Combination therapy consisting of benfo-oxythiamine and / or oxythiamine and radionuclide therapy

Abstract

The substances benfo-oxythiamine (B-OT) and / or oxythiamine (OT) are administered as active ingredient(s) in parallel with an ongoing radionuclide therapy (RNT), in particular a radioimmunotherapy (RIT) and / or a radiopeptide or radioligand or radiopeptide ligand therapy (RET) in the treatment of patients with tumors, in particular malignant tumors. The B-OT and / or OT is administered cyclically, i.e. phases of the administration of B-OT and / or OT ("B-OT / OT administration cycles") alternate with treatment pauses (administration pauses). In each B-OT / OT administration cycle, the B-OT and / or OT is administered on one day or multiple successive days in a previously determined dosage (mg per kg of body weight of the patient). A treatment pause is then carried out in which neither B-OT nor OT is administered, followed by the next B-OT / OT administration cycle.

Description

[0001] COMBINATION THERAPY OF BENFO-OXYTHIAMIN AND / OR OXYTHIAMIN WITH RADIONUCLIDE THERAPY

[0002] Description

[0003] The invention relates to the substances benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use in combination with radiotherapy in the treatment of patients with tumors, in particular with malignant tumors (synonyms: malignancy, cancerous tumor, carcinoma).

[0004] For patients with tumor(s) (tumor patients), and especially with cancerous tumor(s) (cancer patients), both with and without metastases, who are to receive radiotherapy, various radiation therapy techniques are available. Generally, a distinction can be made between radiotherapy with an external (outside the patient's body) radiation source and radiotherapy with an internal (located within the patient's body) radiation source. Radionuclide therapy is included in the latter.

[0005] In radionuclide therapy, a radioactive substance, called a radiopharmaceutical, is introduced into the body. It travels directly to the tumor cells via the bloodstream. The radioactive substance is either absorbed by the tumor cells or binds to them. There, it decays, releasing radiation.

[0006] The basic idea of ​​radionuclide therapy in patients with tumors, particularly malignant / cancerous tumors, is to reduce radiation damage to normal tissue by causing the radiopharmaceutical to bind specifically to the tumor tissue, thereby damaging it significantly more than normal tissue. This is usually achieved by coupling the nuclides to a suitable carrier that docks as specifically as possible to target structures on the cell surface of the tumor cells. In the case of so-called radioimmunotherapy (RIT), the carrier is an antibody that selectively binds to an antigen that is specifically expressed only or primarily by the targeted tumor cells. In the case of so-called radiopeptide therapy or radioligand therapy or radiopeptide ligand therapy (RLT), the carrier is a cell-specific or tumor cell-specific peptide ligand that selectively binds to a receptor that is specifically over- or exclusively expressed by the targeted tumor cells.

[0007] In radioiodine therapy for the treatment of thyroid cancer, radioactive iodine is used as a radiopharmaceutical and primarily penetrates the thyroid cells. With the help of these radionuclide therapies, a tumor can be irradiated with a high dose of radiation without causing significant damage to healthy tissue. Radiopeptide or radioligand therapy (RLT) is used in clinical practice primarily in patients with inoperable or metastatic cancerous tumors / malignancies.

[0008] Well-known established radiopeptide or radioligand therapies (RLTs) include, for example, the treatment of somatostatin receptor type 2 positive neuroendocrine tumors in inoperable or metastatic stages with radiolabeled glycosylated peptide receptor ligands, such as [ 90 Y] DOTA-TOC (1,4,7, 10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Tyr(3)]octreotide) or [ 177 Lu] DOTA-TOC (Kwekkeboom et al, 2005).

[0009] As radionuclides in pharmaceuticals for radiopeptide or radioligand therapies (RLT), α- and β-emitters are particularly suitable, as their radiation has a significantly shorter range than gamma emitters. β-emitters are generally used for the treatment of solid tumors with nodules in the mm range. Due to their relatively short range of approximately 100 pm, α-emitters are suitable for the treatment of intracavitary tumor cell clusters and single cells. Well-known β-emitters used in radionuclide therapy for the treatment of, for example, non-Hodgkin's lymphoma (NHL), bladder carcinoma, and ovarian carcinoma include: 188 Re, 186 Re, 67 Cu and 177 Lu (cf. (Goldenberg, 2002).

[0010] Depending on the active ingredient and the location of the tumor, the radiopharmaceutical is administered orally or by injection. The drug is absorbed by the body and transported to the target organ via the blood. Upon reaching its destination, the radioactive substance decays and releases radiation.

[0011] A long-standing problem with all radiotherapies for the treatment of tumors, and especially malignancies, is the phenomenon of radiation resistance or radioresistance, which some tumors develop during the course of radiation therapy.

[0012] The main goal of radiotherapy in malignancy or cancer patients is to cause DNA damage in the cancer cells and trigger their cell death.

[0013] The success of radiotherapy is determined by the relationship between the extent of cellular damage caused by radiation and the extent of repair. Therefore, the goal must be to shift the relationship between the extent of damage caused and the extent of repaired damage in favor of the damage caused.

[0014] In practice, it is repeatedly observed that some cancer cells, or the cancer cells of some patients, appear to possess a particularly high capacity for repair and are therefore able to partially or completely repair radiation damage, thereby dramatically reducing the effectiveness of radiotherapy. However, the biological causes of this radiation or radioresistance are not yet sufficiently understood and are still the subject of investigation.

[0015] In summary, all known radiotherapies, including the newer radionuclide therapies, have shown promising therapeutic results and have therefore been approved, but in practice have led to treatment resistance in some patients. Although radioligand therapies have achieved great therapeutic success in advanced cancer patients, even in those for whom this was the last available treatment option, there are still cancer patients for whom radioligand therapy does not work from the outset or for whom resistance develops during the course of the therapy.

[0016] The object of the present invention is therefore to provide a medicament which can counteract these disadvantages of radionuclide therapy.

[0017] One solution to this problem consists in specifying the use of benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for application as an active ingredient in combination with radionuclide therapy (RNT), in particular radioimmunotherapy (RIT) and / or radiopeptide or radioligand or radiopeptide ligand therapy (RLT) in the treatment of patients with tumors, in particular with malignant tumors (synonyms: malignancy, cancerous tumor), including those that have already formed metastases, wherein the administration of benfo-oxythiamine (hereinafter referred to as "B-OT") and / or oxythiamine (hereinafter referred to as "OT") is carried out in parallel with the ongoing radionuclide therapy, namely cyclically, i.e. phases of administration of B-OT and / or OT or of treatment with B-OT and / or OT - hereinafter referred to as "B-OT / OT administration cycles" - alternate with treatment breaks (administration breaks).In each B-OT and / or OT administration cycle, the B-OT and / or OT is administered on one or more consecutive days at a predetermined dosage (mg per kg of patient body weight). This is followed by a treatment break (i.e., no B-OT or OT is administered), followed by the next B-OT and / or OT administration cycle.

[0018] If radionuclide therapy is also administered in multiple cycles, several B-OT / OT administration cycles are preferably performed per radionuclide therapy cycle. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) are preferably administered systemically, but topical administration is also possible, for example, in the case of oral cancer.

[0019] Benfo-oxythiamine (B-OT) is an inhibitory thiamine (vitamin B1) analogue and prodrug from which oxythiamine (OT) is rapidly released in the human body. OT is known as a thiamine antagonist, and its pharmacology has been studied in vitro and in animal studies. OT acts as an inhibitor of thiamine-dependent enzymes such as transketolase, pyrvat dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain amino acid dehydrogenase, and other thiamine-dependent enzymes. The large number of thiamine-dependent enzymes and the knowledge that some of them catalyze essential reactions in sugar, amino acid, and lipid metabolism has led to the prevailing opinion that oxythiamine, as a nonspecific inhibitor of these enzymes, is unsuitable for clinical use in patients.

[0020] WO 2021 / 259423 (Coy et al.) discloses the use of B-OT and thus OT for the treatment of tumor patients for the purpose of a general, gradual (continuously variable and precisely controllable by means of a dosage regimen) slowing of the patient's overall metabolism, namely the anabolic and / or catabolic and / or energy-releasing metabolic processes in all or almost all cells of the body. During this metabolic slowing, B-OT or OT acts as an inhibiting thiamine analogue and inhibits the enzyme activity of essentially all thiamine-dependent enzymes in all body cells of the patient, including tumor cells, thereby reducing both the synthesis of cellular building blocks and the supply of energy. The enzyme inhibition and the resulting throttling or slowing down of the cellular metabolism of all cells can be controlled in terms of strength and duration and can even lead to a (temporary) complete metabolic blockade.By slowing down the overall metabolism, both health-preserving and disease-causing processes are slowed down simultaneously and thus both processes are non-specifically weakened, but the extent of the disease-causing processes per unit of time is reduced, so that time is gained that is available for another targeted therapy.

[0021] In the course of the investigations that led to the subject matter of the present invention, it was surprisingly discovered that repeated, namely cyclical, administration of B-OT (and thus also OT) in parallel with ongoing radionuclide therapy, whereby each B-OT and / or OT administration cycle is followed by a treatment break without B-OT and / or OT administration, has the effect that the radionuclide therapy, in particular radiopeptide or radioligand or radiopeptide ligand therapy (RLT), damages the tumor cells significantly more effectively. Even in cancer patients whose tumor(s) / metastases had apparently already developed resistance to radionuclide therapy, a renewed sensitivity to radionuclide therapy could be observed, which manifested itself as a regression or disappearance of the tumor(s) / metastases.

[0022] In other words: In the case of the co-therapy according to the invention consisting of radionuclide therapy and cyclic administration of B-OT and / or OT, namely B-OT and / or OT administration cycle (synonym for: administration phase or treatment phase) and treatment break (without B-OT and / or OT administration) in regular alternation, the tumor cell-damaging effect of the radiotherapy is significantly stronger than with pure (mono-) radiotherapy, for example existing (previously observed) resistance of the tumor cells to the radiotherapy in question is overcome or compensated (in previously therapy-resistant patients, the sensitivity to radiotherapy is restored), and (ideally) regression of tumors and / or metastases occurs.

[0023] When administered cyclically (i.e., with intervening administration or treatment breaks), B-OT and thus OT apparently act as a type of radiocellular damage maximizer in the irradiated cells: In combination with RLT, B-OT or OT increases or restores the tumor's sensitivity to radiotherapy. The administration of B-OT and / or OT in cycles with treatment breaks concurrent with radiotherapy thus apparently has the synergistic effect of enhancing the efficacy of the respective radiotherapy.

[0024] The duration of the B-OT and / or -OT administration cycles and the treatment breaks should each be approximately 5 to 10 days, preferably approximately 6 to 8 days, and most preferably approximately 7 days. These periods (for cycle and break lengths) have proven to be very well tolerated by patients in practice.

[0025] The variant with a weekly (7-day) alternation of B-OT / OT administration cycles and treatment breaks (non-dosing) also has the advantage of enabling a clear and manageable treatment plan, thus facilitating patient compliance. Administration of B-OT and / or OT during ongoing radionuclide therapy (RNT) should comprise at least two administration cycles with a treatment break (without B-OT and / or OT administration) in between.

[0026] The dosage of benfo-oxythiamine (B-OT) and / or oxythiamine (OT) should be approximately 0.05 to 0.15 mg, preferably approximately 0.1 to 0.15 mg per 1 kg of patient body weight per day (of the administration cycle).

[0027] One embodiment of the application according to the invention, which can be integrated into everyday clinical practice without any special technical or personnel expenditure, consists in the combination of the benfo-oxythiamine (B-OT) and / or oxythiamine (OT) administration cycles and treatment breaks with a radiopeptide ligand therapy (synonyms: radiopeptide therapy, radioligand therapy), RLT for short, as radionuclide therapy.

[0028] In particular, combinations of the B-OT (and thus also OT) administration cycles according to the invention and B-OT (and thus also OT) treatment breaks with a radiopeptide ligand therapy (RLT) using the nuclide lutetium-177 (177Lu) and / or the nuclide actinium-225 (225Ac) and / or the nuclide iodine-131 ( 131 I) have already proven themselves in practice and have led to surprising therapeutic successes.

[0029] In a preferred embodiment of the application according to the invention, the first B-OT and / or OT administration cycle begins (starts) on the same day as the radionuclide therapy. This has the advantage that the overall efficacy of the combination treatment is particularly effective because the nuclide radiation is highest on the first day of therapy and decreases exponentially thereafter.

[0030] A well-known and frequently used radiopeptide ligand therapy (RLT) is 177 Lutetium prostate-specific membrane antigen radioligand therapy ( 177 Lu-PSMA-RLT is indicated for patients with metastatic prostate cancer whose carcinoma cells express the prostate-specific membrane antigen (PSMA) in positron emission tomography (PET) and for whom conventional systemic therapies such as chemotherapy are (or no longer) effective.

[0031] PSMA is a membrane-bound glycoprotein with enzyme function located on the outer surface of prostate cells and is expressed 1,000 times more frequently in malignant prostate cells than in healthy ones – and this increase increases with the higher the Gleason score. (The Gleason score is a prognostic parameter for assessing prostate cancer and is based on the histological morphology of the glandular pattern.) The more aggressive the tumor, the more PSMA enzyme activity can be expected.

[0032] At the 177 In Lu-PSMA-RLT, ligands that bind to PSMA are coupled with the therapeutically usable radionuclide lutetium-177 and thus radioactively labeled.

[0033] Lutetium-177 ( 177Lu) is a beta emitter with a maximum energy of 0.5 MeV. Its radioactive radiation has a range of only a few millimeters and penetrates tissue to a maximum depth of 2 mm. It can be used to precisely irradiate even small lesions without damaging the surrounding tissue. The radioactive half-life of 177 Lu is given as 6.647 days, the radiation time of the 177 Lu, when coupled to PSMA, for example, is estimated by experts to last approximately 6 weeks. At this point, the radiation intensity is mathematically less than 1.5% of the original radiation intensity at the beginning of day 1.

[0034] After administration to a patient with prostate cancer (usually by injection via a venous access), the 177 Lu-PSMA ligands bind to the PSMA of prostate cancer cells and cause targeted radioactive irradiation of these cells, which should induce their cell death.

[0035] Another well-known and proven radionuclide therapy for patients with metastatic, PSMA-positive prostate cancer is the Actinium-225 prostate-specific membrane antigen radioligand therapy ( 225 Ac-PSMA-RLT). (See Sathekge et al. 2019.) It represents an alternative to the 177 LU-PSMA-RLT, but is also used in combination with it in the so-called TANDEM PRLT (synonym: 225Ac-PSMA / 177Lu-PSMA-TANDEM PRLT). (See Khreish et al. 2020.)

[0036] Radionuclide therapy with iodine-131 ( 131 I) is considered for cancer patients with advanced prostate cancer. (See Zechmann et al. 2014.)

[0037] In the course of the experiments underlying the present invention, it was found that the application according to the invention with a 177 Lutetium prostate-specific membrane antigen radioligand therapy ( 177Lu-PSMA-RLT) as radiopeptide ligand therapy (RET) in cancer patients with metastatic castration-resistant prostate cancer (mCRPC) that expresses the prostate-specific membrane antigen (PSMA) on positron emission tomography (PET) can achieve outstanding therapeutic success. It has been shown that Lu-PSMA-RLT in combination with B-OT (and that also means with OT) is a feasible and effective therapeutic strategy, especially for patients with apparently radiorefractory mCRPC. A dosage regimen that has proven particularly successful in practice requires the administration of B-OT and / or OT simultaneously or shortly after the start of 177Lu-PSMA-RLT begins that it comprises two (2), preferably three (3) B-OT - / OT administration cycles, each with an intermediate treatment break, during the following 5 to 6 weeks, and that the duration of each B-OT- / OT administration cycle and each treatment break is about 5 to 10 days, preferably about 6 to 8 days, more preferably about 7 days.

[0038] The total number of planned B-OT / OT administration cycles is preferably determined based on the half-life of the radionuclide used in radionuclide therapy. This number should preferably include enough B-OT / OT administration cycles (with treatment breaks) to allow for one more B-OT / OT administration cycle at the time when the radioactivity of the radionuclide, calculated based on the radioactive half-life, reaches approximately 3%. However, B-OT / OT administration cycles (with treatment breaks) can easily be planned even after this time.

[0039] Even with a combination therapy according to the invention using B-OT and / or OT together with a TANDEM radionuclide therapy (ie a radionuclide therapy using two different radionuclides), significantly better therapeutic results can be achieved than with the sole use of the TANDEM radionuclide therapy.

[0040] Experiments underlying the present invention have also shown that the application according to the invention with a Lutetium-177-DOTATE radioligand therapy ( 177 LU-DOTATATE-RLT or 177 Lu-DOTA-Tyr 3 -Octreotat-RLT) and / or Actimum-225-DOTATE radioligand therapy ( 225 Ac-DOTATATE-RLT or 225 Ac-DOTA-Tyr 3 - Octreotat-RLT) as radiopeptide ligand therapy (RLT) in cancer patients with advanced neuroendocrine tumors can achieve surprisingly good therapeutic results. The inventive combination (co-therapy) of B-OT (and that also means with OT) and 177 Lu-DOTATATE-RLT and / or 225 Ac-DOTA ATE-RLT are therefore considered feasible and effective therapeutic strategies, especially for patients with apparently radiorefractory neuroendocrine tumors.

[0041] A basic treatment scheme for the inventive application of benfo-oxythiamine (B-OT) in combination with radionuclide therapy (RNT) using a nuclide with a radiation time of about 6 weeks such as 17 Lu (especially in the '' Lu-PSMA-RLT or in the 17 / Lu-DOTATATE-RLT) in 7-day administration cycles in a patient weighing approximately 60 kg includes the following measures in the order mentioned:

[0042] Day 1 : Administration of the radiopeptide ligand and administration of B-OT at a dosage of 6-9 mg

[0043] Day 2 to day 7: daily administration of B-OT at a dosage of 6-9 mg.

[0044] Day 8 to day 14: no administration of B-OT.

[0045] Day 15 to day 21: daily administration of B-OT at a dosage of 6-9 mg.

[0046] Day 22 to day 28: no administration of B-OT.

[0047] Day 29 to day 35: daily administration of B-OT at a dosage of 6-9 mg.

[0048] In this treatment regimen or dosage guide, the applied radioactivity (e.g. the 177 Lu radiation) three times per week (7 days) with simultaneous B-OT exposure and twice per week without B-OT exposure. Previous applications to patients have shown that the majority of B-OT administration cycles with treatment breaks between each two administration cycles make the anti-cancer therapy more effective, namely, the tumor cells are damaged to a greater extent and killed. This treatment regimen also applies in principle to radionuclide therapy using the radionuclide. 225 Ac.

[0049] The invention is explained in more detail below using exemplary embodiments with tables and figures. The figures show:

[0050] Fig. 1 : 3+3 design of the study part to determine the maximum (tolerated) dose (MTD) for the co-therapy of BOT in combination with a 177 Lu-PSMA-RLT. Meaning: 1 77 LU-PSMA = Start of the 177 Lu-PSMA-RLT .

[0051] DLT = dose-limiting toxicity or adverse effects according to NCI CTCAE, version 5.0)

[0052] 1 / 3 DLT = one third of the patients treated so far show DLT(s).

[0053] + 3Pt = three additional patients will be included in the ongoing study.

[0054] DLT 0 / 3 = none of the patients treated so far show DLT(s) and the next study starts with the next higher B-OT dose.

[0055] Fig. 2: Serial 68 Ga-PSMA positron emission tomography (PET) / computed tomography (CT) scans showed significant disease progression after (A) 1 77 Lutetium-PSMA radiopeptide ligand therapy, after (B) a177 Lutetium / 225 Actinium-PSMA radiopeptide ligand therapy ("TANDEM-PRLT") and after (C) chemotherapy with docetaxel.

[0056] Fig. 3: Selected images before and after treatment with 177 Lu-PSMA-RLT in combination with B-OT ("BOT-PRLT") at 3 mg / day (orally) for 5 days. They show partial remission of metastases.

[0057] Fig. 4: Representation of prostate-specific antigen (PSA) over time under different treatments.

[0058] Abbreviations used: LEU = Leuprorelin; RT = Radiotherapy; DOCE = Docetaxel; ENZ = Enzalutamide; PRLT = 177 Lutetium-PSMA radiopeptide ligand therapy; TANDEM PRLT = 177 Lutetium / 225 Actinium-PSMA radiopeptide ligand therapy; BOT-PRLT = 177 Lutetium-PSMA radiopeptide ligand therapy in combination with B-OT (3 mg / day for 5 days; oral administration).

[0059] While all previous therapies without B-OT resulted in an increase in PSA levels, a 50% reduction in PSA levels was observed after B-OT-PRLT.

[0060] Fig. 5: Patient with neuroendocrine tumor disease.

[0061] (A) Extremely extensive bone metastasis despite 10-fold treatment with 177 LU-DOTATATE-RLT.

[0062] (C) almost complete regression of bone metastases and significant regression of liver metastases after combination therapy with B-OT and 225 Ac-DOTATATE-RL

[0063] List of abbreviations used previously and in the following:

[0064] 225 Ac-PSMA = 225 Actinium prostate-specific membrane antigen

[0065] 225 Ac-PSMA-RLT = 223 Actinium prostate-specific membrane antigen radioligand therapy

[0066] AE = Adverse Event

[0067] B-OT = Benfo-Oxythiamine

[0068] NCI CTCAE = Common Terminology Criteria for Adverse Events of the National Cancer Institute (USA)

[0069] DLT = dose-limiting toxicity

[0070] DOTATATE (synonym: edotreotide) = DOTA(0)-Phe(l)-Tyr(3))octreotide

[0071] DSRC = Data Safety Review Committee 131 I-PSMA-RLT = 131 Iodine-prostate-specific membrane antigen radioligand therapy 177 LU-DOTATATE-RLT = 177 Lu-DOTA-Tyr 3 -Octreotate radioligand therapy 177 Lu- PSMA == ^' 'Lutetium prostate-specific membrane antigen

[0072] 1 ' 7 LU-PSMA-RLT = Lutetium Prostate-Specific Membrane Antigen Radioligand Therapy mCRPC = Metastatic Castration-Resistant Prostate Cancer

[0073] MRI = magnetic resonance imaging

[0074] MTD = maximum tolerated dose

[0075] OT = Oxythiamine

[0076] PET = Positron Emission Tomography

[0077] PSMA == Prostate-Specific Membrane Antigen

[0078] RNT = Radionuclide Therapy

[0079] RET = radiopeptide or radioligand or radiopeptide ligand therapy

[0080] R5P = Ribose-5-phosphate

[0081] SPECT / CT = single-photon emission computed tomography / computed tomography

[0082] SAE = Serious Adverse Event

[0083] Example 1: Studies on the tolerability and efficacy of Benfo-Oxythiamine (B-OT) in combination with 177 Lutetium prostate-specific membrane antigen radioligand therapy ( 177 Lu-PSMA-RLT) in patients with prostate-specific membrane antigen (PSMA)-PET-positive mCRPC

[0084] Part A; Safety. Tolerability and Pharmacokinetics

[0085] In Part A (Phase 1), the safety of B-OT in increasing dose levels in combination with 17 'Lu-PSMA radioligand therapy (RLT) is evaluated and the maximum tolerated dose is determined. The investigations or studies are conducted, for example, according to a 3+3 design with increasing doses (administered amounts of) B-OT.

[0086] Cohorts (patient groups with comparable symptoms) of 3 to 6 patients (subjects) with PSMA-PET-positive metastatic castration-resistant prostate cancer (mCRPC) (i.e. with mCRPC that expresses the prostate-specific membrane antigen (PSMA) in positron emission tomography (PET)) will receive 1 "Lutetium Prostate Specific Membrane Antigen Radioligand Therapy ( 177Lu-PSMA-RLT) at a dose of 7.4 GBq (±10%) and administered intravenously. This intravenous administration is repeated a maximum of four (4) times, each at intervals of approximately 6 weeks (± 1 week) (i.e., a maximum of four RLT cycles of 5-7 weeks each are administered). Parallel to each RLT cycle, these patients (subjects) receive cyclic treatment with oral B-OT.

[0087] Four cohorts and four dose levels are planned: 3.0 mg, 5.0 mg, 7.0 mg, and 9.0 mg, with a patient weight of approximately 70-85 kg. The cohorts will be treated with the next higher B-OT dose level at staggered intervals: Cohort 1 will receive the B-OT administration cycles at the 3.0 mg dose; Cohort 2 will receive the B-OT administration cycles at the 5.0 mg dose; Cohort 3 will receive the B-OT administration cycles at the 7.0 mg dose; and Cohort 4 will receive the B-OT administration cycles at the 9.0 mg dose.

[0088] Dose selection and expansion may be modified at the discretion of the investigator and the DSRC. In particular, higher or lower B-OT doses (than those indicated in this example) may be selected for each of the four dose levels. The addition of additional dose levels and, accordingly, additional cohorts is also quite possible.

[0089] The B-OT administration cycles with increasing B-OT doses per cohort are carried out until the maximum tolerated dose (MTD) is reached or, if no MTD is established, a suitable active dose can be determined.

[0090] For example, the following 3+3 design with increasing doses is used here:

[0091] In each B-OT administration cycle, B-OT is administered orally once daily at the dose established for a cohort.

[0092] A sentinel dose is applied to each cohort. (Sentinel dose = in each cohort, the administration of the first dose is designed so that initially, i.e., before the entire study or before the entire cohort, only a single subject receives the dose of the active investigational medicinal product; see EMA guidance "Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products").

[0093] The B-OT treatment, comprising several B-OT administration cycles with B-OT treatment breaks in between, begins on the same day as radiotherapy (Day 1, Week 1). It initially extends over 6 weeks (i.e., until Day 42 in Week 6), namely until the earliest start of the second RLZ cycle (i.e., the second 177 Lu-PSMA injection.

[0094] Each B-OT administration cycle consists of 7 days, meaning B-OT is administered once daily for 7 consecutive days. This is followed by a 7-day B-OT treatment break. This alternation of B-OT administration cycles and B-OT treatment breaks is repeated two more times. In other words, 3 administration cycles (days 1-7, days 15-21, and days 29-35) are performed, with 7-day treatment breaks (days 8-14, days 22-28, and days 36-42) in between.

[0095] The study design is shown graphically in Fig. 1.

[0096] In detail, the B-OT treatment regimen provides the following procedure:

[0097] Each cohort will begin on Day 1 with the intravenous administration of one dose of 177Lu-PSMA radioligands to the first sentinel subject in this cohort (Patient 1). In addition, this Patient 1 will receive the first oral dose of B-OT of the first B-OT administration cycle on this day 1, at the starting dose specified for the cohort. For Cohort 1, in this example, this is 3 mg for a patient weighing approximately 60 kg. (The starting dose is based on the dose used in Germany for compassionate use trials and is one dose below the highest dose tested in the FIH Phase 1 study on healthy volunteers.) This Patient 1 of Cohort 1 will continue to receive a daily dose of B-OT at the starting dose on the following days 2-7 of the first B-OT administration cycle. If no dose-limiting toxicity (DLT) occurs in this patient 1, the second and third patients of the same cohort will be recruited with a minimum time interval of 7 days (1 week) from this patient 1 and treated analogously to patient 1.If no DLT is observed in any of these three patients, testing of the next B-OT dose level, in this example 5 mg B-OT, will begin with Cohort 2. However, if a DLT is observed in one (or 1 / 3) of the patients in Cohort 1, Cohort 1 will be expanded to include three additional patients, and the initial dose will be maintained. If no further DLT is observed in these six patients in Cohort 1 after a minimum interval of 7 days since the start of treatment in Patient 2 and Patient 3, testing will begin at the next higher dose level, in this example 7 mg B-OT, with Cohort 3.

[0098] For each cohort, B-OT treatment starts with the administration of the first B-OT administration cycle (cycle length 7 days) to only one subject, ie only this patient 1 of the respective cohort receives the first B-OT administration cycle (with cycle length 7 days).

[0099] Each subject in a given cohort will receive three B-OT administration cycles with the dose received on Day 1 until the next intravenous administration of the 177 LuPSMA radioligands after 6 weeks, i.e., until the start of the next (second) RLT cycle. This 6-week treatment regimen of concurrent RLT and B-OT administration will be repeated at least twice and no more than four times (at the investigator's discretion), unless discontinuation criteria such as unacceptable toxicity require termination. Dose-limiting toxicities (DLT) are defined as adverse events of the study treatment that occur within the first 7 days of treatment in each patient (DLT period). DLT events are graded according to NCI CTCAE, version 5.0.

[0100] During the treatment period from the start of RLT and the first B-OT administration cycle until at least the end of the second RLT cycle and the sixth B-OT administration cycle, followed by a 7-day B-OT treatment break, safety parameters will be measured in the participating patients, and blood samples will be taken to evaluate the pharmacokinetic properties of B-OT. In addition, a final outpatient follow-up examination will be conducted after the sixth week, i.e., at the end of each RLT cycle and the third B-OT treatment break following the previous third B-OT administration cycle (days 29-36). A follow-up examination will be conducted four (4) weeks after completion of the study to assess any after-effects of B-OT administration.At the end of RLT Cycle 2 and the sixth B-OT treatment break, which is conducted concurrently after the sixth B-OT administration cycle, subjects will undergo an MRI / CT scan to determine whether the patient should continue the study. If no therapeutic response is observed, the patient will be discontinued from the study at the investigator's discretion.

[0101] Treatment-emergent adverse events (AEs) of at least Grade 3 and higher (per NCI CTCAE, version 5.0) are considered potential dose-limiting toxicities (DLTs). The Data Safety Review Committee (DSRC) is responsible for confirming each potential DLT and deciding whether to initiate the next dose-level cohort.

[0102] The DLT period is defined as the first 7 days of treatment with B-OT.

[0103] MTD determination of the maximum tolerated dose of B-OT:

[0104] The MTD of B-OT is defined as the highest dose at which no more than one in six subjects experiences a DLT during the 7-day B-OT administration cycle. This means that three subjects will initially be treated with a given dose. If no DLT occurs, recruitment begins for the next higher dose level.

[0105] If one of three patients / subjects experiences a DLT, three additional patients / subjects will be enrolled at the same dose level. B-OT will only be administered at the next higher dose level if none of these three additional patients / subjects experience a DLT.

[0106] If more than one of three patients / subjects experiences a DLT at any dose level, recruitment will be stopped and three additional patients / subjects will be enrolled at the next lower dose level to confirm it as the MTD.

[0107] Study evaluation - study results:

[0108] — The safety and tolerability of B-OT treatment in combination with 177 Lu-PSMA-RLT is assessed by the proportion of subjects with dose-limiting toxicity (DLT), adverse events (AEs), and serious adverse events (AEs).

[0109] — The pharmacokinetics of B-OT in combination with (i.e. administered concurrently with) 177Lu-PSMA-RLT will be assessed (e.g., using Cmax, tmax, tl / 2, AUC_{0- \Time), Cl / F, z, Vz / F, AUCO-inf and AUClast ).

[0110] — The MTD is determined by the highest dose at which the incidence of DLT occurs in 2 or more of 6 subjects.

[0111] — The preliminary efficacy of B-OT in combination with (i.e., administered concurrently with) 177Lu-PSMA-RLT will be assessed.

[0112] Part B; Efficacy of B-OT administration at the recommended dose determined in Part A

[0113] In Part B (Phase 2), the efficacy of administering the B-OT dose recommended in Part A in combination with 177 Lu-PSMA-RLT was investigated in patients with PSMA-PET-positive mCRPC.

[0114] The patients concerned will receive B-OT administration cycles with the B-OT dose determined after analysis of the data from Part A (Phase 1), in parallel with the 177 Lu-PSMA-RLT. Subjects should receive the selected treatment regimen for a maximum of 4 RLT cycles. At the end of RLT cycle 2, subjects will undergo an MRI / CT scan to determine treatment continuation.

[0115] The DSRC will also monitor safety and activity in Part B (Phase 2) of the study and request dose changes if necessary.

[0116] If no MTD is determined at the end of the planned dose escalation in Part A (Phase 1), including the expansion of the final dose level to 6 subjects, the dose for Part B (Phase 2) will be determined from one of the studied dose levels based on the available preliminary safety and activity evidence. Study analysis - Study results:

[0117] The evaluation of the efficacy of B-OT administration in combination with 177 Lu-PSMA-RLT is based on the study results regarding

[0118] — Radiographic progression-free survival (rPFS, defined as the time from the start of treatment to the first day of documented radiological progression using conventional imaging or death from any cause, whichever occurs first). Radiological progression is assessed by the investigator according to RECIST1 .1 for soft tissue and PCWG3 for bone lesions.

[0119] — PSA progression-free survival (PSA-PFS),

[0120] — ORR

[0121] — Overall survival (OS) and quality of life assessment

[0122] — 50% PSA response rate (P SA-RR)

[0123] — Duration of reaction (DOR)

[0124] — Discontinuation of treatment due to toxicity

[0125] -- Rate of treatment discontinuation due to toxicity

[0126] — PSA progression-free survival (PSA-PFS) [Timeframe: Until study completion],

[0127] — Objective response rate (ORR) according to RECIST 1.1 in patients / subjects with measurable disease [Timeframe: Until completion of investigations or study],

[0128] — Overall survival (OS) [Time frame: Until completion of investigations or study]. OS is defined as the time from the start of treatment until death from any cause.

[0129] — 50% PSA response rate (PSA-RR) [Timeframe: Until completion of the investigations or study],

[0130] — Duration of response (DOR) [time frame: until completion of the investigations or study],

[0131] — Time to treatment response (TTR) in the subgroup of patients / subjects who achieved a 50% PSA response [Timeframe: Until completion of the investigations or study],

[0132] — Treatment discontinuation due to toxicity [timeframe: until completion of the investigations or study],

[0133] — Rate of treatment discontinuation due to toxicity [timeframe: until completion of the investigations or study],

[0134] To ensure the safety of patients / subjects in these investigations or studies, adverse events (AEs), vital signs, physical examination, and laboratory values ​​will be monitored. Any additional diagnostic tests performed as clinically indicated will be assessed. All subjects will be hospitalized for the first 7 days of B-OT administration in RLT Cycle 1 and thereafter as needed to treat disease-related complications. - Toxicity according to CTCAE version 5.0.

[0135] If the combination therapy according to the invention is to be used in patients with cancers other than mCRPC and / or with other recommended / indicated radionuclide therapies (instead of 177LU-PSMA-RLT), the person skilled in the art may apply the measures or investigations or studies outlined here in Part A and Part B analogously to determine the most appropriate dose and the most appropriate administration cycles with treatment breaks for B-OT and / or OT in combination with an indicated radionuclide therapy.

[0136] Example 2: Compassionate use experiments with B-OT as radiocellular damage maximizer:

[0137] Compassionate use is a treatment option that allows the use of a (not yet) approved medicinal product. Under strict conditions, such a medicinal product can be made available to groups of patients suffering from a disease for which there are no satisfactory approved therapies and who cannot participate in clinical trials.

[0138] In the present example, the application of B-OT according to the invention in combination with a 177 Lu-PSMA-RLT namely B-OT administration cycles alternating with B-OT treatment breaks in parallel with a 177 Lu-PSMA-RLT carried out,

[0139] All patients had exhausted all established treatment options. Despite hormone therapy and several cycles of chemotherapy and radiotherapy, no tumor response was observed.

[0140] During the course of the inventive co-therapy B-OT- 177 Lu-PSMA-RLT, all 12 patients received 177Lu-PSMA-RLT and additionally a treatment with 3 mg B-OT per day, administered orally, for five consecutive days. This meant a single B-OT administration cycle with a cycle length of 5 days and a B-OT dosage of 0.05 mg / kg body weight per day. After this B-OT administration during the ongoing 177 No adverse effects were observed in patients treated with Lu-PSMA-RLT. General well-being and clinical condition remained stable or improved slightly. No significant changes were observed in blood counts, liver parameters, or kidney function.

[0141] PET-CT studies of clinical effects have shown tumor stabilization or even tumor remission.

[0142] These results indicate that as a result of the inventive co-therapy of B-OT with or and 177Lu-PSMA-RLT, namely the additional cyclic administration of B-OT (here a single B-OT administration cycle followed by a B-OT treatment break) during, ie with regard to B-OT simultaneously with, a 177 Lu-PSMA-RLT restored patients' sensitivity to radiotherapy. This is strong evidence that B-OT acts as a radiocellular damage maximizer and can help restore sensitivity to radiotherapy in previously treatment-resistant patients.

[0143] Example 3: Co-therapy B-OT- 177 Lu-PSMA-RLT in a patient with mCRPC

[0144] A 79-year-old man with mCRPC who had failed all standard therapies (hormone therapy / chemo-radiotherapy) and 177 Lu-PSMA-RLT and under 177 Lutetium / 225Actinium-PSMA radiopeptide ligand therapy, the so-called TANDEM-PRLT, a progression of the disease was observed (see Fig. 2), received after already five RLT cycles with 177 Lu-PSMA is an inventive co-therapy B-OT- 177 LU-PSMA-RLT according to the following treatment regimen (dosage instructions):

[0145] In the sixth (6th) RLT cycle (with 7.4 GBq 177 Lu-PSMA), the patient (with a body weight of approximately 60 kg) additionally received treatment with B-OT at a dosage of 3 mg / day (oral) for five consecutive days, i.e., one B-OT administration cycle with a cycle duration (cycle length) of 5 days followed by a B-OT treatment break.

[0146] In the seventh (7th) RLT cycle (with 8.6 GBq 177Lu-PSMA), the patient again received a B-OT administration cycle of cycle length 5 days followed by a B-OT treatment break and a B-OT dosage of 3 mg B OT per day, i.e. 0.05 mg / kg body weight per day. Treatment monitoring showed two months later in the 177 Lu-PSMA single-photon emission computed tomography / computed tomography (SPECT / CT) demonstrated excellent regression of metastases, i.e., a significant partial remission of the tumor (see Fig. 3), and a 50% reduction in PSA levels from 264 to 132 ng / ml (see Fig. 4). No significant changes were observed in blood count, liver parameters, or renal function parameters. At the same time, a significant improvement in the patient's clinical symptoms, general condition, and well-being was noted.

[0147] This case demonstrates the good tolerability and exceptional efficacy of the inventive combination therapy of B-OT administration and 177 Lu-PSMA-RLT (“Co-Therapy B-OT- 17 'Lu-PSMA-RLT') in a patient with prostate cancer that was resistant to standard therapies. While the patient showed progression of the disease even after treatment with TANDEM-PRLT, administration of B-OT during an ongoing 177 Lu-PSMA-RLT (co-therapy, comprising the parallel and, with regard to B-OT, simultaneous cyclic administration of B-OT) achieved partial tumor regression. This allows the conclusion that the additional (here, for example, oral) administration of B-OT (ie, the additional systemic B-OT therapy) increases the sensitivity of the tumor cells to radiotherapy. 17 / Lu-PSMA-RLT increased the cellular damage again. B-OT acted as a kind of radiocellular damage maximizer.

[0148] Example 4: Co-therapy B-OT- 225 Ac-DOTATATE-RLT in a patient with neuroendocrine tumor disease

[0149] Neuroendocrine tumors consist of cells that have receptors for the hormone somatostatin on their cell walls. A synthetically produced variant of this hormone somatostatin is (DOTA(0)-Phe(l)-Tyr(3))octreotide, or DOTATATE for short, or edotreotide. DOTATATE exhibits significantly higher stability in the body than somatostatin and is therefore suitable as a ligand for radionuclide therapy with, for example, the nuclide 177 Lutetium or the nuclide 225 Actinium. Together with 177 Lu will be 177 Lu-DOTA-Tyr 3 - Octreotate or 177 Lu-DOTATATE is used. (This 177 Lu-DOTATATE complex is approved under the name Lutathera® in Europe and the USA.)

[0150] A young patient with a neuroendocrine tumor disease showed no improvement despite 10 treatments with Lutetium-177 DOTATATE, ie after 10 RLT cycles with 177 Lu-DOTATATE or 177 Lu-DOTA-Tyr 3 -Octreotate, an extremely extensive bone metastasis (see Fig. 5 A). After application of the inventive combination therapy of B-OT administration cycle followed by B-OT treatment break during an ongoing actinium 225 -DOTATATE radioligand therapy ( 225 Ac-DOTATATE-RLT or 225 Ac-DOTA-Tyr 3 After treatment with octreotate (RLT), an almost complete regression of the osseous metastases and a significant regression of the liver metastases was observed (see Fig. 5 C). The treatment plan was as follows: Beginning with the start of RLT, one B-OT administration cycle with a cycle duration of 10 days and a dosage of 0.15 mg B-OT / kg per day, or 0.05 mg / kg three (3) times daily.

[0151] Cited non-patent literature:

[0152] Goldenberg D.M.; Targeted therapy of cancer with radiolabeled antibodies; J. Nucl. Med.; (43); 2002; 693-713.

[0153] Khreish F., Ebert N., Ries M., Maus S., Rosar F., Bohnenberger H., Stemler T., Saar M., Bartholoma M., Ezziddin S.: 225 Ac-PSMA-617 / 177 Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nucl Med Mol Imaging 2020, 47, 721-728, doi: 10.1007 / s00259-019-04612-0. Epub 2019 Nov 22.

[0154] Kwekkeboom D.J., Mueller-Brand J., Paganelli G., Anthony L.B., Pauwels S., Kvols L.K., O'dorisio T.M.,Valkema R., Bodei L., Chinol M., Maecke H.R., und Krenning E.P.; Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs; J. Nucl. Med.; (46 Suppl 1); 2005; 62S-66S).

[0155] Sathekge, M., Bruchertseifer, F. , Knoesen, O., Reyneke, F., Lawai, I., Lengana, T., Davis, C., Mahapane, J., Corbett, C., Vorster, M., Morgenstern A.: 225 Ac-PSMA-617 in chemotherapienaive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging 2019, 46, 129-138, doi: 10.1007 / s00259-018-4167-0.

[0156] Zechmann C.M., Ali Afshar-Oromieh A., Armor T., Stubbs J.B., Mier W., Hadaschik B., Joyal J., Kopka K., Babich J.W., Haberkom U.: Radiation dosimetry and first therapy results with a (124)V (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014; 41, 1280-92. doi: 10.1007 / s00259-014-2713-y. Epub 2014 Feb 28.

Claims

Claims 1. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use as an active ingredient in combination with radiotherapy in the treatment of patients with a tumor, in particular a malignant tumor, characterized in that the radiotherapy is a radionuclide therapy (RNT), in particular a radioimmunotherapy (RIT) and / or a radiopeptide or radioligand or radiopeptide ligand therapy (RLT), and that the administration of benfo-oxythiamine (B-OT) and / or oxythiamine (OT) is carried out cyclically and in parallel with the ongoing radionuclide therapy, each B-OT and / or OT administration cycle being followed by a treatment break without B-OT and / or OT administration.

2. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to claim 1, characterized in that the duration of each administration cycle and each treatment break is about 5 to 10 days, preferably about 6 to 8 days, particularly preferably about 7 days.

3. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to claim 1 or 2, characterized in that the administration of B-OT and / or OT during ongoing radionuclide therapy (RNT) comprises at least two B-OT and / or OT administration cycles with an intermediate treatment break without B-OT and / or OT administration.

4. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to one of claims 1 to 3, characterized in that the administration of benfo-oxythiamine (B-OT) and / or oxythiamine (OT) is carried out in a dosage of about 0.05 to 0.15 mg, preferably about 0.1 to 0.15 mg per 1 kg of body weight of the patient and per day (of the administration cycle).

5. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to any one of claims 1 to 4, characterized in that the administration is systemic.

6. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to one of claims 1 to 5, characterized in that the radionuclide therapy is a radiopeptide ligand therapy (synonyms: radiopeptide therapy, radioligand therapy), abbreviated to RLT.

7. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to claim 6, characterized in that in radiopeptide ligand therapy (RLT) the nuclide used is lutetium-177 ( 177 Lu) and / or Actinium-225 ( 225 Ac) and / or iodine-131 ( 131 I) is used.

8. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to any one of claims 1 to 7, characterized in that the first B-OT and / or OT administration cycle begins on the day of the start of radionuclide therapy.

9. Benfo-oxythimine (B-OT) and / or oxythiamine (OT) for use according to one of claims 1 to 8, characterized in that the tumor is a metastatic castration-resistant prostate cancer (MCRPC) which has the prostate-specific membrane antigen (PSMA) in positron emission tomography (PET), and in that the radiopeptide ligand therapy (RLT) is a lutetium-177 prostate-specific membrane antigen radioligand therapy ( 177Lu-PSMA-RLT) and / or Actinium-225 Prostate Specific Membrane Antigen radioligand therapy ( 225 Ac-PSMA-RLT) and / or a 225 Ac-PSMA / 177 Lu-PSMA-TANDEM PRLT and / or iodine-131 prostate-specific membrane antigen radioligand therapy ( 131 I-PSMA-RLT).

10. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to claim 9, characterized in that the administration of B-OT and / or OT is carried out simultaneously or shortly after the start of the 177 Lu-PSMA-RLT begins that it comprises two (2), preferably three (3) administration cycles with intermediate treatment breaks during the following 5 to 8 weeks, and that the duration of each administration cycle and each treatment break is about 5 to 9 days, preferably about 6 to 8 days, most preferably about 7 days.

11. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to any one of claims 1 to 8, characterized in that the tumor is a neuroendocrine tumor, and that the radiopeptide ligand therapy (RLT) is a lutetium-177-DOTATE radioligand therapy ( 177 Lu-DOTATATE-RLT or 177 Lu-DOTA-Tyr 3 -Octreotate- RLT) and / or Actinium-225-DOTATE radioligand therapy ( 225 Ac-DOTATATE-RLT or 225 Ac-DOTA-Tyr 3 -Octreotate-RLT).

12. Benfo-oxythiamine (B-OT) and / or oxythiamine (OT) for use according to one of claims 1 to 11, characterized in that the duration of each administration cycle and each treatment break is approximately 5 to 10 days, preferably approximately 6 to 8 days, particularly preferably approximately 7 days, and in that the total number of administration cycles provided is determined on the basis of the half-life of the radionuclide used in the radionuclide therapy, the last cycle being provided for the time at which the radiation activity of the radionuclide calculated on the basis of the half-life is approximately 3%.

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