. Typically, a second infusion is given a short time after the amino acid infusion. Due to this route of administration, the radionuclide does not mix with the amino acid therapy. With this separated administration, gastrointestinal side effects can be largely avoided.

[0027] In a series of experiments, the first intravenous infusion administered 20 grams of arginine contained in 2000 mL of 10% glucose solution, followed by normal saline; 30 minutes (range 20 minutes to 1 hour) after the first intravenous infusion, a second intravenous infusion was given, which contained 7.4 GBq ± 10% (200 mCi ± 10%) lutetium-177-DOTATOC dissolved in 8 mL of normal saline (range 7 to 10 mL). Importantly, the two infusions must be given through separate infusion lines and in separate peripheral veins on both sides of the body (e.g., through the hand). The second infusion lasted 30 minutes (range 20 to 40 minutes).

[0028] The results based on the present invention indicate that, according to the method disclosed in the present invention, no patient experienced any deterioration of renal function, nor any adverse gastrointestinal side effects before, during and after the infusion of Lu-177-DOTATOC.

[0029] The patients underwent serum renal function tests as well as complete blood count, liver function tests, lactate dehydrogenase, urate, and thyroid function tests twice a week in the first month, then monthly in the second and third months, and every 3 months thereafter. All patients had serum renal function within the normal reference range of 44.2–132.6 μmol / L (or equivalent to 0.5–1.5 mg / dL), and creatinine clearance did not change by more than 5% 1 year after PRRT.

[0030] In addition, no patient experienced any adverse gastrointestinal side effects, including but not limited to nausea, vomiting, indigestion, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain, and bloating, 1 year after PRRT.

[0031] Premedication with 8 mg ondansetron, 8 mg dexamethasone, and 40 mg esomeprazole was given by bolus injection 30 minutes before the start of the lutetium-177-DOTATOC infusion.

[0032] After the arginine infusion was completed, subjects were given intensive intravenous rehydration with normal saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) for 16 hours (range 15 to 17 hours).

[0033] like Figure 1 and Figure 2 As shown, DOTATOC and DOTATATE (such as The difference between DOTATOC and DOTATATE is that DOTATOC incorporates the synthetic somatostatin analog octreotide, which contains the amino acid phenylalanine, while DOTATATE contains another analog, octreotate, which contains the amino acid tyrosine. While DOTATATE has high specificity and affinity for somatostatin receptor subtype 2 (SSTR) and is highly effective against gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with high SSTR2 expression, the chemical structure of DOTATOC has a broader receptor affinity, allowing for simultaneous targeting of SSTR2, SSTR3, and SSTR5.

[0034] In addition to infusing lutetium-177-DOTATOC and amino acids into different peripheral veins in different hands, the present invention is also different from the present invention in the selection of amino acids as kidney protective agents. Combination. Although LysaKare uses both lysine and arginine as renal protective agents, in the present invention, only arginine in the form of L-arginine hydrochloride is used as a renal protective agent.

[0035] Examples

[0036] Recommended workflow for implementing PRRT management

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

[0038] 1. Management before and during PRRT infusion: -PRRT sent the patient to an isolation ward equipped with radiation protection and shielding equipment at 8 am that day - Acceptable diets allowed -Intake / output chart (asking the patient to record intake and urine output) - Check electrocardiogram (ECG) - Check blood pressure, temperature and blood oxygen saturation (SaO2) on admission - Serum complete blood count (CBC), liver and kidney function tests (LRFT), bone profile, urate, lactate dehydrogenase (LDH), and thyroid function tests (TFT) on admission - Prepare arginine 5 x 4 intravenous injections in 500 ml of 10% glucose solution per vial - Prepare ondansetron 8 mg IV (or equivalent dose of other type 5-HT3 antagonist), dexamethasone 8 mg IV, esomeprazole 40 mg IV (or equivalent dose of other type proton pump inhibitor) -Set up 2 heparin blocks (HB) with 3-way stopcocks (1 x 20 gauge angiocatheter for PRRT infusion and the other 1 x 20 gauge angiocatheter for arginine + D10 infusion and / or rescue medications) - Start a 6-hour IV infusion of normal saline (0.9% sodium chloride or 308 mOsm / L sodium chloride solution) 500 mL via a heparin block with a three-way stopcock - Instruct patients to fast (except for medications) at 1pm on the day of PRRT - Ask patients to empty their bladder / bowel prior to ondansetron (or other types of 5-HT3 antagonists), dexamethasone, esomeprazole (or other types of proton pump inhibitors), arginine infusion, and PRRT -Ondansetron 8 mg (or equivalent dose of another type of 5-HT3 antagonist) injected 30 minutes before PRRT infusion (to minimize nausea / vomiting after PRRT) - Dexamethasone 8 mg injected 30 minutes before PRRT infusion (to minimize pain episodes after PRRT) - 5 grams of arginine in 1 pint of glucose solution per 500 mL, prepare 4 pints and infuse them intravenously, infuse 4 pints per hour, then infuse normal saline (0.9% sodium chloride, or 308 mOsm / L sodium chloride solution) at a rate of 500 mL per pint every 4 hours, for a total of 4 pints -Measure the radiation dose level in the patient 4 hours after PRRT (i.e. 6 pm) -Patients are allowed to resume eating and drinking at 6 pm

[0039] 2. Devices required for PRRT infusion: - Two three-way stopcocks for pipe connection - Two 20 ml screw-on syringes for priming the tubing and saline flushing - Two extension tubes (1500 mm long) for connecting the PRRT syringe and NS bag to the patient - Two pairs of sterile long forceps for handling NS tubes - 4 pints of 10% glucose 500ml + arginine infusion, 4.5 to 6 grams per hour x 4 hours - One 100ml saline flush after PRRT infusion - Four bottles of 10ml saline for flushing - Two red stopcocks flushed with saline -Latex gloves

[0040] 3. (Optional) Prescription of emergency medications as needed during ward isolation: -Ondansetron 8 mg IV every 12 hours (or equivalent dose of another type of 5-HT3 antagonist) for nausea and / or vomiting -Metoclopramide 10 mg IV every 8 hours for nausea and / or vomiting - Oral acetaminophen 1000 mg every 6 hours for pain relief - Oral tramadol 50 mg every 6 hours for pain relief

[0041] 4. Procedures before and during PRRT infusion: - Prime all lines with saline -Prepare a protective plexiglass shielding box - Connect a primed line to a heparin block using a three-way stopcock and a 250ml bag of saline -Set the infusion pump rate to 16 to 20 mL / hour (to infuse the entire PRRT in 30 minutes, range 20 to 40 minutes) - Place the PRRT syringe into the infusion pump and lock the syringe accordingly -Securely connect the saline infusion three-way stopcock to the PRRT syringe - Ensure the three-way stopcock is in the correct position to facilitate PRRT flow into the patient - Press the start button on the infusion pump to start PRRT infusion -Continue arginine infusion concurrently with PRRT infusion - Patients are asked to report any symptoms during PRRT infusion -After PRRT infusion, disconnect the saline tube with forceps and place it in the shielding box -Use long forceps to handle the catheter after PRRT injection

[0042] 5. Management after PRRT infusion: - Single photon emission computed tomography (SPECT) or computed tomography (CT) scan scheduled the day after PRRT - Patients were examined at 12 noon on the second day after PRRT. If the radiation level was less than 20 μSv / hour, the patient was considered for discharge.

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

[0044] The embodiment was chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to understand the invention for various embodiments and with various modifications as are suited to the particular use contemplated.

Claims

1. An improved method of administering a peptide receptor radionuclide to treat a neuroendocrine tumor to avoid adverse gastrointestinal side effects and to avoid worsening renal function in a subject, the method comprising: Performing a first intravenous infusion, wherein the infusion comprises administering to the subject 20 grams of L-arginine hydrochloride dissolved in 2000 mL of 10% glucose solution within 3 to 5 hours, followed by administering 2000 mL of normal saline solution (0.9% sodium chloride, or 308 mOsm / L) within 15 to 17 hours, and controlling the respective infusion rates by an infusion pump; and A second intravenous infusion was started 20 to 60 minutes after the start of the L-arginine hydrochloride infusion, wherein the second infusion contained 7.4 GBq ± 10% (200 mCi ± 10%) lutetium-177-DOTATOC) dissolved in 7 to 10 mL of normal saline solution (0.9% sodium chloride) and infused into the subject over 20-40 minutes, with the infusion rate controlled by an infusion pump; wherein the first infusion and the second infusion are respectively performed through different infusion lines; wherein the first infusion and the second infusion are administered through different peripheral veins in different hands; The serum renal function of the subjects remained at 44.2–132.6 μmol / L (or equal to 0.5–1.5 mg / dL) after one year of administration; wherein the subject's creatinine clearance changes by less than 5% within one year after administration of PRRT relative to the baseline prior to initiation of PRRT; and No adverse gastrointestinal side effects were observed in the subjects within one year after the administration of PRRT.

2. The method of claim 1, wherein the second intravenous infusion is initiated about 20 to 60 minutes after the first intravenous infusion.

3. The method of claim 1, wherein the second intravenous infusion is administered over a period of 20 to 40 minutes.

4. The method of claim 1, wherein the gastrointestinal adverse side effects include nausea, vomiting, indigestion, gastroesophageal reflux symptoms, diarrhea, constipation, abdominal pain and bloating.

5. The method according to claim 1, further comprising premedication, comprising: 5-HT3 antagonists; Dexamethasone; as well as Proton pump inhibitors; The premedication was administered 20 to 40 minutes before the first and second infusions.

6. The method of claim 5, wherein the 5-HT3 antagonist is ondansetron.

7. The method of claim 5, wherein the proton pump inhibitor is esomeprazole.

8. A system for administering a peptide receptor radionuclide to avoid adverse gastrointestinal side effects and to avoid worsening renal function in a subject, the system comprising: An infusion regulation module, the infusion regulation module is used to: Performing a first intravenous infusion, wherein the infusion comprises administering to the subject 20 grams of L-arginine hydrochloride dissolved in 2000 mL of 10% glucose solution within 3 to 5 hours, followed by administering 2000 mL of normal saline solution (0.9% sodium chloride, or 308 mOsm / L) within 15 to 17 hours, and controlling the respective infusion rates by an infusion pump; and A second intravenous infusion was started 20 to 60 minutes after the start of the L-arginine hydrochloride infusion, wherein the second infusion contained 7.4 GBq ± 10% (200 mCi ± 10%) lutetium-177-DOTATOC) dissolved in 7 to 10 mL of normal saline solution (0.9% sodium chloride) and infused into the subject over 20-40 minutes, with the infusion rate controlled by an infusion pump; wherein the first infusion and the second infusion are respectively performed through different infusion lines; and wherein the first infusion and the second infusion are administered through different peripheral veins in different hands; The subjects' serum renal function was maintained at 44.2–132.6 μmol / L (or 0.5–1.5 mg / dL) after one year of administration; The change in creatinine clearance in the subject is less than 5% within one year after PRRT administration relative to the baseline before the start of PRRT administration; and No adverse gastrointestinal side effects were observed in the subjects within one year after the administration of PRRT.

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