Combination cancer therapy

Abstract

The present invention relates to combination therapy comprising a targeted radiopharmaceutical agent and an immune checkpoint inhibitor and their use for the treatment of cancer, wherein the radiopharmaceutical agent comprises a sarcophagine chelator bound to a somatostatin type 2 receptor binding moiety.

Description

Combination cancer therapyField

[0001] The present invention relates to combination therapy comprising a targeted radiopharmaceutical agent and an immune checkpoint inhibitor and their use for the treatment of cancer.Background

[0002] This application claims priority from Australian Provisional Application No.2025900189, filed on 24 January 2025, the entire contents of which is incorporated by reference.

[0003] Traditional treatment of a cancer in a subject often involves the administration of a chemotherapeutic agent that destroys the cancer cells and prevents further proliferation and growth. Drawbacks of such an approach to treatment is the various side effects experienced by the patient due to the use of traditional chemotherapy and also resistance to the administered agent.

[0004] Immune system cells (e.g., T-cells) use immune checkpoints to monitor and modulate the immune response. Blocking checkpoints allow for immune system cells to better kill cancer cells. Tumours contain checkpoint proteins that are capable of binding receptors associated with checkpoints on immune system cells - binding of these proteins allows the tumour to “bypass” these checkpoints and deactivate the immune system response. As an example, tumour cells express a PD-L1 protein that is capable of binding and inhibiting PD-1, which is present on T-cells. When the PD-L1 protein on tumour cells binds PD-1 on the T-cells of the host, the immune system T-cell response is neutralised, and the tumour remains. The use of a checkpoint inhibitor, e.g., an anti-PD-Ll antibody, binds to PD-L1 on the tumour and prevents the interaction of PD-L1 with PD-1 on the T-cells of the host. This then allows the T-cells to produce an immune response and subsequently recognise and kill the tumour.

[0005] One approach for cancer therapy is to administer an immune checkpoint inhibitor, i.e., a compound that binds to immune checkpoints and prevents the tumour cell from dampening the immune response that would ordinarily target and destroy cancer cells. One disadvantage of this therapy is that not all patients respond to immune checkpoint inhibitors alone.Furthermore, the administration of immune checkpoint inhibitors is often associated with various adverse events and toxicities associated with gastrointestinal, endocrine, dermatological, neurological, cardiovascular and / or pulmonary systems.

[0006] There remains a need for new methods that make immunotherapy effective in more patients diagnosed with cancer.Summary of the invention

[0007] The present inventors have found that the combined radionuclide and immunotherapy disclosed herein results in a reduction in tumour volume, i.e. therapy comprising the administration of a compound of Formula (I) complexed with a radionuclide and an immune checkpoint inhibitor. The administration of the combination therapy as disclosed herein also results in an increase in the survival of the subject and slower tumour growth, when compared with controls.

[0008] Histopathology results shown herein indicate that the tumours show the presence of SSTR2 throughout tumours, which corresponds to the presence of proliferating tumour cells. Other results presented herein visualise the location of various biomarkers associated with tumour proliferation and immune cells, e.g. B-cells, T-cells and NK cells. The present inventors have shown that while treatment with radionuclide therapy alone does result in the expression of T-cells at the periphery of a tumour, the use of a combination therapy (i.e. with added immunotherapy) results in the infiltration of T-cells into the tumour. This suggests that the combined radionuclide and immunotherapy approach disclosed herein leads to an improved treatment option for tumours, since the core of the tumour is infiltrated (and is therefore accessible) meaning that both the surface and the core of the tumour are treated. Through various histopathological techniques, the present inventors have shown that the infiltration into the tumours treated with this combined approach correlates well with the tumour architecture and vasculature.

[0009] Without wishing to be bound by theory, the present inventors believe that although radionuclide therapy or immunotherapy alone are options for the treatment of a tumour, the present results show that a combined radionuclide and immunotherapy approach for the treatment of cancer is more efficacious since the core of the tumour is better infiltrated and therefore available for treatment and potentially more susceptible to active agents.

[0010] Cross sections of tumours showed heterogenous uptake of the compound of Formula (I), as visualised through Cherenkov imaging. Given the heterogeneity of the images obtained, this not only suggests that the compound of Formula (I) is localised at the tumour site (since there are receptors for binding at SSTR2) and that the tumours show some vascularisation and necrosis.

[0011] The present inventors believe that the combinations disclosed herein provide methods for the treatment of a cancer. Accordingly, in one aspect the present invention provides a method of treating a cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0012] Without wishing to be bound by theory, the present inventors believe that the methods disclosed herein allow for the treatment of a cancer or for reduction in the size of a tumour since the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof complexed with a radionuclide increases the susceptibility of the cancer or tumour associated with the cancer to the action of an immune checkpoint inhibitor. This means that in the methods disclosed herein, the compound of Formula (I) is administered before the one or more immunecheckpoint inhibitors. This is because the spontaneous decay products of the radionuclide complexed with the compound of Formula (I) that is administered (and bound to the surface of the tumour) "weaken" the tumour and thus make the tumour more susceptible to the activity of the immune checkpoint inhibitors that are administered subsequently. As shown in the images in Figures 13, 15, 16 and 17, the methods of treatment disclosed herein increase the susceptibility of the tumour to immune checkpoint inhibitors, as evidenced by the increased presence of immune cells (e.g. T-cells, B-cells and NK cells) in the core of the tumour.

[0013] In certain embodiments, the method comprises the administration of:i) a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide, andii) one or more immune checkpoint inhibitors.

[0014] In certain embodiments, the methods of treatment of a cancer as disclosed herein comprises the administration of multiple doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the one or more checkpoint inhibitors.

[0015] In certain embodiments, the one or more checkpoint inhibitors is administered more than once.

[0016] In certain embodiments, the one or more checkpoint inhibitors is administered twice, three times, four times or five times.

[0017] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered more than once.

[0018] In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered twice, three times, four times or five times.

[0019] In certain embodiments, one cycle of a method of treatment as disclosed herein comprises the administration of:i) one dose of a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally Osubstituted amide, optionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide, andii) one dose of one or more immune checkpoint inhibitors.

[0020] In certain embodiments, the method comprises the administration of more than one cycle of treatment. In certain embodiments, the method comprises the administration of two cycles of treatment, for example, a first dose of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more checkpoint inhibitors is followed by a second dose of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more checkpoint inhibitors. In certain embodiments, the method comprises the administration of three cycles, four cycles or five cycles of treatment.

[0021] In other embodiments, one cycle of a method of treatment comprises the administration of one dose of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and more than one dose of one or more immune checkpoint inhibitors. In certain embodiments, one cycle of a method of treatment comprises the sequential administration of one dose of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and two or more doses of one or more immune checkpoint inhibitors. In certain embodiments, the two or more doses of an immune checkpoint inhibitor are administered after the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments where one cycle of therapy comprises the administration of more than two doses of the immune checkpoint inhibitor, the time between sequential doses may be the same or different. In other embodiments, the doses of the immune checkpoint inhibitors may be the same or different.

[0022] In certain embodiments, the time between administration of a dose of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and the one or more checkpoint inhibitors is about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days. In other embodiments, the administration of any dose of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and the one or more checkpoint inhibitors is about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.

[0023] In certain embodiments, the radionuclide is selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,mIn,177Lu,188Re,211As,212Pb and225Ac. In some embodiments of the methods disclosed herein, the radionuclide complexed with the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is a Cu radionuclide. In some embodiments, the Cu radionuclide is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In some embodiments, the Cu radionuclide is64Cu. In other embodiments, the Cu radionuclide is67Cu.

[0024] The present inventors have found that the administration of a compound of Formula (I) that is complexed with a radionuclide in combination with one or more immune checkpoint inhibitors provides a method for the treatment of a cancer. Specifically, the use of a radionuclide that is chelated by the compound of Formula (I) provides radiation therapy to the subject in need thereof, while the one or more immune checkpoint inhibitors administered prevents the cancer cells present from interacting with the immune cells in the subject. The cancer cells are no longer able to inhibit the subject's immune response and are therefore susceptible. In combination with radiation therapy provided by the compound of Formula (I) chelated with a radionuclide, the present inventors believe that the methods discussed herein employing the combinations now disclosed provide an effective method for the treatment of a cancer. The present inventors also believe that the methods disclosed herein allow for the reduction in the size of a tumour.

[0025] The present invention also provides the use of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:Formula (I)in the manufacture of a medicament for treating cancer, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0026] In another aspect, the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor; and-L- and -L'- where present is a linker moiety.

[0027] In a further aspect, the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer:Formula (I)wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor; and-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0028] In some embodiments, the immune checkpoint inhibitor is an antibody or fragment thereof.

[0029] In some embodiments, the immune checkpoint inhibitor is associated with PD-1, PD-L1 or CTLA-4.

[0030] In other embodiments, the immune checkpoint inhibitor is associated with PD-L2, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, A2AR, TIM-3 or VISTA.

[0031] In certain embodiments, the one or more immune checkpoint inhibitors is an antibody against an immune checkpoint protein.

[0032] In some embodiments, the one or more immune checkpoint inhibitors is an anti-PD-Ll antibody, anti -PD-1 antibody or anti-CTLA-4 antibody.

[0033] In some embodiments, the combination comprises more than one immune checkpoint inhibitor. In other embodiments, the combination comprises an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

[0034] In some embodiments the one or more immune checkpoint inhibitors is selected from the group consisting of durvalumab, avelumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, envafolimab, BMS-936559, CK-301, CS-1001, and SHR-1316.

[0035] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (la):Formula (la)

[0036] In other embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (lb):Formula (lb)

[0037] In some embodiments, the radionuclide complexed with the radionuclide of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is a Cu radionuclide. In some embodiments, the Cu radionuclide is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In some embodiments, the Cu radionuclide is64Cu. In other embodiments, the Cu radionuclide is67Cu.

[0038] In certain embodiments, the cancer is associated with a somatostatin type 2 receptor (SSTR2). In certain embodiments, the cancer is a tumour and expresses SSTR2 on the surface of the tumour.

[0039] In some embodiments, the cancer is selected from the group consisting of epithelial ovarian cancer, ovarian carcinoma, osteosarcoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer,endometrial carcinoma, pancreatic adenocarcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, breast cancer, invasive ductal carcinoma of the breast, oral squamous cell carcinoma, esophageal cancer, renal cell cancer, insulinoma, prostate cancer, neuroendocrine differentiated prostate cancer, pheochromocytoma, adenoid cystic cancer, hepatocellular carcinoma, cervical cancer, small intestine cancer, neuroendocrine tumour, anal cancer, chordoma, desmoid tumour, head and neck cancer, thymus cancer, pancreatic cancer, cholangiocellular carcinoma, esophageal cancer, salivary gland cancer, sarcoma and carcinoma of unknown primary cancer.

[0040] In certain embodiments, the cancer is a lung cancer. In other embodiments, the cancer is a small cell lung cancer (SCLC).

[0041] In another aspect, the present invention provides a kit for treating a cancer, the kit comprising:i) a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally Osubstituted amide, optionally substituted aryl and H ;R and R1where present are each independently a moiety capable of binding to SSTR2;-L- and -L1- where present is a linker moiety; andii) one or more immune checkpoint inhibitors.Brief description of the figures

[0042] By way of example only, one or more embodiments of the present invention are described herein.

[0043] Figure 1. PET / CT images of mice bearing RP116 xenograft tumours at 1 hour (Figure 1A), 4 hours (Figure IB) and 24 hours (Figure 1C) after administration of [64Cu]Cu-Sartate. Accumulation is seen in tumours of the mice and the kidneys. Excretion of the administered compound through the kidneys is observed over time, with signals corresponding to the kidneys reducing in intensity over time. This is corroborated with ex vivo studies. These figures show that Sartate coordinated with a Cu radionuclide targets tumours expressing SSTR2 has good accumulation one hour after administration and rapid kidney clearance.

[0044] Figure 2. Charts showing ex vivo biodistribution of [67Cu]Cu-Sartate (Figure 2A) and [64Cu]Cu-Sartate (Figure 2B) in mice bearing RP116 xenograft tumours, with uptake determined at 1 hour, 4 hours and 24 hours post-injection. Uptake of the67Cu-labelled tracer (Figure 2A) is highest in the kidney after 1 hour, which is consistent with the known excretion patterns of other octreotate peptide tracers. Other than the kidneys, only tumours with SSTR2+ expression showed significant uptake of the tracer, with mean values of 11% ID / g at 1 hour and 9.4% ID / g at 24 hours. The biodistribution of [64Cu]Cu-Sartate (Figure 2B) is consistent with the uptake and retention observed for the same tracer containing67Cu (i.e. in Figure 2A).Biodistribution studies demonstrated high tumour-specific uptake for [64Cu]Cu- and [67Cu]Cu-Sartate in this syngeneic mouse model for small cell lung cancer.

[0045] Figure 3. Representative CD3 staining for T cells (CD3, brown DAB staining with blue haematoxylin counterstain in a tumour from a mouse bearing RP116 xenograft tumours after treatment with saline (Figure 3A), [67Cu]Cu-Sartate (Figure 3B), anti-PDLl and anti-CTLA4 antibodies (Figure 3C) and a combination of anti-PDLl and anti-CTLA4 antibodies with [67Cu]Cu-Sartate (Figure 3D). Staining patterns observed after treatment with either saline (Figure 3A) or [67Cu]Cu-Sartate (Figure 3B) showed that T cells present were largely restricted to the periphery and had limited infiltration into the core of the tumour. In contrast, antibody-treated tumours, i.e. with anti-PDLl and anti-CTLA4 antibodies (Figure 3C) and a combination of anti-PDLl and anti-CTLA4 antibodies with [67Cu]Cu- Sartate (Figure 3D) showed extensive infiltration of CD3+ T cells into the centre of the tumour, as evidenced by staining in the centre of the tumour. These figures show that tumours retained high SSTR2expression after treatment with Sartate, with heterogeneity in tracer uptake by PET imaging potentially determined by tumour vasculature and necrosis. The increase in CD3+ T-cells in the antibody -treated tumours was consistent with infiltration of T-cells towards the core of the tumour after therapy.

[0046] Figure 4. Charts showing mean tumour volume (Figure 4A) and probability of survival (Figure 4B) in mice bearing RP116 xenograft tumours. The mice were treated with either saline + IgGl isotype antibody + IgG2b isotype antibody (in blue), 30 MBq [67Cu]Cu-Sartate (in red), saline and anti-PD-Ll and anti-CTLA4 immunotherapy (in purple) or 30 MBq [67CU]CU-SARTATE + anti-PD-Ll + anti-CTLA4 immunotherapy (in green). The treatment phase for each mouse consisted of 3 doses of the specified treatment on days 1, 4 and 8. Figure 4A shows mean tumour volume (± SEM) for each group shown until experimental endpoint according to protocol, i.e. until the first mouse reaches end point in each group. Figure 4B shows survival (according to Kaplan-Meier) or ethical endpoint in each treatment group. Antibodies were delivered at a dose of 200 pg in a single intraperitoneal injection per mouse (n = 10 / group), while saline and [67Cu]Cu-Sartate were delivered by IV. These figures show that the administration of [67Cu]Cu-Sartate combined with immune checkpoint inhibitor therapy (i.e. immunotherapy) increased survival and inhibited tumour growth, when compared with single-treatment control groups.

[0047] Figure 5. Tumours from the four biomarker groups differed in their shape and size at the time of harvest, displaying varying levels of necrosis and haemorrhage. The mice were treated with either saline alone (“saline”), [67Cu]Cu-Sartate (“Sartate”), saline and anti-PD-Ll and anti-CTLA4 immunotherapy (“Antibody”) or [67Cu]Cu-Sartate + anti-PD-Ll + anti-CTLA4 immunotherapy (“Combination”). The elevation in CD3+ T cells (and CD28+ activated T cells) in the antibody treated tumours was evident in the overall tumour levels, with B and NK cells showing only minimal levels in all groups.

[0048] Figure 6. PET / CT images of 5 RP-116 tumour-bearing mice at 24 h after injection of [64Cu]Cu-Sartate. Tumours indicated with white arrow.

[0049] Figure 7. Graph showing the mean ± SEM of [67Cu]Cu-Sartate and [64Cu]Cu-Sartate tracer uptake (percent injected dose per gram, %ID / g) for ex vivo biodistribution in RP116 tumour-bearing mice at indicated times after tracer injection. [64Cu]Cu-Sartate biodistributiondata is indicated by the last two columns for each tissue (black border); 1 h data was not available. The biodistribution data shown here is re-plotted from the biodistribution data shown in Figures 2A and 2B for [64Cu]Cu-Sartate and [67Cu]Cu-Sartate.

[0050] Figure 8: Cherenkov luminescence ex vivo imaging of RP116 tumours harvested 1 h postinjection with [67Cu]Cu-Sartate. This image shows the heterogeneity of tumours harvested from various mice. The heterogenous nature of the uptake as observed likely reflects a combination of the uptake of [67Cu]Cu-Sartate itself, vascularisation of the tumour and presence of necrosis within the tumour.

[0051] Figure 9. Staining of a control tumour (i.e. treated with saline only) showing necrosis and haemorrhage with (A) haematoxylin and eosin (H&E), or (B) Ki-67, brown DAB staining with blue haematoxylin counterstain. Differences in histology of tumours observed was most evident in the Ki-67 staining of proliferation, where viable proliferating tumour cells formed both large uninterrupted bulk or discrete islands within tumour stroma or areas of necrosis.

[0052] Figure 10. Images showing cell staining with Ki-67 (brown DAB staining with blue haematoxylin counterstaining) of RP116 tumours treated with [67Cu]Cu-Sartate showing (A) islands of proliferating tumour cells and (B) a large area of proliferating tumour cells. These images show solid tumour masses surrounded by recipient mouse stroma, where the tumours have increasing necrosis at the core. Areas of internal haemorrhage / necrosis left islands of surviving / proliferating tumour cells, while peripheral areas had large areas of proliferating tumour bulk.

[0053] Figure 11. Graph comparing levels of Ki-67 staining as a percentage of tumour area stained for mice that were treated with either saline alone (“saline”), [67Cu]Cu-Sartate (“S ART ATE”), saline and anti-PD-Ll and anti-CTLA4 immunotherapy (“Antibody”) or [67Cu]Cu-Sartate + anti-PD-Ll + anti-CTLA4 immunotherapy (“Combination”), calculated by Ki-67 positive nuclear area divided by total nuclear area. Individual tumours are shown with points and the mean ± SEM shown with bars and error bars. The single tumour in the combination therapy group is shown for comparison only. The percentage of cell area stained by Ki-67 was similar across the various treatment groups. Proliferation was heterogeneous in each tumour with considerable diversity in tumour morphology and distribution of proliferating tumour regions.

[0054] Figure 12. Cell staining for SSTR2 (brown DAB staining with blue haematoxylin counterstain) in RP166 tumours treated with (A) with [67Cu]Cu-Sartate only, or (B) dualantibody therapy (i.e. anti-PDLl and anti-CTLA4). In each case, the tumours stained retained strong SSTR2 staining across the whole tumour bulk, which correspond with areas of actively proliferating tumour. These images also indicate no loss of target expression.

[0055] Figure 13. Cell staining for CD3+ T-cells (brown DAB staining with blue haematoxylin counterstain) in (A) a saline-treated control tumour, (B) a [67Cu]Cu-Sartate-treated tumour, or (C) a dual-antibody (i.e. anti-PD-Ll and anti-CTLA-4) treated tumour. Staining of the control tumour in (A) showed poor infiltration of the T-cells, while the tumour treated with [67Cu]Cu-Sartate only in (B) showed more (but still limited) infiltration of T cells into the core of the tumour. Where T-cell infiltration was visualised, this was largely restricted to the periphery of the tumour with little infiltration towards the core. Staining of the tumour treated with a dual-antibody approach in (C), i.e. treatment with both anti-PD-Ll and anti-CTLA-4 antibodies, showed extensive infiltration of the tumour with T-cells. While not shown here, treatment of a tumour with combination therapy (i.e. treatment with a dual antibody and [67Cu]Cu-Sartate) also resulted in extensive infiltration of CD3+ T-cells into the core of the tumour mass.

[0056] Figure 14. Graph showing the correlation of CD3+ staining with CD28 staining in tumour sections where the tumour was treated with either saline only, [67Cu]Cu-Sartate (SARTATE) only, combined anti-PD-Ll and anti-CTLA-4 antibodies (aPDLl / aCTLA4) or a combination of [67Cu]Cu-Sartate and dual-antibody treatment (Combo). Staining for CD28 (a marker of T-cell activation) correlated with staining for CD3+ T-cells, where staining associated with CD28 was physically co-located with staining associated with CD3+ T-cells. Tumours having a high percentage of CD3+ cell staining also showed increased staining for CD28, thus highlighting the same cell population.

[0057] Figure 15. Staining (brown DAB staining with blue haematoxylin counterstain) of tumour cells treated with a dual antibody approach (i.e. anti-PD-Ll and anti-CTLA-4 antibodies) for (A) CD3+ T-cells only, and serial staining for (B) both CD3+ and CD28 T-cells, (C) both CD3+ and B220+ B cells, and (D) both CD3+ and NK cells (NCR1 staining). Regions in (A) identified as being associated with CD3+ T-cell expression correlated with the presence of CD28 T-cells, as shown in (B). These images co-identified infiltrating T-cells,which are particular abundant in the dual-antibody treated cells, as well as areas of high local density that appear to correspond with tumour architecture / vasculature. Serial sections in (C) and (D) show the simultaneous co-infiltration of B-cells (C) and NK cells (D) to areas of T-cell infiltration, however co-infiltration of the B-cells and NK cells is at a lower frequency when compared to CD28 cells (as shown in (B)).

[0058] Figure 16. Staining for CD3+ T-cells (brown DAB staining with blue haematoxylin counterstain) in cells treated with (A) saline only, (B) [67Cu]Cu-Sartate, and (C) dual antibody (anti-PD-Ll and anti-CTLA-4 antibodies). These images show that CD3+ T-cells show a tendency to be enriched at the periphery of the tumour, while dual antibody treatment results in the increased invasion of the T-cells into the bulk of the tumour.

[0059] Figure 17. Cell staining for CD3+ T-cells (brown DAB staining with blue haematoxylin counterstain) in a tumour treated with combination therapy (i.e. dual antibody and [67Cu]Cu-Sartate). Similar to the dual antibody treated sections in Figure 16, treatment with a combination therapy results in increased invasion of the CD3+ T-cells into the bulk of the tumour, meaning that treatment with both the compound of Formula (I) complexed with a radionuclide and immune checkpoint inhibitors allows for better infiltration and therefore treatment of the tumour.Detailed description

[0060] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. For the purposes of the present invention, the following terms are defined below.

[0061] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0062] The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In general, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of up to 10% (e.g. 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1%).

[0063] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0064] As discussed herein, the present invention relates to combinations and uses thereof comprising one or more immune checkpoint inhibitors and a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2;-L- and -L'- where present is a linker moiety;wherein the compound is complexed with a radionuclide.

[0065] The compound of Formula (I) comprises a macrocyclic fragment (i.e. 5-[[8-amino-3,6,10,13,16,19-hexaazabicyclo-[6.6.6]eico-l-yl)amino]-5-oxo-pentanyl), which is also known as a sarcophagine. The terminal position on the sarcophagine of Formula (I) is substituted with the group X. Where the group X in the compound of Formula (I) is a methyl group (i.e. where the macrocyclic sarcophagine comprises a terminal methyl group), this fragment may be referred to as "MeCOSar".

[0066] Alternatively, the group X may be the group H , such that the compound of Formula (I) comprises the group R and R', meaning that the compound of Formula (I) comprises two moieties (R and R') that are capable of binding to SSTR2.

[0067] The compound of Formula (I) also comprises a linker L and, where present, L'. The linker may be selected fromwhere n, m, a, b and c are integers from 1 to 10; andthe wavy lines indicate the points of attachment to the compound of Formula (I) and the moiety capable of binding to SSTR2.

[0068] In certain embodiments, the linker L is:

[0069] "Alkyl" refers to a saturated monovalent hydrocarbon radical which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms or 1 to 9 carbon atoms (i.e., C1-C4 alkyl). Examples of such alkyl groups include methyl, ethyl, w-propyl, Ao-propyl, / / -butyl, Ao-butyl, w-hexyl, and the like

[0070] "Alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms, where one hydrogen atom has been removed from a carbon atom in the alkyl group. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.

[0071] "Alkenylene" refers to a divalent hydrocarbon radical with at least one site of unsaturation, z.e., a carbon-carbon, sp2double bond, which may be straight chained or branchedand preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 carbon to carbon double bond. An alkenylene radical includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include ethenyl (-CH=CH-), / / -propenyl (-CH2CH=CH-), Ao-propenyl (-C(CH3)=CH-), but-2-enyl (-CH2CH=CHCH2-), and the like.

[0072] "Alkynylene" refers to a linear or branched divalent hydrocarbon radical with at least one site of unsaturation, z.e., a carbon-carbon sp triple bond, preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 carbon to carbon triple bond. Examples of alkynyl groups include ethynyl (-C=C-), propargyl (-CH2C=C-), pent-2-ynyl (-CH2C=CCH2-CH2-), and the like.

[0073] "Aryl" refers to a group or part of a group denoting (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Typically an aryl group is a Ce-Cis aryl group.

[0074] "Arylene" refers to divalent aryl groups preferably having from 5 to 12 atoms in the aryl ring, where two hydrogen atoms have been removed from two different carbon atoms in the aryl ring. An example of an arylene group includes a benzylene group, i.e. a -CeFL- group.

[0075] The term “amino acid” refers to a molecule which contains both an amino and a carboxyl functional group. The amino acid may be a natural or unnatural amino and may also be in equilibrium with its zwitterionic form. The amino acid may contain modifications at either the amino and / or carboxyl terminus, or may contain a free amino group or carboxyl group. Further modification of the amino acid side chain or additional substitutions at other parts of the amino acid are also contemplated.

[0076] Naturally occurring amino acids are the L- or D-form of the twenty amino acids commonly found in nature. These are glycine (Gly, G), alanine (Ala, A), valine (Vai, V), leucine (Leu, L), isoleucine (He, I), methionine (Met, M), proline (Pro, P), phenylalanine (Phe,F), tryptophan (Trp, W), serine (Ser, S), threonine (Thr, T), asparagine (Asn, N), glutamine (Gin, Q), tyrosine (Tyr, Y), cysteine (Cys, C), lysine (Lys, K), arginine (Arg, R), histidine (His, H), aspartic acid (Asp, D), and glutamic acid (Glu, E).

[0077] In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like, and may also include a bond to a solid support material, (for example, substituted onto a polymer resin). For instance, an "optionally substituted amino" group may include amino acid and peptide residues.

[0078] In an embodiment the "optionally substituted" group is selected from halo (e.g., chloro, fluoro or bromo), -CN, -NO2, -CO2H, -CO2Ci-6alkyl, -CONH2, -CONH(Ci-6alkyl), -CONH(Ci-ealkyl)2, -OH, hydroxyCi-ealkyl, Ci-ealkoxy, Ci-ealkyl, Ci-eacyl, carboxyCi-ealkyl, acetyl, trifluoromethyl, benzyloxy, phenyl, phenoxy, -NH2, -NH(Ci-6alkyl) or -N(Ci-6alkyl)2.

[0079] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3, CH2CH3, OH, 0CH3, CF3, 0CF3, NO2, NH2, COOH, COOCH3 and CN.

[0080] The compounds of Formula (I) or the pharmaceutically acceptable salts or solvates thereof contain a nitrogen-containing macrocycle, which is capable of chelating metal ions to form a complex. The macrocycle is a 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane and may be referred to as a "sarcophagine". The sarcophagines of Formula (I), or the salts or solvates thereof contain six nitrogen atoms, where one or more of the nitrogen atoms may be protected with a suitable protecting group.

[0081] As used herein, the term "complex" refers to a moiety comprising a ligand and a metal coordinated with a suitable part of the ligand. For example, the compounds of Formula (I) as disclosed herein acts as a ligand for a metal ion, where the metal ion is coordinated to the ligand via the sarcophagine.

[0082] In some embodiments, the compound of Formula (I), or the salt or solvate thereof, is complexed with a radionuclide selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,inIn,177Lu,188Re,211As,212Pb and225Ac. The present compounds have been found to be particularly useful in binding copper ions. In some embodiments, the metal ion is a radionuclide selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu. In some embodiments, the radionuclide is60Cu. In some , the radionuclide is61Cu. In some embodiments, the radionuclide is62Cu. In some embodiments, the radionuclide is64Cu. In some embodiments, the radionuclide is67Cu.o

[0083] In further embodiments, X is H and the compound of Formula (I) or the salt or solvate thereof comprises at least two linkers and two moieties capable of binding to a biological target, where L' and R’ are as defined above.

[0084] In certain embodiments, the compound of Formula (I) comprises a linker L and L'. The linker may be the same or different and is selected from:where n, m, a, b and c are integers from 1 to 10; andthe wavy lines indicate the points of attachment to the compound of Formula (I) and the moiety capable of binding to SSTR2.

[0085] In certain embodiments, the linker L' is:

[0086] In some embodiments, both L and L' are present in the compound of Formula (I) and may be the same or different. In certain embodiments, the linkers L and L' are:

[0087] The present inventors have found that compounds of Formula (I) show a particular affinity for a biological target. Furthermore, the presence of the linker provides a complex that is capable of administration to a subject and subsequent localization of the radionuclide at sites expressing the biological target, i.e. in this case, SSTR2. The compounds of the present invention also have the requisite stability with respect to the radionuclide. For example, the sarcophagine present in the compound is capable of chelating a radionuclide such that the radionuclide remains coordinated upon administration to a subject and subsequent binding at the target site. Since the radionuclide remains coordinated and localized to the target site due to binding of the compound as a whole, radiation damage at other sites (e.g., healthy tissue) is minimized.

[0088] Compounds of Formula (I) comprise one or two moieties "R" and "R"', where each are capable of binding to SSTR2.

[0089] The compounds of Formula (I) of the present invention, or the salts or solvates thereof, may contain a single moiety capable of binding to a SSTR2 receptor or they may be multimeric constructs, comprising two moieties capable of binding to a SSTR2 receptor. This is desirable in some circumstances, as a multimeric construct may possess higher affinity for a target than its monomeric equivalent. This is in part due to an increase in the local concentration of the targeting group, allowing it to compete more effectively with endogenous ligands. In addition, in circumstances where there is sufficient length between two or more targeting groups within a multimeric construct, cooperative binding is possible, and two or more targeting groups may bind to two or more targets. Indeed, it has been observed that in vivo, a multimeric construct often demonstrates higher target tissue accumulation than its monomeric equivalent. Without wishing to be bound by theory, it is thought that this is due to the higher affinity of the multimeric construct for the target receptor than that of the monomeric construct. Furthermore,the multimeric construct has a higher molecular weight than the monomeric construct and therefore prolonged bioavailability (as it is more resistant to degradation in the physiological environment). This can result in increased accumulation and retention in target tissue.

[0090] In the compounds of the present invention, the moiety capable of binding to a biological target is a moiety that is capable of binding to the somatostatin type 2 receptor (SSTR2). Accordingly, in one embodiment the present invention provides a method of treating cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0091] In another embodiment the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2; and-L- and -L'- where present is a linker moiety.

[0092] In a further embodiment, the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancerFormula (I)wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2; and-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0093] Somatostatin type 2 receptors (SSTR2) are G-protein coupled receptors that are expressed on the surface of some cancerous tumours. Binding at these receptors may inhibitgrowth of the tumour, while delivery of radiation by exposure of the tumour to a radionuclide may further inhibit growth of the tumour.

[0094] Targeting SSTR2 is especially useful in the treatment of cancers that over express the receptor including, but not limited to, a cancer selected from the group consisting of pituitary tumours, neuroendocrine tumours, renal cell cancer, lung cancer, breast cancer, meningioma, glioma, neuroblastoma, colorectal cancer, pheochromocytoma, medullary thyroid cancer, ovarian cancer, head and / or neck cancer, gastric cancer, adrenal cancer, brain cancer, and a hematologic malignancy such as lymphoma or leukaemia. In particular embodiments, the cancer is a neuroendocrine tumour, such as a carcinoid tumour in the lung, appendix, digestive tract, prostate, thymus or rectum or a pancreatic neuroendocrine tumour. In further embodiments, the cancer is a neuroendocrine tumour such as a gastrinoma, insulinoma or nonfunctioning islet cell tumour.

[0095] A number of suitable moi eties that bind to SSTR2 are known in the art and include, but are not limited to:-octreotate.

[0096] In one embodiment, the moiety capable of binding to SSTR2 is selected from octreotide, lanreotide, pasireotide, octreotate, Tyr-3-octreotate and combinations thereof. In a preferred embodiment, the moiety capable of binding to SSTR2 is Tyr-3 -octreotate, i.e. D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH.

[0097] In certain embodiments, the compound of Formula (I) has the structure of Formula (la):Formula (la)

[0098] In the compound of Formula (la), the moiety that binds to SSTR2 is a Tyr-3 -octreotate. The compound of Formula (la) is also known as Sartate, SarTATE or ucasreotide dasaroxetan. In the compound of Formula (la), X is a methyl (i.e. CEE) group. As seen in the structure depicted above, the linker in the compound of Formula (la) comprises an alkylene group. The linker also comprises a carbonyl group. As seen in the structure of Formula (la), the group corresponding to the linker L has the following structure:

[0099] In other embodiments, the compound of Formula (I) has the structure of Formula (lb):Formula (lb)

[0100] The compound of Formula (lb) contains two moieties that bind to SSTR2, where each moiety is the same and is a Tyr-3-octreotate moiety. As seen above, the linker joining each of the moieties that bind SSTR2 to the remainder of the compound is the same in each case. The compound of Formula (lb) is also known as bis-Sartate.

[0101] Compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, comprising a moiety that binds to SSTR2 may be prepared, for example, via a coupling reaction between a sarcophagine ligand and the moiety that binds to SSTR2, where the macrocyclic sarcophagine and the moiety that binds to SSTR2 are synthesised individually prior to coupling. The sarcophagine of Formula (I) is itself derived from an amino-capped macrocyclic ligand coupled with an aliphatic carboxylate group. The synthetic route to access the compound of Formula (I), and the component sarcophagine and octreotate fragments, has been previously disclosed in Dalton Trans., 2015, 43, 1386.

[0102] Various protection and deprotection steps may be employed in the synthesis, where the conditions for each step are compatible with the remainder of the compound. An exemplary synthetic scheme is provided in Scheme 1:Scheme 1. Synthesis of compounds of Formula (I).

[0103] Scheme 1 describes a synthesis of a compound of Formula (I) where the sarcophagine is coupled with two moieties of the linker-octreotate group at the same time. The reaction may be performed under standard peptide coupling conditions with a suitable peptide-coupling reagent and a base, where the linker-octreotate group contains the amine functional group and the metal chelator contains the carboxylic acid functional group that will participate in the coupling reaction.

[0104] Alternatively, the compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, comprising a moiety that binds to SSTR2 may be synthesised according to Scheme 2:Scheme 2: Synthesis of compounds of Formula (I).

[0105] Scheme 2 also depicts a particular embodiment of a process as described herein. Two moieties of the linker-octreotate group are coupled with a sarcophagine, however in this synthetic route, the amine group that participates in the coupling reaction is found on sarcophagine, while the carboxylic acid group is found on the linker-octreotate group. The reaction may also be performed under standard peptide coupling reaction conditions with a peptide coupling reagent and a base.

[0106] Exemplary compounds of Formula (I) comprising one or two moieties that bind to SSTR2 include:

[0107] In further embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof comprising two moieties capable of binding to a biological target, wherein each moiety capable of binding to a biological target is capable of binding to a different target. In one embodiment, the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is represented by the Formula (II):Formula (II)wherein:each m is independently an integer from 1 to 10;Y is a linker having the formula, where n is an integer from 1 to 10;R is a moiety capable of binding to SSTR2; andZ is an albumin-binding group.

[0108] Accordingly, in one embodiment the present invention provides a method of treating cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (II):Formula (II)wherein:each m is independently an integer from 1 to 10;Y is a linker having the formula, where n is an integer from 1 to 10;R is a moiety capable of binding to SSTR2; andZ is an albumin-binding group; andwherein the compound is complexed with a radionuclide.

[0109] In another embodiment the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (II):Formula (II)wherein:each m is independently an integer from 1 to 10;Y is a linker having the formula, where n is an integer from 1 to 10;R is a moiety capable of binding to sSSTR2; andZ is an albumin-binding group.

[0110] In a further embodiment, the present invention provides a combination comprising one or more immune checkpoint inhibitors and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancerFormula (II)wherein:each m is independently an integer from 1 to 10;Y is a linker having the formula, where n is an integer from 1 to 10;R is a moiety capable of binding to SSTR2; andZ is an albumin-binding group; andwherein the compound is complexed with a radionuclide.[oni] The present inventors have found that compounds of Formula (I) containing a group capable of binding to serum albumin, i.e., Z in a compound of Formula (II), can lead to better accumulation of the compound at the biological sites targeted by the group R of the compound. The albumin-binding group may interact with serum albumin through non-covalent binding or covalent binding. Without wishing to be bound by theory, the present inventors believe that the presence of the albumin-binding group facilitates increased binding of compounds of Formula (II) to the desired target site through the group R of the compound by slowing the elimination of the compound from circulation after administration. Since the time over which the compounds persist in the circulation is increased (i.e., increased residence time due to reduced renal filtration and excretion), the overall effect is that compounds of Formula (II) show binding and uptake at the desired target site. When compared to analogous compounds without the albumin-binding group, the binding of the compounds of the present invention is increased. Where a greater proportion of the administered dose of the compound is able to bind to thedesired biological target, this may allow for a smaller dose or amount to be administered, which improves overall efficacy. The presence of an albumin-binding group may also permit administration of a single dose of the compound, rather than repeat dosing (i.e., administration of multiple doses) to ensure sufficient binding of the compound at the target site for the purposes of imaging or therapy.

[0112] In some embodiments, Z is an albumin-binding group of Formula (ii):wherein:R1is an optionally substituted C1-C12 alkyl group, optionally substituted C1-C20 alkoxy group, halogen or CN group; andR2is an optionally substituted C2-C16 alkylene group, wherein one or more alkylene units in the alkylene group may be replaced with a group selected from a urea, thiourea, amine, amide, carbonyl heteroatom or arylene group, wherein the arylene group may be optionally substituted.

[0113] In some embodiments, the group Z of Formula (II) has one of the following structures:

[0114] In one embodiment, Z is a C10-C22 alkyl group. In another embodiment, Z is a C10-C22 alkyl group where one or more alkylene units is replaced with a carbonyl group. In a further embodiment, Z is a C10-C22 alkyl group where one or more alkylene units is replaced with a carboxylic acid group. In another embodiment, Z is a C10-C22 alkyl group where one or more alkylene units is replaced with a polyethylene oxide group. In yet another embodiment, Z is a C10-C22 alkyl group where one or more alkylene groups is replaced with an amide group. In one embodiment, Z is a C10-C22 alkyl group having a terminal carboxylic acid group.

[0115] Further embodiments of Z are depicted below:

[0116] In one embodiment, Z is a derivative of iodophenylbutyric acid. In another embodiment, Z has the following structure:

[0117] Exemplary compounds of Formula (II) include:

[0118] Where the compound comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the compound may be prepared and / or isolated as a pharmaceutically acceptable salt.

[0119] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the above-identified compounds and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic and arylsulfonic acids. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of a compound with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting a compound with the appropriate base via a variety of known methods.

[0120] The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecyl sulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemi sulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3 -phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds,agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0121] The compounds of the present invention, or the pharmaceutically acceptable salts or solvates thereof are administered to a subject in need thereof in combination with one or more immune checkpoint inhibitors. The combination may allow for separate, sequential or simultaneous administration of a compound of Formula (I) or (II) as hereinbefore described and the one or more immune checkpoint inhibitors. The combination may be provided in the form of a pharmaceutical composition.

[0122] The term "combination" as used herein refers to a composition or kit of parts where the combination of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and one or more immune checkpoint inhibitors can be dosed dependently or independently, or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously or at different time points. The combination partners can then be administered, for example, simultaneously or chronologically staggered, that is, at different time points and with equal or different time intervals for any part of the kit of parts. The ratio of the total amounts of the combination partners to be administered in the combination can be varied, for example, in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient, whereby different needs can be due to age, sex, body weight, etc. of the patients.

[0123] As used herein, the term "immune checkpoint inhibitor" refers to a compound that modulates the function of the immune system of a subject. Cancer cells are able to proliferate since they have the ability to bypass a patient’s immune system at various “checkpoints” by binding to and deactivating immune cells that would otherwise target and destroy cancer cells. In the context of cancer therapy, immune checkpoint inhibitors and their administration in order to inhibit the immunosuppressive effect that a cancer cell may have on the immune system of a patient are well known. Immune checkpoint inhibitors are often proteins that bind to either the tumour cell or a cell of the immune system in order to prevent the deactivation of the patient’s immune system. Conversely, an immune checkpoint inhibitor may be considered to enhance the immune response generated in the presence of an antigen, i.e., a cancer cell. Immune checkpoint proteins include PD-1 (also known as CD279), PD-L1 (also known as CD274), CTLA-4, A2AR, B7-H3 (also known as CD276), B7-H4 (also known as VTCN1),BTLA (also known as CD272), IDO, KIR, LAG3, TIM-3 and VISTA. Immune checkpoint inhibitors may be specific for a particular immune checkpoint protein, i.e., anti-immune checkpoint antibodies. Such antibodies include anti-CTLA4 antibodies (e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab, pidilizumab, tislelizumab, and RG7446), and anti-PD-Ll antibodies (e.g., BMS-93655, MPDL3280A, MSBOO10718C and MED14736). Preferred immune checkpoint inhibitors are antibodies that bind to a specific immune checkpoint protein, whether the protein is the immune checkpoint protein itself, a receptor thereof or a ligand thereof.

[0124] In some embodiments, the one or more immune checkpoint inhibitor is an antibody or fragment thereof. Suitable antibodies include an anti-PDl antibody or fragment thereof, an anti-PDLl antibody or fragment thereof and an anti-CTLA4 antibody or fragment thereof. Accordingly, in some embodiments, the checkpoint inhibitor is associated with PD-1, PD-L1 or CTLA-4.

[0125] In some embodiments, the immune checkpoint inhibitor is associated with PD-L1. In some embodiments the immune checkpoint inhibitor is associated with CTLA-4. In some embodiments, more than one immune checkpoint inhibitor is administered as part of the methods disclosed herein or included as part of the combinations disclosed herein. In certain embodiments, two immune checkpoint inhibitors are used, where one inhibitor is associated with PD-L1 and one inhibitor is associated with CTLA-4. In certain embodiments, one inhibitor is an anti-PD-Ll inhibitor, and one inhibitor is an anti-CTLA-4 inhibitor.

[0126] In certain embodiments, the immune checkpoint inhibitor is an anti-PD-Ll antibody. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. In other embodiments, more than one immune checkpoint inhibitor is used in the combinations disclosed herein. In certain embodiments, the immune checkpoint inhibitors used are an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

[0127] In other embodiments, the checkpoint inhibitor is associated with PD-L2, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, A2AR, TIM-3 or VISTA.

[0128] In certain embodiments, the one or more immune checkpoint inhibitor is an antibody against an immune checkpoint protein.

[0129] In some embodiments, the one or more immune checkpoint inhibitor is selected from the group consisting of durvalumab, avelumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, cemiplimab, envafolimab, BMS-936559, CK-301, CS-1001, and SHR-1316.

[0130] The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found at least one container having a unit dosage of the agent(s). Conveniently, in the kits, single dosages can be provided in sterile vials so that the clinician can employ the vials directly, where the vials will have the desired amount and concentration of compound and radio nucleotide which may be admixed prior to use. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, imaging agents or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0131] The compounds are typically used in the form of pharmaceutical compositions, which are formulated depending on the desired mode of administration. The compositions are prepared in manners well known in the art.

[0132] As used herein, the term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.

[0133] While the combinations as hereinbefore described may be the sole active ingredients administered to the subject, the administration of other active ingredient(s) with the combination is within the scope of the invention. For example, the conjugate could be administered with one or more additional therapeutic agents.

[0134] Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0135] These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.

[0136] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0137] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0138] Methods disclosed herein comprise administration of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more immune checkpoint inhibitors. Administration of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and the one or more immune checkpoint inhibitor may be separate, sequential or simultaneous administration. In one embodiment, the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof is administered to the subject first, followed by the subsequent administration of one or more immune checkpoint inhibitor. In this case, the present inventors believe that the initial administration of the compound of Formula (I) results in the weakening of the targeted cancer cell. In cases where the cancer cells were unresponsive to initial therapy by administration of an immune checkpoint inhibitor, i.e., where the cancer cells are able to deactivate the immune checkpoints and therefore evade detection, weakening of the cancer cell as a result of treatment with a compound of Formula (I) may result in the cancer cell becoming susceptible to therapy by immune checkpoint inhibitors. Without wishing to be bound by theory, the present inventors believe that a method for the treatment of a cancer in a subject in need thereof may comprise the administration of a compound of Formula (I), followed by the subsequent administration of one or more immune checkpoint inhibitor.

[0139] As used herein the terms "treating", "treatment", “preventing”, “prevention" and grammatical equivalents refer to any and all uses which remedy the stated disorder, prevent, retard or delay the establishment of the disease, or otherwise prevent, hinder, retard, or reverse the progression of the disease. Thus, the terms "treating" and “preventing” and the like are to be considered in their broadest context. For example, treatment does not necessarily imply that a patient is treated until total recovery. Where the disease displays or is characterized by multiple symptoms, the treatment or prevention need not necessarily remedy, prevent, hinder, retard, or reverse all of said symptoms, but may prevent, hinder, retard, or reverse one or more of said symptoms.

[0140] As used herein, the term “cancer” broadly encompasses neoplastic diseases characterised by abnormal cell growth with the potential to invade or spread to other parts of the body. The cancer may be benign, which does not spread to other parts of the body. The cancer may be malignant, meaning that the cancer cells can spread through the circulatory system or lymphatic system. The term as used herein includes all malignant, i.e., cancerous, disease states. The cancer may be present as a tumour. Accordingly, the term "tumour" is usedgenerally to define any malignant cancerous or pre-cancerous cell growth, and may include leukemias, but is particularly directed to solid tumours or carcinomas such as melanomas, colon, lung, ovarian, skin, breast, pancreas, pharynx, brain, prostate, CNS, and renal cancers (as well as other cancers).

[0141] The methods disclosed herein relate to the treatment of a cancer. In certain embodiments, the cancer is associated with somatostatin type-2 receptor (SSTR2). This means that the cancer is characterised by the expression of the SSTR2 receptor, where the receptor is expressed at a level or concentration that is higher than in a normal subject that is not suffering from the cancer.

[0142] In some embodiments, the cancer is selected from the group consisting of epithelial ovarian cancer, ovarian carcinoma, osteosarcoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, non-small cell lung cancer, gastric cancer, endometrial carcinoma, pancreatic adenocarcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, breast cancer, invasive ductal carcinoma of the breast, oral squamous cell carcinoma, esophageal cancer, renal cell cancer, insulinoma, prostate cancer, neuroendocrine differentiated prostate cancer, pheochromocytoma, adenoid cystic cancer, hepatocellular carcinoma, cervical cancer, small intestine cancer, neuroendocrine tumour, anal cancer, chordoma, desmoid tumour, head and neck cancer, thymus cancer, pancreatic cancer, cholangiocellular carcinoma, esophageal cancer, salivary gland cancer, sarcoma and carcinoma of unknown primary cancer.

[0143] As used herein, the term "subject" refers to mammals and includes humans, primates, livestock animals (e.g., sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), performance and show animals (e.g., horses, livestock, dogs, cats), companion animals (e.g., dogs, cats) and captive wild animals. Preferably, the mammal is human or a laboratory test animal. Even more preferably, the mammal is a human.

[0144] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. For the purposes of radioimaging, an effective amount is sufficient for an image showing the localisation of the compound of Formula (I) administered to the subject, owing to the detection of the products of decay from the radionuclide that is complexed with the compound. For the purposes of treatment, an effectiveamount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow and / or delay the progression of the cancer.

[0145] In certain embodiments, the one or more immune checkpoint inhibitor is an anti-PDl antibody or fragment thereof. In other embodiments, the one or more immune checkpoint inhibitor is an anti-PD-Ll antibody or fragment thereof. In other embodiments, the one or more immune checkpoint inhibitor is an anti-CTLA4 antibody or fragment thereof.

[0146] In some embodiments, the one or more immune checkpoint inhibitors are an anti-PDl antibody or fragment thereof and an anti-CTLA4 antibody or fragment thereof. In another embodiment, the one or more immune checkpoint inhibitors are an anti-PD-Ll antibody or fragment thereof an anti-CTLA4 antibody or fragment thereof.

[0147] In view of the results now provided, the present inventors have demonstrated the effect obtained from the administration of a combination of a compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors in the treatment of a cancer. As shown in Figure 1, administration of an immune checkpoint inhibitor (i.e. an anti-PD1 / PDL1 antibody or anti-CTLA4 antibody) did not limit tumour growth. When an immune checkpoint inhibitor was administered after a compound of Formula (I) complexed with a radionuclide, the combination of these compounds increased the susceptibility of the cancer cells to treatment and improved overall survival when compared to administration of an immune checkpoint inhibitor alone. The present inventors have demonstrated that the administration of a combination of the compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors, the present invention may not only result in a beneficial effect, but an additive or even synergistic therapeutic effect may be provided.

[0148] In accordance with the present invention, the combination of a compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors may be administered in a method where each component is administered simultaneously or sequentially in any order. In other embodiments, the combination of a compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors may be administered in a method where each component is administered concurrently. The dosages of the compound of Formula (I) complexed with a radionuclide and the one or more immune checkpoint inhibitors may be administered daily, in intermittent dosages or in a cyclicalregimen. The combination may be administered jointly in therapeutically effective amounts or in generally synergistically effective amounts. In addition to any synergistic therapeutic effect, the administration of a combination as disclosed herein may inhibit, alleviate or ameliorate one or more symptoms, or delay the progression of a cancer. Other effects that may be attributed to the combinations now disclosed may include fewer adverse side effects, an improved quality of life and decreased morbidity when compared to the administration of a single component of the combination.

[0149] The terms “administration concurrently”, “administering concurrently” or “administered concurrently” and the like refer to the administration of a single composition containing two or more actives, or the administration of each active as separate compositions and / or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such actives are administered as a single composition. By “simultaneously” is meant that the active agents are administered at substantially the same time, and desirably together in the same formulation. By “contemporaneously” it is meant that the active agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and preferably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term “same site” includes the exact location, but can be within about 0.5 to about 15 centimeters, preferably from within about 0.5 to about 5 centimeters, where appropriate.

[0150] In certain embodiments, the compound of Formula (I) complexed with a radionuclide is administered before the administration of one or more immune checkpoint inhibitors. In other embodiments, the compound of Formula (I) complexed with a radionuclide is administered after the administration of one or more immune checkpoint inhibitors. In some embodiments, the methods disclosed herein comprise the administration of one or more cycles of therapy, wherein each cycle comprises the administration of a compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors. In other embodiments, each cycle of therapy comprises the administration of one dose of a compoundof Formula (I) complexed with a radionuclide and more than one dose of one or more immune checkpoint inhibitors.

[0151] In certain embodiments, the methods disclosed herein comprise the administration of 1, 2, 3, 4, 5, 6, 7 or 8 cycles of therapy, where each cycle is separated by a time of one or more days, one or more weeks or one or more months. In certain embodiments, the methods disclosed herein comprise the administration of more than one cycle of therapy, where the time between each cycle of therapy is 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. In certain embodiments, the time between the administration of a compound of Formula (I) complexed with a radionuclide and one or more immune checkpoint inhibitors is 1, 2, 3, 4, 5, 6 or 7 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.

[0152] In some embodiments, one cycle of therapy comprises the administration of a compound of Formula (I) complexed with a radionuclide followed by the administration of more than one dose of one or more immune checkpoint inhibitors. In certain embodiments, one cycle of therapy comprises the administration of two doses of one or more immune checkpoint inhibitors. In certain embodiments, one cycle of therapy comprises the administration of three doses of one or more immune checkpoint inhibitors. In other embodiments, one cycle of therapy comprises the administration of four doses of one or more immune checkpoint inhibitors. In some embodiments, each dose of the immune checkpoint inhibitor that is administered comprises one immune checkpoint inhibitors. In other embodiments, each dose of the immune checkpoint inhibitor that is administered comprises two immune checkpoint inhibitors. In other embodiments, each dose of the immune checkpoint inhibitor that is administered comprises three immune checkpoint inhibitors. In certain embodiments, each dose of the immune checkpoint inhibitor comprises an anti-PD-Ll antibody. In some embodiments, each dose of the immune checkpoint inhibitor comprises an anti-CTLA4 antibody.

[0153] Where one cycle of therapy comprises the administration of more than one dose of the immune checkpoint inhibitor, the time between sequential doses of the immune checkpoint inhibitor is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, or 1, 2, 3, 4, 5, 6 ,7, 8, 9 or 10 weeks. Where one cycle of therapy comprises the administration of more than two doses of the immune checkpoint inhibitor, the time between sequential doses may be the same or different. Whereone cycle of therapy comprises the administration of more than one dose of the immune checkpoint inhibitor, the doses may be the same or different.

[0154] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered intravenously. In other embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof is administered intraperitoneally. In some embodiments, the one or more immune checkpoint inhibitors is administered intravenously. In other embodiments, the one or more immune checkpoint inhibitors is administered intraperitoneally.

[0155] It will be appreciated that the combination partners may be presented as a “kit of parts” for use in the treatment of cancer. The kit may comprise a package where the combination partners are supplied separately for co-administration with instructions for use in the particular therapy.

[0156] In another aspect, the present invention provides a kit for treating a cancer, the kit comprising:i) a compound of Formula (I):""Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally Osubstituted amide, optionally substituted aryl and H ;R and R1where present are each independently a moiety capable of binding to SSTR2;-L- and -L1- where present is a linker moiety; andii) one or more immune checkpoint inhibitors.

[0157] In certain embodiments, the kit further comprises a radionuclide. In certain embodiments, the radionuclide included with the kit is selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,mIn,177Lu,188Re,211As,212Pb and225Ac. In other embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is complexed with a radionuclide. In some embodiments, the radionuclide is a Cu radionuclide and is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

[0158] In certain embodiments, the kit comprises one immune checkpoint inhibitor. In other embodiments, the kit comprises two or more immune checkpoint inhibitors. Where the kit comprises more than one immune checkpoint inhibitors, each different immune checkpoint inhibitor is provided separately in the kit. In certain embodiments, the kit comprises an anti-PD-L1 immune checkpoint inhibitor. In other embodiments, the kit comprises an anti-CTLA4 immune checkpoint inhibitor. In further embodiments, the kit comprises an anti-PD-Ll immune checkpoint inhibitor and an anti-CTLA4 immune checkpoint inhibitor, where each immune checkpoint inhibitor is provided in discrete containers.

[0159] The kits defined herein may also comprise instructions for the administration of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, and the one or more immune checkpoint inhibitors.

[0160] The effective dosage of each of the combination partners employed in the combination of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, and the severity / grade of the cancer being treated.

[0161] According to another embodiment of the invention, the present invention provides use of one or more immune checkpoint inhibitors and a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclidein the manufacture of a medicament for the treatment of a cancer.

[0162] According to a further embodiment, the present invention provides use of a compound of Formula (I):"Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclidein the manufacture of a medicament for the treatment of a cancer, wherein the medicament is for co-administration with one or more immune checkpoint inhibitors.

[0163] In yet another embodiment, the present invention provides the use of one or more immune checkpoint inhibitors in the manufacture of a medicament for the treatment of a cancer, wherein the medicament is for co-administration with a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to SSTR2;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

[0164] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof has the structure of Formula (la) or Formula (lb):Formula (la)Formula (lb)

[0165] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0166] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.Examples

[0167] The following examples are illustrative of the disclosure and should not be construed as limiting in any way the general nature of the disclosure of the description throughout this specification.General experimental

[0168] The compound of Formula (I), and the component sarcophagine and octreotate fragments, were prepared in accordance with procedures disclosed in Dalton Trans., 2015, 43, 1386, the entire content of which is incorporated herein by reference.

[0169] Female C57BL / 6 mice were obtained from the WEHI Animal Facility breeding colony. All experiments were performed under Peter MacCallum Cancer Centre Animal EthicsCommittee approval 2023-07. The data were analysed using Prism 10 for Windows (GraphPad).

[0170] Mouse small-cell lung cancer (SCLC) RP-116 cells were obtained from the Models of Cancer TRC inventory, and cells were confirmed to be free of mycoplasma and murine viruses by routine testing. For tumour implantation, 2 million RP-116 cells were implanted subcutaneously on the right flank in a 1:1 mix of Matrigel / PBS with mice under brief 2.5% isoflurane anaesthesia.

[0171] Tumour volumes were calculated from length and width measurements with electronic callipers, performed at least twice per week.

[0172] [67Cu]Cu-Sartate having the QC parameters below was used in efficacy studies:[67Cu]Cu-Sartate (Efficacy) - 1247 MBq in 3000 pL at 60 MBq / pg, in dilution buffer (8% ethanol + 0.5% sodium gentisate in normal saline).

[0173] [64Cu]Cu-Sartate having the QC parameters below was used in imaging studies:[64Cu]Cu-Sartate (Imaging) - 67.6 MBq in 300 pL at 10 MBq / pg, in dilution buffer (8% ethanol + 0.5% sodium gentisate in normal saline).

[0174] InVivoPlus anti-mouse CTLA-4, InVivoPlus mouse IgG2b isotype control, InVivoPlus mouse IgGl isotype control, RecombiMAb anti-mouse PD-L1 were obtained from Bioxcell.Example 1 - Biodistribution studies

[0175] A dose of ~5 MBq [64Cu]Cu-Sartate was administered to RP116 (a murine SCLC cell line expressing SSTR2) tumor-bearing immunocompetent C57BL / 6 mice. Biodistribution and tumor uptake was assessed via PET imaging at 1, 4 and 24 h post IV injection.

[0176] Tumor uptake of of [67Cu]Cu-Sartate was confirmed by ex vivo biodistribution and Cherenkov imaging, with no significant radiotoxicity observed via body condition and body weight measurements in mice receiving injected activities up to the maximum tested dose of 30 MBq.

[0177] The combination of 30 MBq [67Cu]Cu-Sartate, with both anti-PD-Ll and anti-CTLA4, improved median survival by 3, 7, or 13 days, compared to dual antibody treatment-only (anti-PD-Ll plus anti-CTLA4), [67Cu]Cu-Sartate-only or saline-only treated groups respectively.Example 2 - Dose escalation studies

[0178] Dose escalation studies based on the combination of a compound of Formula (I) as disclosed herein complexed64Cu or67Cu and one or more immune checkpoint inhibitors was performed to evaluate the therapeutic efficacy of the copper-64 based or copper-67-based radiotherapy and the potential synergistic effect of the combination therapy. Tumour growth and whole-blood analyses were monitored weekly.Example 3 - Efficacy studies

[0179] After completion of a dose escalation study, an efficacy study in the same mouse model was performed using 30 MBq [67Cu]Cu-Sartate, dual mouse antibody analogues (i.e. anti-PD-Ll and anti-CTLA4 antibodies) and the combination of [67Cu]Cu-Sartate and dual-antibody treatment.

[0180] On Day 21 (20 days after tumour implantation), mice with RP 116 tumours between 187 mm3and 386 mm3were block-randomised by tumour volume into four efficacy groups of n = 10 mice, with mean tumour volumes of 288 mm3(group means 286 - 290 mm3).

[0181] Mice (n = 10) were treated on Day 21 (Day 1 of treatment) with intraperitoneal (IP) or intravenous (IV) injections as follows:• Group 1 : Saline IV + IgGl isotype antibody + IgG2b isotype antibody IP;• Group 2: 30 MBq [67Cu]Cu Sartate IV;• Group 3 : 30 MBq [67Cu]Cu-Satate IV + anti-PD-Ll + anti-CTLA-4 immunotherapy IP; or,• Group 4: Anti-PD-Ll + anti-CTLA-4 immunotherapy IP

[0182] Mice were then treated with either the two isotype antibodies, or anti-PD-Ll + anti-CTLA-4 antibodies also on Day 4 and Day 8 of treatment phase. Each antibody (IgGl isotype, IgG2b isotype, anti-PD-Ll, anti-CTLA-4) was delivered at 200 pg per mouse in a single IP injection per mouse.

[0183] Mice were monitored for tumour condition, tumour volume and body weight at least twice per week until reaching experimental endpoint 1200 mm3, or ethical endpoint (including complete tumour breakdown).

[0184] As described above, mice were administered either an amount of a compound of Formula (I) as disclosed herein complexed with64Cu or67Cu and one or more of an anti-PDLl antibody and / or an anti-CTLA4 antibody. It was found that the use of a combination of a64Cu or67Cu radiolabelled compound with either an anti-PDLl antibody or an anti-CTLA4 antibody improved the overall survival by approximately 7 days compared to control groups treated only with an anti-PDLl antibody and an anti-CTLA4 antibody, or with saline alone.

[0185] Treatment with 30 MBq [67Cu]Cu-Sartate, the use of anti-PD-Ll and anti-CTLA4 antibodies, or both therapies together delayed tumour growth (see Figure 4A) with significant reductions in tumour growth index (TGI) at Day 10 (ANOVA P = 0.0003, adjusted T tests P < 0.05). By Day 15, the combination of the radiopharmaceutical and immunotherapies showed a significant reduction in tumour growth compared to the individual treatments (ANOVA P = 0.0058, P = 0.0265 vs. [67Cu]Cu-Sartate alone, P = 0.0078 vs. antibodies alone). The effects of the treatments could be seen in survival to tumour or ethical endpoint, with significant increases in survival for the combination treatment compared to the vehicle control group (see Table 1), and for the combination treatment compared to both individual treatments.Table 1: Pairwise Log-Rank Statistics for Survival to Experimentalor Ethical EndpointExample 4 - Immunohistochemistry

[0186] The mice were monitored for 7 days after injection, after which time the mice were euthanised and the tumours harvested into 10% neutral buffered formalin. These tumours were stained with biomarkers to assess immunohistochemistry.Example 5 - Biodistribution Experiment

[0187] On Day 21 (20 days after tumour implantation) mice with tumours between 435 and 623 mm3were block-randomised by tumour volume into 3 biodistribution groups of n = 5 mice, with mean tumour volumes of 498 mm3(group means 484 - 512 mm3).

[0188] Mice were treated on Day 21 (Day 1 of treatment) with a nominal activity of 30 MBq [67Cu]Cu-Sartate delivered intravenously (mean 28.9 MBq injected activity). Mice were euthanised at 1 h, 4 h or 24 h post-injection for blood collection by cardiac puncture under isoflurane anaesthesia followed by tissue harvest for biodistribution.

[0189] For the standard organ panel, organs were weighed and the Captus 4000e well counter used to measure the amount of radioactivity in the organ sample, which was decay-corrected to the time of injection.

[0190] In RP116 tumour-bearing mice, the [67Cu]Cu-Sartate tracer had highest uptake in the kidney (see Figure 2B), which is consistent with the known renal excretion of octreotate peptide tracers. Other than the kidney, only RP116 tumours showed significant tracer uptake, with a mean injected dose per gram of 11% (%ID / g) at 1 h, with significant retention out to 24 h postinjection (mean 9.4% ID / g).Example 6 - Imaging Experiment

[0191] On Day 30 (29 days after tumour implantation) n = 10 tumour-bearing mice not used for the [67Cu]Cu-Sartate experiments (tumour volumes 131 - 794 mm3) were injected intravenously with a nominal activity of 5 MBq [64Cu]Cu-Sartate tracer, with a mean injected dose of 4.5 MBq.

[0192] Five mice were imaged by PET / CT at 1 h, 4 h and 24 h post-injection (10 min scan) before undergoing a biodistribution tissue harvest. An additional five tumour-bearing mice were euthanised and harvested for biodistribution at 4 h post-injection.

[0193] From the PET / CT imaging (Sofie / PE G8 PET / CT under isoflurane anaesthesia), DICOM images were pre-processed to convert the PET acquisitions into SUV calibrated images (using injected activity and mouse body weight) using VivoQuant v3.5. Maximum projection images of the PET / CT overlay are shown with the same SUV pseudo-colour scalefor all images in each figure. For the standard organ panel, organs were weighed and the Captus 4000e well counter used to measure the amount of radioactivity in the organ sample, which was decay-corrected to the time of injection.

[0194] The localisation of Sartate to RP116 tumours, excretion through the kidneys and substantial retention 24 h post injection seen in the [67Cu]Cu-Sartate biodistribution experiment was also observed via PET / CT and ex vivo biodistribution of [64Cu]Cu-Sartate in RP116 tumour bearing mice (see Figure 1, Figure 2, Figure 6 and Figure 7).Example 7 - Cherenkov Experiment

[0195] RP116 tumour-bearing mice (n = 3) were treated on Day 21 (Day 1 of treatment) with 11 MBq of [67Cu]Cu- Sartate delivered intravenously with mice euthanised and tumours harvested 1 h post-injection.

[0196] Tumours were sliced into three cross-sections with a scalpel and the internal facing surfaces placed facing upwards within the IVIS Lumina III imager. A photographic reference image was taken followed by a 4 h Cherenkov acquisition.

[0197] Tumour uptake of [67Cu]Cu-Sartate measured in the biodistribution study could be observed directly in tumour cross-sections using Cherenkov luminescence imaging (see Figure 8). Heterogeneous uptake may indicate a combination of target expression (i.e. SSTR2), vascularisation of the tumours and the presence of necrosis.Example 8 - Biomarker Experiment

[0198] RP116 tumour-bearing mice with tumour volumes from 388 - 506 mm3were treated (n = 3) on Day 21 (Day 1 of treatment) with intravenous (IV) or intraperitoneal (IP) injections as follows:• Group 1 : Saline IV• Group 2: 30 MBq [67Cu]Cu-Sartate IV; or• Group 3: anti-PD-Ll + anti-CTLA-4 immunotherapy IP

[0199] Group 3 mice received anti-PD-Ll + anti-CTLA-4 immunotherapy IP on Day 4 and Day 8 (3 and 7 days after first treatment). Mice were monitored for tumour condition, tumourvolume and body weight until 7 days after tracer injection, when mice were euthanised and tumours harvested into 10% neutral buffered formalin.

[0200] The n = 3 mice in Group 1 (Saline IV) were euthanised with tumour harvest 3 days after tracer injection (Day 24) due to uncontrolled tumour growth.

[0201] A mouse from the efficacy study (Group 3, 30 MBq [67Cu]Cu-Sartate IV + anti-PD-Ll + anti-CTLA-4 immunotherapy IP) was euthanised on the same day as Biomarker Group 2 and 3 (above). This tumour was also harvested and analysed as a single tumour representing combined therapy.

[0202] Tumours from the three biomarker groups differed in their shape and size at the time of harvest, displaying varying levels of necrosis and haemorrhage. The histology differences in the tumours observed in the H&E staining was most evident in the Ki-67 staining of proliferation, where viable proliferating tumour cells formed both large uninterrupted bulk or discrete islands within tumour stroma or areas of necrosis (see Figure 9).

[0203] Over the whole tumour mass, levels of proliferation (as a percentage of cell area stained for Ki-67) were similar across the treatment groups (see Figure 10), however proliferation was heterogeneous in each tumour with considerable diversity in tumour morphology and distribution of proliferating tumour regions.

[0204] All tumours showed strong SSTR2 staining, corresponding to all areas of viable / proliferating tumour (see Figure 12) indicating no loss of target expression. Tumours in the saline treated and [67Cu]Cu-Sartate only treated groups generally showed low levels of immune cells within the tumour bulk, with CD3+ T cells representing the most abundant of the immune subsets assessed. Where CD3+ T cells were present, they were largely restricted to the periphery with limited infiltration towards the core of the tumour (see Figure 13). The antibody-treated tumours and single combination therapy tumour showed more extensive infiltration of CD3+ T cells into the centre of the tumour mass. Staining for CD28, as a marker of T cell activation, correlated with CD3+ T cell staining, and was physically co-located with areas of CD3 staining (in serial sections, see Figure 13).

[0205] Analysis of serial sections by immunohistochemistry for B220 and NCR1 showed that B and NK cells were also more likely to be found in areas with abundant CD3+ T cells, but at lower levels (see Figure 14). The elevation in CD3+ T cells (and CD28+ activated T cells) in the antibody treated tumours was evident in the overall tumour levels (see Figure 15), with B and NK cells showing only minimal levels in all groups. A representative section from each tumour, i.e. treated with saline only, [67Cu]Cu-Sartate only or dual antibody (see Figure 16) demonstrates the tendency for the CD3+ T cells to be enriched only at the tumour periphery, with antibody treatment indicating an increased invasion of the cells into the bulk of the tumour. A similar section is shown for the single combination therapy treated tumour (i.e. treatment with an antibody and [67Cu]Cu-Sartate) for reference (see Figure 17).

Claims

Claims1. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

2. The method of claim 1, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,mIn,177Lu,188Re,211As,212Pb and225Ac.

3. The method of claim 1, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

4. The method of claim 1, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from64Cu and67Cu.

5. The method of any one of claims 1 to 4, wherein -L- and -L'-, where present for the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is an optionally substituted -Ci-Cioalkylene-, -C2-Cioalkenylene- or -C2-Cioalkynylene- group, one or more amino acids residues, one or more PEG groups, or combinations thereof; wherein one or more of the carbon atoms in the alkylene, alkenylene or alkynylene group may be replaced with NH, S, O, a Cs-Cs aromatic or aliphatic cyclic group or a Cs-Cs aromatic or aliphatic heterocyclic group.

6. The method of any one of claims 1 to 5, wherein -L- and -L'- where present for the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, comprises one or more of the following fragments:where n is an integer from 1 to 10.

7. The method of any one of claims 1 to 5, wherein -L- and -L'- where present for the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of:where n, m, a, b and c are integers from 1 to 10; andthe wavy lines indicate the points of attachment to the compound of Formula (I) and the moiety capable of binding to a SSTR2 receptor.

8. The method of any one of claims 1 to 7, wherein X for the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is an optionally substituted C1-C12 alkyl group.

9. The method of any one of claims 1 to 7, wherein X for the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is unsubstituted methyl.

10. The method of any one of claims 1 to 7, wherein X for the compound of Formula (I),Oor the pharmaceutically acceptable salt or solvate thereof, is H11. The method of any one of claims 1 to 7, wherein the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof has the structure of Formula (la):Formula (la)12. The method of any one of claims 1 to 7, wherein the compound of Formula (I) or pharmaceutically acceptable salt or solvate thereof has the structure of Formula (lb):Formula (lb)13. The method of any one of claims 1 to 12, wherein the one or more immune checkpoint inhibitors is an antibody or a fragment thereof.

14. The method of any one of claims 1 to 13, wherein the one or more immune checkpoint inhibitors is an antibody or a fragment thereof against an immune checkpoint protein.

15. The method of any one of claims 1 to 14, wherein the one or more immune checkpoint inhibitors is associated with PD-1, PD-L1, PD-L2, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, A2AR, TIM-3 or VISTA.

16. The method of any one of claims 1 to 15, wherein the one or more immune checkpoint inhibitors is an anti-PD-Ll antibody, anti -PD-1 antibody, an anti-CTLA-4 antibody, or a combination thereof.

17. The method of any one of claims 1 to 16, wherein the one or more immune checkpoint inhibitors is selected from the group consisting of atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, CK-301, CS-1001, SHR-1316 (adebrelimab), nivolumab, pembrolizumab, cemiplimab, ipilimumab, or a combination thereof.

18. The method of any one of claims 1 to 17, wherein the one or more checkpoint inhibitors is administered concurrently with the compound of Formula (I) or pharmaceutically acceptable salt thereof.

19. The method of any one of claims 1 to 17, wherein the one or more checkpoint inhibitors is administered after administration of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

20. The method of any one of claims 1 to 19, wherein more than one immune checkpoint inhibitor is administered.

21. The method of any one of claims 1 to 20, wherein the immune checkpoint inhibitors administered comprises an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

22. A method for the treatment of a cancer in a subject in need thereof, the method comprising administering to the subject one cycle of treatment, wherein one cycle of treatment comprises:i) a first dose of a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally Osubstituted amide, optionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide, andii) a first dose of one or more immune checkpoint inhibitors.

23. The method of claim 22, wherein time between the administration of the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and a first dose of one or more immune checkpoint inhibitors is about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days.

24. The method of claim 22, wherein one cycle of treatment further comprises administering:iii) a second dose of one or more immune checkpoint inhibitors.

25. The method of claim 24, wherein the time between the administration of a first dose and a second dose of the one or more immune checkpoint inhibitors is about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days26. The method of claim 24, wherein one cycle of treatment further comprises administering:iv) a third dose of one or more immune checkpoint inhibitors.

27. The method according to any one of claims 22 to 26, wherein the method comprises the administration of more than one cycle of treatment.

28. The method according to claim 27, wherein the method comprises the administration of two, three, four or five cycles of treatment.

29. The method according to claim 27 or 28, wherein the time between cycles of treatment is 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.

30. The method of any one of claims 1 to 29, wherein the cancer is associated with expression of a somatostatin type 2 (SSTR2) receptor.

31. The method of any one of claims 1 to 29, wherein the cancer is selected from the group consisting of epithelial ovarian cancer, ovarian carcinoma, osteosarcoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, endometrial carcinoma, pancreatic adenocarcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, breast cancer, invasive ductal carcinoma of the breast, oral squamous cell carcinoma, esophageal cancer, renal cell cancer, insulinoma, prostate cancer, neuroendocrine differentiated prostate cancer, pheochromocytoma, adenoid cystic cancer, hepatocellular carcinoma, cervical cancer, small intestine cancer, neuroendocrine tumour, anal cancer, chordoma, desmoid tumour, head and neck cancer, thymus cancer, pancreatic cancer, cholangiocellular carcinoma, esophageal cancer, salivary gland cancer, sarcoma and carcinoma of unknown primary cancer.

32. Use of one or more immune checkpoint inhibitors in combination with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:Formula (I)in the manufacture of a medicament for treating cancer, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor;-L- and -L'- where present is a linker moiety; andwherein the compound is complexed with a radionuclide.

33. Use according to claim 32, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (la):Formula (la)34. Use according to claim 32, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (lb):Formula (lb)35. Use according to any one of claims 32 to 34, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,inIn,177Lu,188Re,211AS,212Pb and225Ac.

36. Use according to claim 35, wherein the radionuclide complexed to the compound of Formula (I) or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

37. Use according to claim 36, wherein the radionuclide complexed to the compound of Formula (I) or pharmaceutically acceptable salt thereof is64Cu or67Cu.

38. A combination comprising one or more immune checkpoint inhibitors and a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally substituted amide,Ooptionally substituted aryl and H ;R and R' where present are each independently a moiety capable of binding to a somatostatin type 2 (SSTR2) receptor; and-L- and -L'- where present is a linker moiety.

39. A combination according to claim 38, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (la):Formula (la)40. A combination according to claim 38, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof has the structure of Formula (lb):Formula (lb)41. A combination according to any one of claims 38 to 40, wherein the compound is complexed with a radionuclide.

42. A combination according to claim 41, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu,67Cu,68Ga,90Y,mIn,177Lu,188Re,211As,212Pb and225Ac.

43. A combination according to claim 42, wherein the radionuclide complexed to the compound of Formula (I), or the pharmaceutically acceptable salt or solvate thereof, is selected from the group consisting of60Cu,61Cu,62Cu,64Cu and67Cu.

44. A combination according to any one of claims 38 to 43, wherein the one or more immune checkpoint inhibitors is associated with PD-1, PD-L1, PD-L2, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, A2AR, TIM-3 or VISTA.

45. A combination according to any one of claims 38 to 44, wherein the one or more immune checkpoint inhibitors is an anti-PD-Ll antibody, anti-PD-1 antibody, an anti-CTLA-4 antibody, or a combination thereof.

46. A combination according to any one of claims 38 to 45, wherein the combination comprises more than one immune checkpoint inhibitors.

47. A combination according to claim 46, wherein the immune checkpoint inhibitors comprise an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

48. A kit for treating a cancer, the kit comprising:i) a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of H, OH, halogen, cyano, NO2, NH2, optionally substituted C1-C12 alkyl, optionally substituted amino, optionally Osubstituted amide, optionally substituted aryl and H ;R and R1where present are each independently a moiety capable of binding to SSTR2;-L- and -L1- where present is a linker moiety; andii) one or more immune checkpoint inhibitors.

49. A kit according to claim 48, further comprising a radionuclide.

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