Novel therapy

Abstract

Provided herein are methods of treating a cancer in a subject, and methods of improving responsiveness of a subject to a cancer therapy. Also provided herein is tigilanol tiglate and pharmaceutical compositions thereof for use in such methods, and uses of tigilanol tiglate and pharmaceutical compositions thereof for treating cancer and improving responsiveness to a subsequent cancer therapy, such as immune checkpoint inhibitors, gemcitabine, docetaxel, or temololomide.

Description

[0001] NOVEL THERAPY

[0002] Related application

[0003] The present application claims priority from United States Provisional Patent Application No. 63 / 703,416 filed on 4 October 2024, the entire contents of which is incorporated herein by this cross-reference.

[0004] Field

[0005] The present disclosure relates to methods of treating a cancer in a subject and to methods of improving responsiveness of a subject to a cancer therapy. The present disclosure also relates to compounds and pharmaceutical compositions for use in such methods, and to uses of compounds and pharmaceutical compositions for treating cancer and improving responsiveness to cancer therapy.

[0006] Background

[0007] Cancers are one of the most common causes of death worldwide, causing around 10 million deaths in 2020 (https: / / www.who.int / news-room / fact-sheets / detail / cancer).

[0008] In recent decades, a range of treatment options have been developed including surgery, radiotherapy, and treatment with chemical and / or biological agents. Further options for expanding the therapies available to patients include using combinations of therapeutic agents, and many standard of care therapies involve the use of combination regimes.

[0009] However, despite significant progress in developing therapies, many types of cancer still have limited poor therapeutic options. Further, although surgery, chemotherapy and ionising radiation are the mainstays for local treatment of solid tumours, their application and effectiveness can be limited by factors such as the condition of the participant, proximity and / or infiltration of tumours into adjacent vital tissues, inaccessibility, large tumour volume, intolerance of normal tissue to repeated courses of treatment, and the presence of metastases (Bentz and Kraus, 2006; Kim and Glisson, 2006; De Crevoisier et al., 2006; Blanchard et al., 2011; Keereweer et al., 2013).

[0010] In addition, for many cancers, whilst they may initially be responsive to treatment with a particular agent or combination of agents, the cancer can become refractory or resistant to the therapy over the time, such that the treatment becomes ineffective. Patients can be moved onto further (e.g. second, third, fourth etc.) lines of treatment, but the cancer may also be or over time may become refractory to the second or third line treatment. Furthermore, many cancer therapies have significant side effects. Some patients may poorly tolerate certain cancer therapies due to those side effects, at least at doses which will have efficacy at treating the cancer. In some cases, patients may require a ‘holiday’ period from the therapy, i.e. a pause before recommencing treatment, or may need to stop taking that therapy.

[0011] Research and development to identify new therapies and increase treatment options for medical conditions such as cancers is a highly challenging task. It typically takes 10 years or longer for a new medicine to complete the journey from discovery to authorisation for use in the marketplace with there being a high rate of failure.

[0012] Tigilanol tiglate is a small molecule currently in development as a therapeutic agent for the treatment of cancers. The molecule has the structure: and is described in, for example, W02007 / 070985A1.

[0013] It would be desirable to provide further and improved therapies for treating cancers. It would also be desirable to provide treatments which can improve or restore the responsiveness of refractory and / or resistant cancers to cancer therapies (e.g. cancer therapies which the cancer was previously refractory or resistant to). It would further be desirable to provide treatments which allow cancer therapies to be administered at dosages which are effective to treat cancer but which are not poorly tolerated by the patient.

[0014] Summary

[0015] The present disclosure is based, at least in part, on the unexpected and surprising finding that administration of tigilanol tiglate can improve the responsiveness of a tumour to a cancer therapy. Even after administration of a course of tigilanol tiglate has ceased, it has been found that patients who are later administered other cancer therapies, now respond to those therapies and demonstrate significant responses and improvement in their condition. Patients evaluated include those with very late stage metastatic disease with resistant cancers who have been moved on to e.g. second, fourth or even seventh line treatment regimes. Positive results have been observed with different cancer types and with different cancer therapies.

[0016] Accordingly, in a first aspect, there is provided a method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being refractory to treatment with the previously administered cancer therapy, and the method comprising: administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

[0017] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer in a subject, wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy; and wherein the treating comprises administering the medicament to the subject, and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject. There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject, wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy; and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

[0018] In some embodiments, the subsequent cancer therapy is the same cancer therapy as the previously administered cancer therapy.

[0019] There is also provided a method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and the method comprising: administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

[0020] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the treating comprises administering the medicament to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

[0021] There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject; wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

[0022] In some embodiments, administration of tigilanol tiglate improves responsiveness of the subject to the subsequent cancer therapy.

[0023] In some embodiments, the subject has previously been administered multiple lines of cancer therapy, and is refractory to those multiple lines of cancer therapy prior to being administered tigilanol tiglate.

[0024] In some embodiments, tigilanol tiglate is administered during a washout period for a previously administered cancer therapy.

[0025] In some embodiments, the washout period is in the range of from two to six weeks, optionally about four weeks.

[0026] In some embodiments, during the time period when the subject is administered tigilanol tiglate, the subject is not administered another cancer therapy.

[0027] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate.

[0028] In some embodiments, the subject is administered a course of tigilanol tiglate, the course comprising administration of from 1 to 15 doses of tigilanol tiglate.

[0029] In some embodiments, the subject is administered tigilanol tiglate once per week, or wherein the subject is administered tigilanol tiglate once per two weeks, or wherein the subject is administered tigilanol tiglate once per four weeks.

[0030] In some embodiments, the tigilanol tiglate is administered intratumorally.

[0031] In some embodiments, the subject has more than one tumor, and wherein tigilanol tiglate is administered to at least one of the tumors.

[0032] In some embodiments, for each dose, tigilanol tiglate is administered in an amount of up to about 3.6 mg per m2body surface area of the subject.

[0033] In some embodiments, the cancer is selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer, a basal cell carcinoma, and breast cancer.

[0034] In some embodiments, the cancer is a sarcoma; optionally wherein the sarcoma is a fibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma; or optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma. In some embodiments, the cancer is a breast cancer, optionally wherein the breast cancer is a triple negative breast cancer.

[0035] In some embodiments, the cancer therapy is a standard of care therapy for the cancer.

[0036] In some embodiments, the cancer therapy comprises a combination of anti-cancer therapeutic agents.

[0037] In some embodiments, the cancer therapy is selected from the group consisting of: irradiation; temozolomide; doxorubicin; epirubicin; dacarbazine; ifosfamide;

[0038] - trabectedin; gemcitabine; docetaxel; paclitaxel; vinorelbine;

[0039] - trabectedin; pazopanib;

[0040] - tazemetostat; larotrectinib; entrectinib; eribulin; regorafenib; dactinomycin; melphalan; sirolimus protein-bound particles; imatinib; an immune checkpoint inhibitor, optionally an anti-CTLA-4, a-PD-1 or a PD-L1 therapy, optionally pembrolizumab, atezolizumab, nivolumab, and / or avelumab;

[0041] (pegylated) liposomal doxorubicin; docetaxel -loaded mPEG-PLA nanoparticles; albumin-paclitaxel; a tyrosine kinase inhibitor, optionally sunitinib; a T-cell therapy, optionally an engineered T-cell receptor therapy, a chimeric antigen receptor T-cell therapy or a tumor-infiltrating lymphocyte therapy; a cancer vaccine, optionally talimogene laherparepvec, LV305 or CMB305; a colony-stimulating factor-1 inhibitor;

[0042] - TTI-621; a DR5 agonist antibody; envafolimab; liposomal mifamurtide; liposomal daunorubicin; avelumab and regorafenib

[0043] NXBTXR3 and irradiation;

[0044] - BO-112 and nivolumab; envafolimab and ipilumumab; paclitaxel and nivolumab; doxorubicin and TTI-621;

[0045] - talimogene laherparepvec and pembrolizumab;

[0046] CMB305 and atezolizumab; melphalan and pembrolizumab; doxorubicin and ifosfamide; epirubicin and ifosfamide doxorubicin and dacarbazine; epirubicin and dacarbazine; doxorubicin and pembrolizumab; gemcitabine and pembrolizumab; pembrolizumab and lenvatinib; pembrolizumab and cabozantinib; pembrolizumab and epacadostat; gemcitabine and docetaxel; gemcitabine and vinorelbine; gemcitabine and dacarbazine; gemcitabine and pazopanib; sunitinib and nivolumab; melphalan, pembrolizumab and dactinomycin; - trabectedin, ipilimumab and nivolumab; docetaxel, gemcitabine and a PD-1 therapy;

[0047] - vincristine, dactinomycin and cyclophosphamide; ifosfamide, doxorubicin and dacarbazine; doxorubicin, ifosfamide and mesna; ifosfamide, epirubicin and mesna; ifosfamide, doxorubicin and lenograstim; retifanlimab, gemcitabine and docetaxel; sintilimab, doxorubicin and ifosfamide; camrelizumab, doxorubicin and ifosfamide; mesna, doxorubicin, ifosfamide and dacarbazine; cyclophosphamide, vincristine, doxorubicin and dacarbazine; and nivolumab, gemcitabine, doxorubicin and docetaxel.

[0048] In some embodiments, the subject is a human.

[0049] There is also provided a method of improving responsiveness of a subject to a cancer therapy, comprising: administering tigilanol tiglate, or administering a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer.

[0050] There is also provided use of tigilanol tiglate

[0051] for the manufacture of a medicament for improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

[0052] There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

[0053] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy.

[0054] In some embodiments, prior to administration of tigilanol tiglate, the subject is refractory to treatment with a cancer therapy.

[0055] In some embodiments, prior to administering tigilanol tiglate, the subject is administered a cancer therapy.

[0056] In some embodiments, during the time period whilst the subject is administered tigilanol tiglate, the subject continues to be administered a cancer therapy.

[0057] In some embodiments, during the time period when the subject is administered tigilanol tiglate, the subject is not administered a cancer therapy.

[0058] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate. In another aspect, there is provided a method of treating a cancer, comprising: administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer; and subsequently administering a cancer therapy to the subject; wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

[0059] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer; wherein the use comprises administering the medicament to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy. There is also provided tigilanol tiglate,

[0060] or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer; wherein the use comprises administering tigilanol tiglate or the pharmaceutical composition to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

[0061] In another aspect, there is provided a method of priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy, comprising administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject.

[0062] There is also provided use of tigilanol tiglate

[0063] or of a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for the manufacture of a medicament for priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

[0064] There is also provided tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

[0065] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy.

[0066] In some embodiments, the subject is refractory to treatment with a cancer therapy.

[0067] In some embodiments, prior to administering tigilanol tiglate, the subject is administered a cancer therapy.

[0068] In some embodiments, during the time period whilst the subject is administered tigilanol tiglate, the subject continues to be administered a cancer therapy.

[0069] In some embodiments, during the time period when the subject is administered tigilanol tiglate, the subject is not administered a cancer therapy.

[0070] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate. In some embodiments, the subject is administered a course of tigilanol tiglate, the course comprising administration of from 1 to 15 doses of tigilanol tiglate.

[0071] In some embodiments, the subject is administered tigilanol tiglate once per week.

[0072] In some embodiments, the subject is administered tigilanol tiglate once per two weeks.

[0073] In some embodiments, the subject is administered tigilanol tiglate once per four weeks.

[0074] In some embodiments, the tigilanol tiglate is administered intratumorally.

[0075] In some embodiments, the subject has more than one tumor, and tigilanol tiglate is administered to at least one of the tumors.

[0076] In some embodiments, for each dose, tigilanol tiglate is administered in an amount of up to about 3.6 mg per m2body surface area of the subject.

[0077] In some embodiments, the cancer is selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer, a basal cell carcinoma and breast cancer.

[0078] In some embodiments, the cancer is a sarcoma; optionally wherein the sarcoma is a fibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma; or optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma.

[0079] In some embodiments, the cancer is a breast cancer, optionally wherein the cancer is a triple negative breast cancer.

[0080] In some embodiments, the cancer therapy is a standard of care therapy for the cancer.

[0081] In some embodiments, the cancer therapy comprises a combination of anti-cancer therapeutic agents.

[0082] In some embodiments, the cancer therapy is selected from the group consisting of: irradiation; temozolomide; doxorubicin; epirubicin; dacarbazine; ifosfamide;

[0083] - trabectedin; gemcitabine; docetaxel; paclitaxel; vinorelbine;

[0084] - trabectedin; pazopanib;

[0085] - tazemetostat; larotrectinib; entrectinib; eribulin; regorafenib; dactinomycin; melphalan; sirolimus protein-bound particles; imatinib; an immune checkpoint inhibitor, optionally an anti-CTLA-4, a-PD-1 or PD-

[0086] L1 therapy, optionally pembrolizumab, atezolizumab, nivolumab and / or avelumab;

[0087] (pegylated) liposomal doxorubicin; docetaxel -loaded mPEG-PLA nanoparticles; albumin-paclitaxel; a tyrosine kinase inhibitor, optionally sunitinib; a T-cell therapy, optionally an engineered T-cell receptor therapy, a chimeric antigen receptor T-cell therapy or a tumor-infiltrating lymphocyte therapy; a cancer vaccine, optionally talimogene laherparepvec, LV305 or CMB305; a colony-stimulating factor-1 inhibitor;

[0088] - TTI-621; a DR5 agonist antibody; envafolimab; liposomal mifamurtide; liposomal daunorubicin; avelumab and regorafenib;

[0089] NXBTXR3 and irradiation;

[0090] - BO-112 and nivolumab; envafolimab and ipilumumab; paclitaxel and nivolumab; doxorubicin and TTI-621;

[0091] - talimogene laherparepvec and pembrolizumab;

[0092] CMB305 and atezolizumab; melphalan and pembrolizumab; doxorubicin and ifosfamide; epirubicin and ifosfamide doxorubicin and dacarbazine; epirubicin and dacarbazine; doxorubicin and pembrolizumab; gemcitabine and pembrolizumab; pembrolizumab and lenvatinib; pembrolizumab and cabozantinib; pembrolizumab and epacadostat; gemcitabine and docetaxel; gemcitabine and vinorelbine; gemcitabine and dacarbazine; gemcitabine and pazopanib; sunitinib and nivolumab; melphalan, pembrolizumab and dactinomycin;

[0093] - trabectedin, ipilimumab and nivolumab; docetaxel, gemcitabine and a PD-1 therapy;

[0094] - vincristine, dactinomycin and cyclophosphamide; ifosfamide, doxorubicin and dacarbazine; doxorubicin, ifosfamide and mesna; ifosfamide, epirubicin and mesna; ifosfamide, doxorubicin and lenograstim; retifanlimab, gemcitabine and docetaxel; sintilimab, doxorubicin and ifosfamide; camrelizumab, doxorubicin and ifosfamide; mesna, doxorubicin, ifosfamide and dacarbazine; cyclophosphamide, vincristine, doxorubicin and dacarbazine; and nivolumab, gemcitabine, doxorubicin and docetaxel.

[0095] In some embodiments, the subject is a human.

[0096] Brief Description of the Drawings

[0097] Figure 1 shows cross-sectional images of the lungs of a 45-year old male with lung metastatic myxofibrosarcoma that was refractory to standard of care therapy on study entry a) following treatment with a course of two injections of tigilanol tiglate; and b) 5 months after treatment with a course of tigilanol tiglate and following commencement of treatment with a standard of care therapy which was a combination of gemcitabine, docetaxel and a PD-1 inhibitor. Figure 1 b) shows a significant response to the standard of care therapy.

[0098] Figure 2 shows an image of the body of a 54-year old female with leiomyosarcoma that was Stage IV and refractory to standard of care therapy on study entry a) pre administration of a single injection of tigilanol tiglate; and b) 2 / i months following treatment with tigilanol tiglate during which period the patient was administered temozolomide.

[0099] Figure 3 shows cross-sectional images of the lungs of a 68-year old male with lung metastatic myxofibrosarcoma that was Stage III on study entry. The patient had 6 tumours each treated with up to three injections of tigilanol tiglate. Following treatment the patient had 4 tumours which had a complete response, one which had a partial response, and one which had progressive disease. The images are at a) shortly after entry into the trial, where lung metastases can be seen; and b) 2 months following treatment with tigilanol tiglate during which period the patient was administered a combination of gemcitabine and docetaxel, and had surgery of the partial response and progressive disease tumours.

[0100] Detailed Description

[0101] Definitions

[0102] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art.

[0103] The present disclosure may refer to the contents of certain documents being incorporated herein by reference. In the event of any inconsistent teaching between the teaching of the present disclosure and the contents of those documents, the teaching of the present disclosure takes precedence.

[0104] It is to be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art.

[0105] As used herein, the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0106] As used herein, the term “and / or”, e.g., “X and / or Y” shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning. As used herein, the term “about”, unless stated to the contrary, refers to + / - 10%, of the designated value.

[0107] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

[0108] Unless otherwise indicated, terms such as "first," "second," etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and / or a higher-numbered item (e.g., a “third” item).

[0109] As used herein, the phrase “at least one of’, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.

[0110] Each embodiment of the present disclosure described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise or required otherwise by context.

[0111] Methods of Improving Responsiveness to Cancer Therapy

[0112] As discussed above, the present disclosure is based, at least in part, on the unexpected and surprising finding that administration of tigilanol tiglate can improve the responsiveness of a tumor to a cancer therapy. Even after administration of a course of tigilanol tiglate has ceased, it has been found that patients who are later administered other cancer therapies, now respond to those therapies and demonstrate significant responses and improvement in their condition. The compound is considered to have a priming effect in patients, i.e. priming patients to be more responsive to various existing cancer therapies than is otherwise the case. Patients evaluated include those with very late stage metastatic disease with resistant cancers who have been moved on to e.g. second, fourth or even seventh line treatment regimes. Positive results have been observed with different cancer types and with different cancer therapies.

[0113] Accordingly, there is provided a method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being refractory to treatment with the previously administered cancer therapy, and the method comprising: administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

[0114] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer in a subject, wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy; and wherein the treating comprises administering the medicament to the subject, and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

[0115] There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject, wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy; and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

[0116] There is also provided a method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and the method comprising: administering tigilanol tiglate

[0117] or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

[0118] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the treating comprises administering the medicament to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously. There is also provided tigilanol tiglate,

[0119] or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject; wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subj ect is intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

[0120] There is also provided a method of improving responsiveness of a subject to a cancer therapy, comprising: administering tigilanol tiglate, or administering a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer.

[0121] There is also provided use of tigilanol tiglate

[0122] for the manufacture of a medicament for improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

[0123] There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

[0124] In another aspect, there is provided a method of treating a cancer, comprising: administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer; and subsequently administering a cancer therapy to the subject; wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

[0125] There is also provided use of tigilanol tiglate for the manufacture of a medicament for treating a cancer; wherein the use comprises administering the medicament to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

[0126] There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer; wherein the use comprises administering tigilanol tiglate or the pharmaceutical composition to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

[0127] In some embodiments, following completion of administration of tigilanol tiglate (e.g. of a course of tigilanol tiglate), the subject has improved responsiveness to the cancer therapy (i.e. a cancer therapy other than tigilanol tiglate) for a period of at least 1 month, at least 2 months, at least 3 months, or at least 6 months, or at least a year. In some embodiments, following completion of administration of tigilanol tiglate (e.g. of a course of tigilanol tiglate), the subject has improved responsiveness to the cancer therapy (i.e. a cancer therapy other than tigilanol tiglate) for a period of at least up to 1 year, or up to 6 months, or up to 3 months, or up to 2 months, or up to 1 month. In some embodiments, following completion of administration of tigilanol tiglate, and on administration of a subsequent cancer therapy, the subject’s cancer may resolve.

[0128] In another aspect, there is provided a method of priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy, comprising administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject.

[0129] There is also provided use of tigilanol tiglate or of a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for the manufacture of a medicament for priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

[0130] There is also provided tigilanol tiglate

[0131] or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

[0132] The methods and uses of the present disclosure relate to improving responsiveness of a subject with a cancer to a cancer therapy.

[0133] As used herein, the term “improving responsiveness” means that, following administration of tigilanol tiglate, the subject has an improved response to administration of a cancer therapy than would otherwise be the case where the subject had not received tigilanol tiglate. It includes the situation where the subject’s cancer becomes responsive to treatment (e.g. one or more tumours shrink or resolve) when previously the cancer was non-responsive, and also, in some embodiments, includes the situation where the subject’s cancer has an increased response (e.g. one or more tumours shrink and / or resolve at a faster rate).

[0134] Improving responsiveness may include restoring responsiveness, for example it may include the situation where a subject was previously administered a cancer therapy, and the cancer became refractory to that cancer therapy, but following administration of tigilanol tiglate, the cancer again becomes responsive to the cancer therapy.

[0135] Accordingly, in some embodiments, the methods and uses are for restoring responsiveness of a subject to a cancer therapy.

[0136] In some embodiments, the subject has previously been administered a cancer therapy (i.e. a cancer therapy other than tigilanol tiglate), and the subject is refractory to treatment with the previously administered cancer therapy.

[0137] The subject may for example have previously been administered a course of a single cancer therapy (e.g. one course of a single agent, or one course of a combination of agents), or may previously have received multiple lines of therapy (e.g. a course of a first agent or combination of agents is administered to the patient, and at some stage, for example due to the patient becoming poorly or non-responsive to that treatment, the patient was moved on to a course of a second agent or combination of agents).

[0138] In some embodiments, the subject has previously been administered multiple lines of cancer therapy, and is refractory to those multiple lines of cancer therapy prior to being administered tigilanol tiglate. For example, the subject may have been administered 2 lines of cancer therapy, or 3 lines of cancer therapy, or 4 lines of cancer therapy, or 5 lines of cancer therapy, or more.

[0139] Typically, following administration of tigilanol tiglate, the subject is administered a cancer therapy (e.g. a cancer therapy which includes an anticancer agent other than tigilanol tiglate).

[0140] Where the subject was previously administered a cancer therapy prior to being administered tigilanol tiglate, in some embodiments the subsequent cancer therapy (i.e. which is administered following administration of tigilanol tiglate) is the same cancer therapy as the previously administered cancer therapy. For example, a subject may be administered a cancer agent or combination of cancer agents other than tigilanol tiglate, and where it is found that the subject is refractory to that cancer therapy, the subject is then taken off that line of therapy. A course of tigilanol tiglate is then administered to the subject. Following completion of the course of tigilanol tiglate, the subject is then put back on to the previous course of cancer therapy (e.g. they receive the same agent or combination of agents that they received previously).

[0141] In some embodiments, prior to administration of tigilanol tiglate, the subject has a cancer which is resistant and / or refractory to treatment with a cancer therapy.

[0142] Determining responsiveness of a subject to a cancer therapy and / or whether a subject has a cancer which is resistant and / or refractory to treatment, can be carried out by any suitable means. For example, a subject may be administered a cancer therapy, and following treatment an assessment made as to whether and to what extent the cancer is responding to the therapy (e.g. whether one or more tumours are shrinking and / or resolving, and at what rate). As a further example, the subject may have a biopsy and a sample of cancerous tissue may be evaluated (e.g. assessed for the presence and / or level of biomarkers) to determine whether it is responsive to a given cancer therapy. A suitably qualified medical practitioner is able to assess responsiveness.

[0143] Similarly, determination of improved responsiveness to a cancer therapy following administration of tigilanol tiglate may be carried out using any suitable technique, such as those discussed above. The methods and uses of the present disclosure also relate to the priming of a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

[0144] It is considered that tigilanol tiglate has a priming effect, resulting in many patients becoming more susceptible to treatment with other cancer therapies than would otherwise be the case. As demonstrated by the examples, after administration of a course of tigilanol tiglate has ceased, it has been found that patients who are then later administered other cancer therapies, now respond to those therapies and demonstrate significant responses and improvement in their condition. Patients evaluated include those with very late stage metastatic disease with resistant cancers who have been moved on to e.g. second, fourth or even seventh line treatment regimes, prior to being administered tigilanol tiglate.

[0145] Without wishing to be bound by any particular theory, it is postulated that tigilanol tiglate may have an immune priming effect.

[0146] Tigilanol tiglate may also be considered to be a neoadjuvant, in that it is a therapy which can be administered before a main treatment. Accordingly, there is also provided use of tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient as a neoadjuvant. There is also provided tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use as a neoadjuvant. There is also provided a method of treating cancer, comprising administering tigilanol tiglate, or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject, wherein the tigilanol tiglate acts as a neoadjuvant, and wherein subsequent to administration of tigilanol tiglate, the subject is administered a cancer therapy.

[0147] In some embodiments, the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered. For example, in order to achieve an effect in treating the patient’s cancer or cancers, the dosage of the agent or agents may be at a level which cause significant side effects to the patient such that the patient does not tolerate the agent or combination of agents.

[0148] In some embodiments, the methods and uses comprise administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously. It will be appreciated that, by improving responsiveness such that the subject has an improved response to subsequent administration of a cancer therapy, that the cancer therapy can be administered at a lower dose than was previously possible, still achieve beneficial effects in treating the patient’s disease, but have lower side effects and can now be tolerated by the patient.

[0149] The dose reduction of the cancer therapy compared with that which was administered previously may be, for example, in the case of a single agent, at least 10%, at least 20%, at least 30%, at least 40% or at least 50% of the amount administered previously, or in the case of a combination of agents, the dose reduction may be in respect of any one, or all, of the agents used in the combination, e.g. at least 10%, at least 20%, at least 30%, at least 40% or at least 50% of the amount administered previously.

[0150] Tigilanol tiglate may be administered by any suitable means.

[0151] In some embodiments, tigilanol tiglate, or the pharmaceutical composition comprising tigilanol tiglate, is administered intratumourally, e.g. it is administered directly to one or more tumours. Injection of local therapies directly into tumours reduces systemic exposure, minimises off-target toxicity, and limits the total amount of drug used (Good et al., 2011; Kepp et al., 2020; Melero et al., 2021).

[0152] In some embodiments, the subject has a single tumour. In some other embodiments, the subject has multiple tumours.

[0153] In some embodiments, the subject has metastatic cancer.

[0154] In some embodiments, the subject has more than one tumor, and tigilanol tiglate is administered to at least one of the tumors. For example, in some embodiments, the subject may have one or more tumours which are on the surface of their body and / or which are readily accessible by injection through the skin, and may have other tumours which are not easily accessible, and the tigilanol tiglate may be administered to one or more of the accessible tumours.

[0155] An effective amount of tigilanol tiglate is administered to the patient. An "effective amount" means an amount necessary at least partly to attain the desired response (e.g. to improve responsiveness of the patient to a cancer therapy). The amount varies depending upon the health and physical condition of the individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors.

[0156] An appropriate dosage amount of tigilanol tiglate, or of the pharmaceutical composition comprising tigilanol tiglate, and an appropriate dosing regime, is utilised.

[0157] In some embodiments, for each dose, tigilanol tiglate is administered in an amount of up to about 3.6 mg per m2body surface area of the subject.

[0158] Since tigilanol tiglate itself may have direct therapeutic effects against the cancer, in some embodiments, as well as improving responsiveness of a subject to a cancer therapy, the tigilanol tiglate may itself have direct treatment effects. For example, where a patient has multiple tumours, some tumours (e.g. some or all of those to which the tigilanol tiglate is administered) may shrink or resolve.

[0159] As used herein, the term “treating” includes curing a disease or disorder, as well as alleviation of or reduction of symptoms associated with a disease or disorder or condition. The term treating also includes slowing the progression of a disease or disorder.

[0160] As used herein, the term “prevention” includes prophylaxis, and includes reducing the likelihood of contracting a disease or disorder or a symptom thereof.

[0161] Tigilanol tiglate may be administered according to any appropriate dosing regimen.

[0162] In some embodiments, the subject may be administered tigilanol tiglate on a single occasion. For example, where tigilanol tiglate is administered intratumourally, a single injection into a single tumour may be given, or if tigilanol tiglate is to be administered to multiple tumours, a single set of injections may be given into those tumours.

[0163] Alternatively, the subject may be administered tigilanol tiglate on multiple occasions, e.g. a course of tigilanol tiglate may be administered. Again, if tigilanol tiglate is being administered intratumourally to a single tumour, a series of injections to that tumour may be given. On the other hand, if tigilanol tiglate is to be administered to multiple tumours, a series of injections to each tumour may be administered.

[0164] In some embodiments, the subject is administered a course of tigilanol tiglate, and the course comprises administration of from 1 to 15 doses of tigilanol tiglate, or from 1 to 10 doses of tigilanol tiglate, or from 1 to 5 doses of tigilanol tiglate, or from 5 to 10 doses of tigilanol tiglate, or from 10 to 15 doses of tigilanol tiglate, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 doses.

[0165] In some embodiments, the subject is intratumourally administered a course of tigilanol tiglate to a single tumour, and the course comprises administration of from 1 to 15 doses of tigilanol tiglate, or from 1 to 10 doses of tigilanol tiglate, or from 1 to 5 doses of tigilanol tiglate, or from 5 to 10 doses of tigilanol tiglate, or from 10 to 15 doses of tigilanol tiglate.

[0166] In some embodiments, the subject is intratumourally administered a course of tigilanol tiglate to multiple tumours, and the course comprises administration of from 1 to 15 sets of doses of tigilanol tiglate (e.g. each set involving administration of tigilanol tiglate intratumourally to each tumour), or from 1 to 10 sets of doses of tigilanol tiglate, or from 1 to 5 sets of doses of tigilanol tiglate, or from 5 to 10 sets of doses of tigilanol tiglate, or from 10 to 15 sets of doses of tigilanol tiglate. Where a course of tigilanol tiglate is administered, any suitable dosing interval may be utilised. For example, tigilanol tiglate may be administered once per week, once per fortnight, or once per four weeks, or once per month, or once per two months.

[0167] In some embodiments the subject is administered tigilanol tiglate once per week.

[0168] In some embodiments, the subject is administered tigilanol tiglate once per two weeks.

[0169] In some embodiments, the subject is administered tigilanol tiglate once per four weeks.

[0170] Typically, after the time period when the subject is administered tigilanol tiglate, the subject is administered a cancer therapy.

[0171] In some embodiments, the tigilanol tiglate is not administered at the same time as a cancer therapy. For example, the subject may be administered a cancer therapy (e.g. a standard of care therapy for a particular cancer) and, once it is determined that the subject’s cancer is refractory to treatment with the cancer therapy or is not responding sufficiently well to treatment with the cancer therapy, administration of that therapy may cease. The subj ect may then be administered tigilanol tiglate (e.g. a single injection or course of tigilanol tiglate) following which the subject is then administered a further course of the previous cancer therapy.

[0172] In some embodiments, tigilanol tiglate is administered during a washout period for a previously administered cancer therapy. A washout period is typically the period of time after treatment of one cancer therapy ceases, and before a different cancer therapy is administered. This period allows ‘washout’ of the previous therapeutic agent or agents from the patient’s body, reducing the potential for drug-drug interactions. In some embodiments, the washout period is in the range of from two to six weeks, optionally about four weeks (e.g. 28 days). In some embodiments, the washout period is about one month.

[0173] In some embodiments, tigilanol tiglate is administered during a holiday period. A holiday period is a period where a subject pauses taking a cancer therapy, for example due to concerns over side effects becoming difficult to tolerate. The holiday period may for example be a period in the range of from two to six weeks, optionally about four weeks (e.g. 28 days), or about a month.

[0174] Alternatively, in some embodiments, a subject may be administered a predetermined course of a cancer therapy (e.g. a standard of care therapy for a particular cancer). Following completion of that course, an assessment of the responsiveness of the subject’s cancer to the cancer therapy may be made, and the subject may then be administered tigilanol tiglate. Again, following administration of tigilanol tiglate, the subject may then be administered a further course of the previous cancer therapy. Accordingly, in some embodiments, prior to administering tigilanol tiglate, the subject is administered a cancer therapy.

[0175] In some embodiments, whilst a course of tigilanol tiglate is administered, the subject does not receive any other cancer therapy. However, in some other embodiments, the subject may also receive another cancer therapy whilst tigilanol tiglate is being administered (e.g. during the period whilst a course of tigilanol tiglate is being administered). For example, in some embodiments a subject may receive a cancer therapy, and where it is determined that the subject’s cancer is refractory to treatment with that cancer therapy or is responding insufficiently well, the subject may then have a course of tigilanol tiglate added to their treatment regime alongside the other cancer therapy.

[0176] Thus, in some embodiments, during the time period whilst the subject is administered tigilanol tiglate, the subject is or continues to be administered a cancer therapy (i.e. a cancer therapy other than tigilanol tiglate).

[0177] In some embodiments, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate. For example, a course of tigilanol tiglate may be administered to the subject having a cancer to prime the subject, and improve the responsiveness of the subject’s cancer to a cancer therapy (i.e. a cancer therapy other than tigilanol tiglate). Treatment with tigilanol tiglate may then be stopped and the subject then treated with the cancer therapy (i.e. the cancer therapy other than tigilanol tiglate).

[0178] Tigilanol Tiglate

[0179] The present disclosure relates to uses and methods involving tigilanol tiglate. Tigilanol tiglate has the following structure:

[0180] Tigilanol tiglate has the chemical name (4S,5S,6R,7S,8R,9R,10S,llR,12R,13S,14R)- 12-(2E)-2-methylbut-2-enoatyl-13-[(2S)-2- methylbutyroyl]-6,7-epoxy-4, 5,9,12,13,20- hexahydroxy- 1 -tigliaen-3 -one. It has the molecular formula C30H42O10, and a molecular weight of 562.65 g mol'1. Tigilanol tiglate may also be referred to by the name EBI-46 or EBC-46.

[0181] Tigilanol tiglate is a short-chain diterpene ester. It can be derived from the seeds of the native Australian blushwood tree Fontainea picrosperma.

[0182] Tigilanol tiglate may be produced by any suitable method. For example it may be obtained as set out in W02007 / 070985A1.

[0183] Any suitable form of tigilanol tiglate may be used.

[0184] Those skilled in the art will appreciate that many organic compounds can form complexes in solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates, such as hydrates, exist when the compound incorporates solvent. It will be understood that tigilanol tiglate, may be present in the form of solvates. Solvates which are suitable are those where the associated solvent is pharmaceutically acceptable. Suitable solvates include hydrates. It will be understood that the present disclosure encompasses the use of unsolvated forms of tigilanol tiglate, as well as solvated forms, such as hydrates.

[0185] Tigilanol tiglate may exist in one or more crystalline or amorphous forms. It will be understood that all such forms are within the scope of the present disclosure.

[0186] Pharmaceutical Compositions

[0187] In some embodiments, tigilanol tiglate is provided in the form of a pharmaceutical composition.

[0188] Suitably, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or an acceptable excipient. By “pharmaceutically acceptable excipient” is meant a solid or liquid filler, diluent or encapsulating substance, or any other pharmaceutically acceptable excipient, such as a binder, disintegrant, lubricant, anti-caking agent, coloring, preservative, antioxidant, buffer or pH-adjusting agent, that may be safely used.

[0189] The pharmaceutical compositions described herein may be provided in unit dosage form. As used herein, a "unit dosage form" means a composition in a form containing an amount of a compound or salt sufficient to provide a single dose or part-single dose of that compound or salt. Examples of unit dosage forms include pills, capsules, caplets, tablets, sachets, and the like.

[0190] The pharmaceutical composition may be formulated for delivery by any suitable route of administration, such as for example topical, rectal, parenteral, sublingual, buccal, intravenous, intraarticular, intra-muscular, intra-dermal, subcutaneous, inhalational, intraocular, intraperitoneal, intracerebroventricular, transdermal and the like.

[0191] Compositions can be prepared according to conventional methods, e.g. dissolution, suspension, mixing, granulating or coating methods.

[0192] Examples of dosage forms include tablets, capsules, caplets, dispersions, suspensions, injections, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches, impregnated (occlusive) dressing, creams, gels and the like. These dosage forms may also include injecting or implanting devices designed specifically for, or modified to achieve, controlled release of the pharmaceutical composition.

[0193] Depending upon the particular route of administration, a variety of carriers, well known in the art may be used. For example, these carriers or excipients may be selected from a group including sugars, starches, cellulose and its derivates, malt, gelatine or other gelling agents, talc, calcium sulphate, vegetable oils, synthetic oils, alcohols and / or polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.

[0194] Pharmaceutically acceptable carriers and acceptable carriers for systemic administration may for example be incorporated into the compositions.

[0195] Pharmaceutical compositions of the present disclosure suitable for administration may for example be presented in discrete units such as syringes, vials, tubes, capsules, sachets or tablets containing a predetermined amount of tigilanol tiglate, as a powder or granules or as a solution or a suspension in an aqueous liquid, a cyclodextrin solution, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion or as a solution or suspension in a cream or gel or as a suspension of micro- or nano-particles, including but not limited to silica or polylactide micro- or nano-particles.

[0196] Such compositions may be prepared by any of the methods of pharmacy, but methods may for example include the step of bringing into association tigilanol tiglate with the carrier which constitutes one or more necessary ingredients. In many cases, the compositions are prepared by uniformly and intimately admixing the active agent with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

[0197] In powders, the carrier may for example be a finely divided solid which is in a mixture with the finely divided active component.

[0198] In tablets, the active component may for example be mixed with the carrier having the necessary binding capacity in suitable proportions and compacted into the shape and size desired. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.

[0199] Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0200] For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, may for example first be melted and the active component then dispersed homogeneously therein, as by stirring. The molten homogenous mixture can then be poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0201] Formulations suitable for vaginal administration may for example be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0202] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in water, aqueous 1,2-propanediol, dimethyl sulfoxide (DMSO), aqueous solutions of gamma cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin, saline solution or polyethylene glycol solution, with or without buffer.

[0203] Tigilanol tiglate may for example be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may for example take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0204] Aqueous solutions suitable for oral use can be prepared by, for example, dissolving the active component in water and adding suitable colorants, flavours, stabilizing and / or thickening agents, as desired.

[0205] Aqueous suspensions suitable for oral use can be made by, for example, dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0206] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0207] For topical administration to the epidermis or other organ, tigilanol tiglate may for example be formulated as a gel, ointment, emulsion, paste, cream or lotion, or as a transdermal patch. Formulations suitable for topical administration may also include solutions or suspensions that may be administered topically in the form of a bath or soak solution or a spray. These formulations may be suitably applied to combat skin irritations, insect bites and foot wounds.

[0208] Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0209] Solutions or suspensions may for example be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the active ingredient may be encapsulated with cyclodextrins, or formulated with agents expected to enhance delivery and retention in the nasal mucosa.

[0210] Administration to the respiratory tract may also be achieved, for example by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0211] Alternatively, the active ingredient may for example be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

[0212] Conveniently, in some embodiments, the powder carrier may form a gel in the nasal cavity. The powder composition may for example be presented in unit dose form, such as in capsules or cartridges of, e.g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0213] In formulations intended for administration to the respiratory tract, including intranasal formulations, the active ingredient may for example be provided having a small average particle size, for example of the order of 1 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.

[0214] Techniques and compositions for making dosage forms as described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004). Pharmaceutical formulation techniques may also be used such as, for example, those disclosed in Remington's The Science and Practice of Pharmacy, 23rdEd., Elsevier (2020), or Remington's Pharmaceutical Sciences, 21stEdition, Mack Publishing, 2005. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332. The contents of each of the aforementioned documents are incorporated herein by reference in their entirety.

[0215] Tigilanol tiglate may be administered in combination with a further active agent. In some embodiments, the pharmaceutical composition comprising tigilanol tiglate also contains one or more further therapeutic agents.

[0216] Subject

[0217] The methods and uses disclosed herein relate to restoring responsiveness of a subject to a cancer therapy.

[0218] The subject may in principle be any subject susceptible to cancer.

[0219] In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. For example, the subject may be a companion animal such as a dog or cat, or a horse, cattle (e.g. cow), sheep, goat or pig.

[0220] In some embodiments, the subject is a human. In some other embodiments, the subject is not a human, for example it may be a nonhuman animal, or a non-human mammal.

[0221] In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult.

[0222] In some embodiments, the subject is at least 20, at least 30, at least 40, or at least 50, or at least 60, or at least 70 years old. In some embodiments, the subject is from 20 to 30, or from 30 to 40, or from 40 to 50, or from 50 to 60, or from 60 to 70, or from 70 to 80, or from 80 to 90, or from 90 to 100 years old.

[0223] In some embodiments, the subject has stage II, stage III or stage IV cancer. In some embodiments, the subject has stage II cancer. In some embodiments, the subject has stage III cancer. In some embodiments, the subject has stage IV cancer.

[0224] In some embodiments, the subject is compromised, e.g. frail or immunocompromised. In some embodiments, the subject is not suitable for undergoing surgery.

[0225] In some embodiments, the subject has received at least one prior line of cancer therapy. In some embodiments, the subject has received at least two prior lines of different cancer therapies. In some embodiments, the subject has received at least three prior lines of different cancer therapies. In some embodiments, the subject has received at least four prior lines of different cancer therapies. In some embodiments, the subject has received at least five prior lines of different cancer therapies.

[0226] Cancer

[0227] The present disclosure relates to the use of tigilanol tiglate for improving responsiveness of a subject having a cancer to a cancer therapy.

[0228] The cancer may for example be a cell proliferative disorder.

[0229] The cancer may for example be a solid tumour.

[0230] Tigilanol tiglate is in clinical development for the local treatment of a wide range of solid tumours (Boyle et al., 2014; Barnett et al., 2019; Miller et al., 2019; Panizza et al., 2019; De Ridder et al., 2020; Cullen et al., 2021).

[0231] Tigilanol tiglate has a multi-modal mode of action (MO A) that includes targeting and activating specific isoforms of Protein Kinase C (PKC), as well as creating a cascade of intracellular signals which generate host responses against the tumour (Boyle et al., 2014; Cullen et al., 2021). Tigilanol tiglate (i) induces a rapid, but highly localised, inflammatory response (ii) significantly increases permeability of the tumour vascular endothelium, and (iii) causes rapid tumour cell death by oncosis, with no viable tumour cells evident four hours after injection by ex vivo culture from a mouse model. These effects result in rapid tumour destruction and subsequent slough of the treated tumour within 4 to 14 days (Boyle et al., 2014; Barnett et al., 2019; Miller et al., 2019; De Ridder et al., 2020; Cullen et al., 2021). Of note, the tumour oncosis manifests as obvious necrosis and sloughing of the injected tumour, resulting in a deficit or wound. Bruising and tumour ooze are also normal responses. These responses are expected and desired as their presence demonstrates the activity of tigilanol tiglate.

[0232] Tigilanol tiglate also induces changes in cytokine signalling and gene expression in both blood derived cells and the surrounding normal tissue (both keratinocytes and fibroblasts) at the tumour deficit site that promote a favourable wound healing response without requiring other interventions (Moses et al., 2020).

[0233] The release of cytokines / chemokines are known to stimulate immune cell recruitment / activity and Damage-Associated Molecular Patterns (DAMPS) which promote antigen uptake and the development of anti-tumour immunity. Experiments in an immunogenic tumour model (CT26) in mice suggest that tigilanol tiglate-directed ablation of tumours can promote systemic immune responses.

[0234] In some embodiments, the cancer is a cancer which is responsive to a protein kinase C activator.

[0235] Examples of cancers include sarcoma, head and neck cancer, melanoma, mast cell tumor, breast cancer, fibroxanthoma, colorectal cancer, adenoid cystic cancer, sarcoid, squamous cell cancer and basal cell carcinoma.

[0236] In some embodiments, the cancer is selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer a basal cell carcinoma and breast cancer.

[0237] In some embodiments, the cancer is a sarcoma; optionally wherein the cancer is a fibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma; optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma.

[0238] In some embodiments, the cancer is a head and neck cancer.

[0239] In some embodiments, the cancer is a melanoma. In some embodiments, the cancer is a metastatic melanoma.

[0240] In some embodiments, the cancer is a mast cell tumour.

[0241] In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a triple negative breast cancer.

[0242] Cancer Therapy The present disclosure relates to improving responsiveness of a subject to a cancer therapy by administration of tigilanol tiglate.

[0243] Unless dictated otherwise by context, as used herein the term “cancer therapy” refers to a cancer therapy other than tigilanol tiglate.

[0244] As discussed above, it has been found that administration of tigilanol tiglate to patients with cancers can improve the responsiveness of a cancer to another cancer therapy. Patients evaluated include those with very late stage metastatic disease with resistant cancers who have been moved on to e.g. second, fourth or even seventh line treatment regimes.

[0245] In some embodiments, the cancer therapy is a single agent.

[0246] In some embodiments, the cancer therapy is a combination therapy, e.g. of a combination of 2, 3, 4 or more agents (e.g. chemotherapeutic and / or biological therapeutic agents).

[0247] In some embodiments, the cancer therapy comprises a combination of anti-cancer therapeutic agents.

[0248] In some embodiments, the cancer therapy is irradiation.

[0249] In some embodiments, the cancer therapy is a combination of irradiation and one or more chemotherapeutic and / or biological therapeutic agents.

[0250] In some embodiments, the cancer therapy is a “standard of care” therapy for the cancer. A standard of care therapy is a treatment which is accepted by medical authorities and is widely used by healthcare professionals in relation to a given disorder.

[0251] In some embodiments, the cancer therapy is a cancer therapy for a cancer which is responsive to a protein kinase C activator.

[0252] In some embodiments the cancer therapy is a cancer therapy for a cancer selected from the group consisting of sarcoma, head and neck cancer, melanoma, mast cell tumor, breast cancer, fibroxanthoma, colorectal cancer, adenoid cystic cancer, sarcoid, squamous cell cancer and basal cell carcinoma.

[0253] In some embodiments the cancer therapy is a cancer therapy for a cancer selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer, basal cell carcinoma and breast cancer.

[0254] In some embodiments the cancer therapy is a cancer therapy for a sarcoma; optionally wherein the cancer is a fibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma, optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma.

[0255] In some embodiments, the cancer therapy is a cancer therapy for a head and neck cancer. In some embodiments, the cancer therapy is a cancer therapy for a melanoma, for example for a metastatic melanoma.

[0256] In some embodiments, the cancer therapy is a cancer therapy for a mast cell tumour.

[0257] In some embodiments, the cancer therapy is a cancer therapy for a breast cancer, for example for a triple negative breast cancer.

[0258] Examples of cancer therapies for sarcomas are described in, for example, Seong and D’Angelo, 2023, and Von Mehren et al, 2022.

[0259] In some embodiments the cancer therapy is a cancer therapy for a head and neck cancer.

[0260] In some embodiments, the cancer therapy is a cancer therapy for a melanoma.

[0261] In some embodiments, the cancer therapy is selected from the group consisting of: irradiation; temozolomide; doxorubicin; epirubicin; dacarbazine; ifosfamide;

[0262] - trabectedin; gemcitabine; docetaxel; paclitaxel; vinorelbine;

[0263] - trabectedin; pazopanib;

[0264] - tazemetostat; larotrectinib; entrectinib; eribulin; regorafenib; dactinomycin; melphalan; sirolimus protein-bound particles; imatinib; an immune checkpoint inhibitor, optionally an anti-CTLA-4, a-PD-1 therapy or a PD-L1 therapy, optionally pembrolizumab, atezolizumab, nivolumab and / or avelumab;

[0265] (pegylated) liposomal doxorubicin; docetaxel -loaded mPEG-PLA nanoparticles; albumin-paclitaxel; a tyrosine kinase inhibitor, optionally sunitinib; a T-cell therapy, optionally an engineered T-cell receptor therapy, a chimeric antigen receptor T-cell therapy or a tumor-infiltrating lymphocyte therapy; a cancer vaccine, optionally talimogene laherparepvec, LV305 or CMB305; a colony-stimulating factor-1 inhibitor;

[0266] - TTI-621; a DR5 agonist antibody; envafolimab; liposomal mifamurtide; and liposomal daunorubicin.

[0267] In some embodiments, the cancer therapy is selected from the group consisting of avelumab and regorafenib;

[0268] NXBTXR3 and irradiation;

[0269] - BO-112 and nivolumab; envafolimab and ipilumumab; paclitaxel and nivolumab; doxorubicin and TTI-621;

[0270] - talimogene laherparepvec and pembrolizumab;

[0271] CMB305 and atezolizumab; melphalan and pembrolizumab; doxorubicin and ifosfamide; epirubicin and ifosfamide doxorubicin and dacarbazine; epirubicin and dacarbazine; doxorubicin and pembrolizumab; gemcitabine and pembrolizumab; pembrolizumab and lenvatinib; pembrolizumab and cabozantinib; pembrolizumab and epacadostat; gemcitabine and docetaxel; gemcitabine and vinorelbine; gemcitabine and dacarbazine; gemcitabine and pazopanib; and sunitinib and nivolumab.

[0272] In some embodiments, the cancer therapy is selected from the group consisting of: melphalan, pembrolizumab and dactinomycin;

[0273] - trabectedin, ipilimumab and nivolumab; docetaxel, gemcitabine and a PD-1 therapy;

[0274] - vincristine, dactinomycin and cyclophosphamide; ifosfamide, doxorubicin and dacarbazine; doxorubicin, ifosfamide and mesna; ifosfamide, epirubicin and mesna; ifosfamide, doxorubicin and lenograstim; retifanlimab, gemcitabine and docetaxel; sintilimab, doxorubicin and ifosfamide; camrelizumab, doxorubicin and ifosfamide; and mesna, doxorubicin, ifosfamide and dacarbazine.

[0275] In some embodiments, the cancer therapy is selected from the group consisting of: cyclophosphamide, vincristine, doxorubicin and dacarbazine; and nivolumab, gemcitabine, doxorubicin and docetaxel.

[0276] In some embodiments, the cancer therapy is selected from the group consisting of: cisplatin; fluorouracil; methotrexate; carboplatin; and paclitaxel.

[0277] In some embodiments, the cancer therapy is selected from the group consisting of: ipilimumab; nivolumab; pembrolizumab; dacarbzine;

[0278] - temololomide; - Nab-paclitaxel;

[0279] - Paclitaxel; cisplatin; and carboplatin.

[0280] In some embodiments, the cancer therapy is avelumab and regorafenib;

[0281] In some embodiments, the cancer therapy is not an immune checkpoint inhibitor.

[0282] In some embodiments, the cancer therapy is not a chemotherapeutic agent that damages DNA.

[0283] In some embodiments, the cancer therapy is not a chemotherapeutic agent that inhibits tumour-associated host-derived cells that support the growth and / or invasion of tumour cells.

[0284] In some embodiments, the cancer therapy is not irradiation.

[0285] The disclosure will now be described with reference to the following Examples which illustrate some preferred aspects of the present disclosure. However, it is to be understood that the particularity of the following description is not to supersede the generality of the preceding description.

[0286] Examples

[0287] Example 1: Synopsis of Phase Ila Study

[0288] Example 2: Treatment of myxofibrosarcoma patient with tigilanol tiglate and restoration of responsiveness to cancer therapy A 45-year old male was admitted into the clinical study described above in Example 1. The subject had myxofibrosarcoma, was at the local recurrence stage, was non-resectable, and refractory to standard of care therapy on study entry.

[0289] The subject was administered a course of two injections of tigilanol tiglate administered at 28 day intervals to an externally located tumor. The injected tumour had a partial response (approximately 35%).

[0290] As shown in Figure 1 a), imaging of the subject’s lungs post treatment with tigilanol tiglate showed that the subject also had lung metastatic disease.

[0291] The subject was followed post-study. Treatment was started with a combination of gemcitabine, docetaxel and a PD-1 inhibitor. The subject’s lungs were imaged again (see Figure 1 b)). Surprisingly, the image indicates that the lung metastases were clearing and now showed significant response when treated with the standard of care therapy at 5 months post -tigilanol tiglate treatment.

[0292] Example 3: Treatment of leiomyosarcoma patient with tigilanol tiglate and restoration of responsiveness to cancer therapy

[0293] A 54-year old female was admitted into the clinical study described above in Example 1. The subject had leiomyosarcoma, was Stage IV, resectable, and refractory to standard of care therapy on study entry.

[0294] The subject was administered a single injection of tigilanol tiglate to a single tumour. The injected tumour had a partial / complete response (approximately 99%).

[0295] As shown in Figure 2 a), imaging of the subject’s body post treatment with tigilanol tiglate showed that the subject had a large number of tumours.

[0296] The subject was followed post-study. Treatment was started with temololomide. At 2.5 months post treatment with tigilanol tiglate, the subject’s body was imaged again (see Figure 2 b)). Surprisingly, the image indicates significant resolution of many tumours, which were now showing significant response when treated with the standard of care therapy, post-tigilanol tiglate treatment.

[0297] Example 4: Treatment of myxofibrosarcoma patient with tigilanol tiglate and restoration of responsiveness to cancer therapy A 68-year old male was admitted into the clinical study described above in Example 1. The subject had myxofibrosarcoma, was Stage III, non-resectable, and refractory to standard of care therapy on study entry.

[0298] The subject was administered a course of up to three injections of tigilanol tiglate administered at 28-day intervals to each of six tumours. Four of the tumours had complete response (12 weeks), one had a partial response (4 weeks), and one had progressive disease (4 weeks).

[0299] As shown in Figure 3 a), imaging of the subject’s lungs post treatment with tigilanol tiglate showed that the subject also had lung metastatic disease.

[0300] The subject was followed post-study. Treatment was started with a combination of gemcitabine and docetaxel. The subject’s lungs were imaged again (see Figure 3 b)). Surprisingly, the image indicates that the lung metastases were clearing and now showed significant response when treated with the standard of care therapy at 2 months post-tigilanol tiglate treatment and post surgery of the partial response and progressive disease tumours.

[0301] Example 5: Treatment of triple negative breast cancer patient with tigilanol tiglate and restoration of responsiveness to cancer therapy

[0302] A pt 4 lady diagnosed with triple negative breast cancer, had a cauliflower exophytic 300 ml tumor on her chest. The tumor was treated by sequential injections of tigilanol tiglate on day 1, day 8 and day 15. There was then a break of 28 days. Local efficacy was observed (also a bystander effect; thick and quite tall tumor became thinner, with decrease of height; however during therapeutic break of 28 days there was tumor regrowth. It was decided to cease tigilanol tiglate therapy and initiate treatment by Regomune. Regomune is a combination of avelumab and regorafenib, a therapy currently in phase 2 clinical trials. Following treatment with tigilanol tiglate, the patient responded much better than expected to the previous combination.

[0303] References:

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[0306] Barnett CME, Broit N, Yap P-Y, Cullen JK, Parsons PG, Panizza BJ, et al. Optimizing intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate. Invest New Drugs. 2019. DOI: 10.1007 / sl0637-018-0604-y.

[0307] Bentz BG and Kraus DH. Advanced head and neck surgery and reconstruction. In (Brockstein, B. and Masters, G. eds.). Head and neck cancer (2006; Vol. 114). Springer Science & Business Media.

[0308] Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiotherapy and oncology, 2011; 100(1), pp.33-40.

[0309] Boyle GM, D’ Souza MMA, Pierce CJ, Adams RA, Cantor AS, Johns JP, et al. Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. PLoS One. 2014; 9(19): el068887. DOI: 10.1371 / joumal.pone.0108887.

[0310] Cullen JK, Boyle GM, Yap PY, Elmlinger S, Simmons JL, Broit N, et al. Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes. Scientific Reports, 2021; 11(1): 1-14.

[0311] De Crevoisier R, Bourhis J and Eschwege F. Modified fractioned radiotherapy in head and neck squamous cell carcinoma (HNSCC) and re-irradiation in recurrent head and neck carcinoma. In (Brockstein, B. and Masters, G. eds.). Head and neck cancer (2006; Vol. 114). Springer Science & Business Media.

[0312] De Ridder TR, Campbell JE, Burke-Schwarz C, Clegg D, Elliot E, Geller S, Kozak, W., Pittenger, S.T, Pruitt, J.B., Riehl, J., White, J, Wiest, M.L., Johannes, C.M., Morton, J., Jones, P.D., Schmidt, P.F., Gordon, V, and Reddell, P. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46). J Vet Intern Med. 2020; 1-15.

[0313] Good LM, Miller MD and High WA. Intralesional agents in the management of cutaneous malignancy: a review. J Am Acad Dermatol. 2011; 64: 413-422.

[0314] Keereweer S, Van Driel PBAA, Snoeks TJA, Kerrebijn JDF, de Jong RJB, Vahrmeijer AL, et al. Optical image-guided cancer surgery: challenges and limitations. Clinical Cancer Research, 2013; 19(14), pp.3745-3754. DOI: 10.1158 / 1078-0432.CCR-12-3598. Kepp, O, Marabelle, A, Zitvogel, L and Kroemer, G. Oncolysis without viruses - Inducing systemic anticancer immune responses with local therapies. Nat Rev Clin One, 2020.17(1): 49- 64.

[0315] Kim ES and Glisson BS. Treatment of metastatic head and neck cancer: chemotherapy and novel agents. In (Brockstein, B. and Masters, G. eds.). Head and neck cancer (2006; Vol. 114). Springer Science & Business Media.

[0316] Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989)

[0317] Melero, I, Castanon, E, Alvarez, M, Champiat, S and Marabelle, A. Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat Rev Clin One, 2021. 18(9), pp.558-576.

[0318] Miller J, Campbell J, Blum A, Reddell P, Gordon V, Schmidt P, et al. Dose characterization of the investigational anticancer drug tigilanol tiglate (EBC-46) in the local treatment of canine mast cell tumors. Frontiers in Veterinary Science, 2019; 6, p.106.

[0319] Modem Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002)

[0320] Moses R, Boyle G, Howard-Jones J, Errington R, Johns J, Gordon V, et al. Novel epoxy- tiglianes stimulate skin keratinocyte wound healing responses and re-epithelialization via protein kinase C activation. Biochemical Pharmacology, 2020; 178: 114048.

[0321] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J P harm Sci and Tech 2011, 65 287-332

[0322] Panizza BJ, de Souza P, Cooper A, Roohullah A, Karapetis CS and Lickliter JD. Phase I Dose- Escalation Study to Determine the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of an Intratumoral Injection of Tigilanol Tiglate (EBC-46). EBioMedicine, 2019; 50:433-411.

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[0326] Seong and D’Angelo, New therapeutics for soft tissue sarcomas: Overview of current immunotherapy and future directions of soft tissue sarcomas, Frontiers in Oncology, 2023, 13: 1150765.

[0327] Von Mehren et al, Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology, JNCCN, Volume 20, 7, July 2022.

[0328] W02007 / 070985A1

Claims

Claims1. A method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being refractory to treatment with the previously administered cancer therapy, and the method comprising: administering tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

2. Use of tigilanol tiglatefor the manufacture of a medicament for treating a cancer in a subj ect, wherein the subj ect has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy;and wherein the treating comprises administering the medicament to the subject, and subsequently administering a cancer therapy which includes an anticancer agent other than tigilanol tiglate, to the subject.

3. Tigilanol tiglate,or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject, wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is refractory to treatment with the previously administered cancer therapy; and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering a cancer therapy which includes an anti cancer agent other than tigilanol tiglate, to the subject.

4. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 3, wherein the subsequent cancer therapy is the same cancer therapy as the previously administered cancer therapy.

5. A method of treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and the method comprising: administering tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject; and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

6. Use of tigilanol tiglatefor the manufacture of a medicament for treating a cancer in a subject, the subject having previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject being intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the treating comprises administering the medicament to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

7. Tigilanol tiglate,or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer in a subject; wherein the subject has previously been administered a cancer therapy which does not comprise tigilanol tiglate, and the subject is intolerant of the agent or agents used in the previous cancer therapy at the previous dose administered, and wherein the use comprises administering tigilanol tiglate or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient to the subject, and subsequently administering to the subject the agent or agents used in the previous cancer therapy, at a lower dose than was administered previously.

8. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 7, wherein administration of tigilanol tiglate improves responsiveness of the subject to the subsequent cancer therapy.

9. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 8, wherein the subject has previously been administered multiple lines of cancer therapy, and is refractory to those multiple lines of cancer therapy prior to being administered tigilanol tiglate.

10. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 9, wherein tigilanol tiglate is administered during a washout period for a previously administered cancer therapy.

11. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 10, wherein the washout period is in the range of from two to six weeks, optionally about four weeks.

12. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 11, wherein during the time period when the subject is administered tigilanol tiglate, the subject is not administered another cancer therapy.

13. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 12 wherein, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate.

14. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 13, wherein the subject is administered a course of tigilanol tiglate, the course comprising administration of from 1 to 15 doses of tigilanol tiglate.

15. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 14, wherein the subject is administered tigilanol tiglate once per week, or wherein the subject is administered tigilanol tiglate once per two weeks, or wherein the subject is administered tigilanol tiglate once per four weeks.

16. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 15, wherein the tigilanol tiglate is administered intratumorally.

17. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 16, wherein the subject has more than one tumor, and wherein tigilanol tiglate is administered to at least one of the tumors.

18. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 17, wherein for each dose, tigilanol tiglate is administered in an amount of up to about 3.6 mg per m2body surface area of the subject.

19. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 18, wherein the cancer is selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer, a basal cell carcinoma, and breast cancer.

20. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 19, wherein the cancer is a sarcoma; optionally wherein the sarcoma is afibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma; or optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma.

21. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 20, wherein the cancer is a breast cancer, optionally wherein the breast cancer is a triple negative breast cancer.

22. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 21, wherein the cancer therapy is a standard of care therapy for the cancer.

23. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 22, wherein the cancer therapy comprises a combination of anti -cancer therapeutic agents.

24. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 23, wherein the cancer therapy is selected from the group consisting of irradiation; temozolomide; doxorubicin; epirubicin; dacarbazine; ifosfamide;- trabectedin; gemcitabine; docetaxel; paclitaxel; vinorelbine;- trabectedin; pazopanib;- tazemetostat; larotrectinib; entrectinib; eribulin;regorafenib; dactinomycin; melphalan; sirolimus protein-bound particles; imatinib; an immune checkpoint inhibitor, optionally an anti-CTLA-4, a-PD-1 or a PD-L1 therapy, optionally pembrolizumab, atezolizumab, nivolumab, and / or avelumab;(pegylated) liposomal doxorubicin; docetaxel -loaded mPEG-PLA nanoparticles; albumin-paclitaxel; a tyrosine kinase inhibitor, optionally sunitinib; a T-cell therapy, optionally an engineered T-cell receptor therapy, a chimeric antigen receptor T-cell therapy or a tumor-infiltrating lymphocyte therapy; a cancer vaccine, optionally talimogene laherparepvec, LV305 or CMB305; a colony-stimulating factor-1 inhibitor;- TTI-621; a DR5 agonist antibody; envafolimab; liposomal mifamurtide; liposomal daunorubicin; avelumab and regorafenibNXBTXR3 and irradiation;- BO-112 and nivolumab; envafolimab and ipilumumab; paclitaxel and nivolumab; doxorubicin and TTI-621;- talimogene laherparepvec and pembrolizumab;CMB305 and atezolizumab; melphalan and pembrolizumab; doxorubicin and ifosfamide; epirubicin and ifosfamide doxorubicin and dacarbazine; epirubicin and dacarbazine;doxorubicin and pembrolizumab; gemcitabine and pembrolizumab; pembrolizumab and lenvatinib; pembrolizumab and cabozantinib; pembrolizumab and epacadostat; gemcitabine and docetaxel; gemcitabine and vinorelbine; gemcitabine and dacarbazine; gemcitabine and pazopanib; sunitinib and nivolumab; melphalan, pembrolizumab and dactinomycin;- trabectedin, ipilimumab and nivolumab; docetaxel, gemcitabine and a PD-1 therapy;- vincristine, dactinomycin and cyclophosphamide; ifosfamide, doxorubicin and dacarbazine; doxorubicin, ifosfamide and mesna; ifosfamide, epirubicin and mesna; ifosfamide, doxorubicin and lenograstim; retifanlimab, gemcitabine and docetaxel; sintilimab, doxorubicin and ifosfamide; camrelizumab, doxorubicin and ifosfamide; mesna, doxorubicin, ifosfamide and dacarbazine; cyclophosphamide, vincristine, doxorubicin and dacarbazine; and nivolumab, gemcitabine, doxorubicin and docetaxel.

25. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 1 to 24, wherein the subject is a human.

26. A method of improving responsiveness of a subject to a cancer therapy, comprising: administering tigilanol tiglateor administering a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer.

27. Use of tigilanol tiglatefor the manufacture of a medicament for improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

28. Tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in improving responsiveness of a subject to a cancer therapy, wherein prior to administration of tigilanol tiglate, the subject has a cancer.

29. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 28, wherein following administration of tigilanol tiglate, the subject is administered a cancer therapy.

30. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 29, wherein prior to administration of tigilanol tiglate, the subject is refractory to treatment with a cancer therapy.

31. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 30, wherein prior to administering tigilanol tiglate, the subject is administered a cancer therapy.

32. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 31, wherein during the time period whilst the subject is administered tigilanol tiglate, the subject continues to be administered a cancer therapy.

33. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 32, wherein during the time period when the subject is administered tigilanol tiglate, the subject is not administered a cancer therapy.

34. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 33, wherein following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate.

35. A method of treating a cancer, comprising: administering tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to a subject having a cancer; and subsequently administering a cancer therapy to the subject; wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

36. Use of tigilanol tiglatefor the manufacture of a medicament for treating a cancer; wherein the use comprises administering the medicament to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

37. Tigilanol tiglate,or a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in treating a cancer; wherein the use comprises administering tigilanol tiglate or the pharmaceutical composition to a subject having a cancer; and subsequently administering a cancer therapy to the subject; and wherein administration of tigilanol tiglate improves responsiveness of the subject to the cancer therapy.

38. A method of priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy, comprising administering tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, to the subject.

39. Use of tigilanol tiglateor of a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for the manufacture of a medicament for priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

40. Tigilanol tiglateor a pharmaceutical composition comprising tigilanol tiglate and a pharmaceutically acceptable excipient, for use in priming a subject having a cancer, to improve the responsiveness of the subject to a subsequent cancer therapy.

41. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 35 to 40, wherein following administration of tigilanol tiglate, the subject is administered a cancer therapy.

42. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 35 to 40, wherein prior to administration of tigilanol tiglate, the subject is refractory to treatment with a cancer therapy.

43. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 35 to 42, wherein prior to administering tigilanol tiglate, the subject is administered a cancer therapy.

44. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 43, wherein during the time period whilst the subject is administered tigilanol tiglate, the subject continues to be administered a cancer therapy.

45. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 35 to 43, wherein during the time period when the subject is administered tigilanol tiglate, the subject is not administered a cancer therapy.

46. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 35 to 45, wherein, following administration of tigilanol tiglate, the subject is administered a cancer therapy in the absence of tigilanol tiglate.

47. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 46, wherein the subject is administered a course of tigilanol tiglate, the course comprising administration of from 1 to 15 doses of tigilanol tiglate.

48. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 47, wherein the subject is administered tigilanol tiglate once per week.

49. A method, use or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 47, wherein the subject is administered tigilanol tiglate once per two weeks.

50. A method, use or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 47, wherein the subject is administered tigilanol tiglate once per four weeks.

51. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 50, wherein the tigilanol tiglate is administered intratumorally.

52. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 51, wherein the subject has more than one tumor, and wherein tigilanol tiglate is administered to at least one of the tumors.

53. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 52, wherein for each dose, tigilanol tiglate is administered in an amount of up to about 3.6 mg per m2body surface area of the subject.

54. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 53, wherein the cancer is selected from the group consisting of a sarcoma, head and neck cancer, melanoma, a mast cell tumor, a sarcoid, a squamous cell cancer, a basal cell carcinoma, and breast cancer.

55. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 54, wherein the cancer is a sarcoma; optionally wherein the sarcoma is a fibrosarcoma, angiosarcoma, clear cell sarcoma, or soft tissue sarcoma; or optionally wherein the cancer is myxofibrosarcoma or leiomyosarcoma.

56. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in claim 54, wherein the cancer is a breast cancer, optionally wherein the breast cancer is a triple negative breast cancer.

57. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 56, wherein the cancer therapy is a standard of care therapy for the cancer.

58. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 57, wherein the cancer therapy comprises a combination of anti-cancer therapeutic agents.

59. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 58, wherein the cancer therapy is selected from the group consisting of: irradiation; temozolomide; doxorubicin;epirubicin; dacarbazine; ifosfamide;- trabectedin; gemcitabine; docetaxel; paclitaxel; vinorelbine;- trabectedin; pazopanib;- tazemetostat; larotrectinib; entrectinib; eribulin; regorafenib; dactinomycin; melphalan; sirolimus protein-bound particles; imatinib; an immune checkpoint inhibitor, optionally an anti-CTLA-4, a-PD-1 or a PD-L1 therapy, optionally pembrolizumab, atezolizumab, nivolumab, and / or avelumab;(pegylated) liposomal doxorubicin; docetaxel -loaded mPEG-PLA nanoparticles; albumin-paclitaxel; a tyrosine kinase inhibitor, optionally sunitinib; a T-cell therapy, optionally an engineered T-cell receptor therapy, a chimeric antigen receptor T-cell therapy or a tumor-infiltrating lymphocyte therapy; a cancer vaccine, optionally talimogene laherparepvec, LV305 or CMB305; a colony-stimulating factor-1 inhibitor;- TTI-621; a DR5 agonist antibody; envafolimab; liposomal mifamurtide;liposomal daunorubicin; avelumab and regorafenibNXBTXR3 and irradiation;- BO-112 and nivolumab; envafolimab and ipilumumab; paclitaxel and nivolumab; doxorubicin and TTI-621;- talimogene laherparepvec and pembrolizumab;CMB305 and atezolizumab; melphalan and pembrolizumab; doxorubicin and ifosfamide; epirubicin and ifosfamide doxorubicin and dacarbazine; epirubicin and dacarbazine; doxorubicin and pembrolizumab; gemcitabine and pembrolizumab; pembrolizumab and lenvatinib; pembrolizumab and cabozantinib; pembrolizumab and epacadostat; gemcitabine and docetaxel; gemcitabine and vinorelbine; gemcitabine and dacarbazine; gemcitabine and pazopanib; sunitinib and nivolumab; melphalan, pembrolizumab and dactinomycin;- trabectedin, ipilimumab and nivolumab; docetaxel, gemcitabine and a PD-1 therapy;- vincristine, dactinomycin and cyclophosphamide; ifosfamide, doxorubicin and dacarbazine; doxorubicin, ifosfamide and mesna; ifosfamide, epirubicin and mesna; ifosfamide, doxorubicin and lenograstim; retifanlimab, gemcitabine and docetaxel; sintilimab, doxorubicin and ifosfamide;camrelizumab, doxorubicin and ifosfamide; mesna, doxorubicin, ifosfamide and dacarbazine; cyclophosphamide, vincristine, doxorubicin and dacarbazine; and nivolumab, gemcitabine, doxorubicin and docetaxel.

60. A method, use, or tigilanol tiglate or pharmaceutical composition for use, as claimed in any of claims 26 to 59, wherein the subject is a human.

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