Methods and uses for treating cancer

Abstract

The present disclosure includes a method for treating or ameliorating cancer or the effects of cancer in a subject in need thereof, comprising administering to the subject an effective amount of a hedgehog inhibitor (HHI) or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent (CTA).

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080050914.2 (application date: May 28, 2020, invention name: Methods and uses for treating cancer).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 853,842, filed May 29, 2019, the entire contents of each of which are hereby incorporated by reference herein. Field of the Invention

[0004] The present disclosure includes methods or uses for treating or ameliorating cancer or the effects of cancer in a subject in need thereof, comprising administering to the subject an effective amount of a hedgehog inhibitor (HHI) or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent (CTA). Background Art

[0005] One of the characteristics that are unique to pancreatic cancer is its stroma, which is often very dense and fibrous. Focus on the stroma is becoming a new strategy for the treatment of pancreatic cancer, and different regimens are currently being tested. For example, preclinical and clinical studies of Nab-P indicate that one of the mechanisms by which the drug exerts its effects is by eliminating the tumor stroma of pancreatic cancer. This elimination is accompanied by improved tumor vascularization and greater penetration of the drug into cancer cells, which may enhance anti-tumor efficacy. Subsequent clinical studies in patients treated with Nab-P have observed similar findings, while also showing that tumors treated with a combination of Gem and Nab-P became more elastic when their elasticity was measured by elastography. Other agents targeting the pancreatic cancer stroma are under development, including PEGPH20, a pegylated hyaluronidase that has shown interesting results in patients with tumors with high hyaluronan content.

[0006] A therapeutic target studied in pancreatic cancer is the Hedgehog (Hh) pathway. In preclinical studies, inhibition of Smo by cyclopamine analogs (IPI-926) resulted in selective stromal elimination, better tumor angiogenesis, and greater effects of Gem chemotherapy in these models. Based on these studies, a series of clinical trials using Smo inhibitors in combination with Gem were started, assuming that stromal elimination and better angiogenesis may be associated with better drug distribution and greater activity. Despite promising preclinical data, these studies did not show better results.

[0007] Subsequent preclinical studies in which Smo was genetically removed (by gene deletion) or treated chronically with Smo inhibitors showed results that could explain the negative data from clinical trials. In these studies, chronic elimination of the stroma led to a significant increase in tumor vascularization and proliferation of malignant cells, which in a sustained manner led to a greater number of metastases and a lower survival rate in treated animals.

[0008] The Hedgehog (Hh) pathway is a master regulator of many fundamental processes in vertebrate embryonic development, including stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. The Hh signaling pathway exerts its biological effects through a signaling cascade, ultimately leading to a change in the balance between the activator and repressor forms of glioma-related oncogene (Gli) transcription factors. Components of the Hh signaling pathway involved in the signaling shift to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), patched receptors (Ptch1, Ptch2), smoothened receptors (Smo), inhibitor of fusion homologs (Sufu), kinesin Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli enters the nucleus and stimulates the transcription of target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1.

[0009] Constitutive activation of the Hh pathway leading to tumorigenesis is found in basal cell carcinoma and medulloblastoma. Inappropriate activation of this pathway has also been demonstrated in a variety of other human cancers. Disregulation of the Hh signaling pathway is associated with developmental abnormalities and cancers, including Golan syndrome and sporadic cancers such as pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and small cell lung cancer. Abnormal activation of the Hh signaling pathway is caused by mutations in related genes (ligand-independent signaling) or by overexpression of Hh signaling molecules (ligand-dependent signaling-autocrine or paracrine). Paracrine Hh signaling from tumors to surrounding stroma has recently been shown to promote tumorigenesis. This pathway has also been shown to regulate the proliferation of cancer stem cells and increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in treating and preventing a variety of types of human cancers.

[0010] Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer therapy. These drugs are seen as promising cancer therapies, especially for patients with refractory / advanced cancer. Other Hedgehog inhibitors include TAK 441, taladegib, sonidegib, saridegib (patidegib) BMS833923 and LEQ506.

[0011] As described by Ohashi et al., due to an improved PK profile based on increased solubility, the pyrrolo[3,2-c]pyridine derivative TAK-441 suppressed the expression of transcription factor Gli1 mRNA in tumor-associated stromal tissue and inhibited tumor growth in a mouse medulloblastoma allograft model (treatment / control ratio, 3%). See, Ohashi et al., Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility, Bioorganic & Medicinal Chemistry, Vol. 20, No. 18, Sept. 15, 2012, incorporated herein by reference for such background teachings.

[0012] TAK-441 is 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, formula (I):

[0013]

[0014] The method of synthesizing TAK-441 is disclosed in U.S. Patent Nos. 8,217,176 and 8,399,449, each of which is incorporated herein by reference in its entirety. In addition, International Application Nos. PCT / JP2017 / 003453, WO 2017 / 135259 disclose certain cocrystals of TAK-441 with L-malic acid or L-tartaric acid, which are also incorporated herein by reference in their entirety. Such cocrystals can be used in the methods of the present disclosure.

[0015] There is a need for improved cancer therapies using hedgehog inhibitors. Summary of the invention

[0016] One embodiment of the present disclosure includes a method for treating a subject having a cancerous tumor, the method comprising transiently administering a hedgehog inhibitor (HHI) to the subject in combination with one or more additional cancer therapies. One embodiment of the present disclosure includes a method of transiently administering a hedgehog inhibitor (HHI) to a cancer patient in combination with one or more additional cancer therapies, wherein administration of the HHI is interrupted prior to initiation of clinically significant depletion of deleterious fibroblasts.

[0017] In one aspect, the HHI is administered prior to administration of at least one additional cancer therapy. In one aspect, administration of the HHI is interrupted prior to discontinuation of at least one additional cancer therapy. In one aspect, at least one additional cancer therapy is a systemically delivered therapy. In one aspect, the systemically delivered therapy is chemotherapy, targeted therapy, or immunotherapy. In one aspect, the additional cancer therapy is administration of a chemotherapeutic agent (CTA), and the HHI is administered prior to administration of the CTA. In one aspect, administration of the HHI is interrupted prior to discontinuation of the CTA. In one aspect, the tumor is a fibrotic tumor. In one aspect, the tumor is a solid tumor. In one aspect, the tumor has a high stromal content. In one aspect, the HHI reduces stromal content. In one aspect, the HHI induces angiogenesis within or around the tumor. In one aspect, the HHI improves tumor uptake of a subsequently administered CTA. In one aspect, administration of the HHI is interrupted such that further reduction of the stroma is stopped or clinically insignificant. In one aspect, administration of the HHI is interrupted such that further depletion of tumor fibroblasts is stopped or clinically insignificant. In one aspect, the administration of HHI improves the effect of another cancer therapy, but is interrupted before promoting clinically significant tumor growth. In one aspect, the administration of HHI is interrupted so that the administration of HHI does not subsequently initiate clinically significant, HHI-induced metastasis. In one aspect, the administration of HHI is interrupted so that the administration of HHI does not significantly increase the likelihood of subsequent tumor metastasis. In one aspect, the administration of HHI improves the efficacy of the cancer therapy subsequently administered. In one aspect, the improvement is confirmed by one or more of the following: metabolic response, positron emission tomography, objective response according to criteria, progression-free survival, overall survival, response based on the level of tumor markers, toxicity, and tumor elasticity. In one aspect, the improvement is confirmed by prolonged survival or prolonged time to disease progression. In one aspect, the improvement is confirmed by progression-free survival. In one aspect, the cancer is pancreatic cancer, esophageal cancer, squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, hepatocellular carcinoma, renal cancer, or bile duct cancer. In one aspect, the cancer is pancreatic ductal adenocarcinoma (PDAC). In one aspect, the cancer is hepatocellular carcinoma. In one aspect, the HHI is a Smo antagonist. In one aspect, the Smo antagonist is selected from TAK 441, glasdegib, taladegib, sonidegib, saridegib, patidegib, BMS833923, LEQ506, and combinations thereof. In one aspect, the HHI is TAK 441.In one aspect, the CTA is selected from gemcitabine, nab-paclitaxel, taxol, irinotecan, temozolomide, capecitabine, topotecan, cisplatin, oxaliplatin, carboplatin, camptothecin, cytarabine, fluorouracil, cyclophosphamide, etoposide phosphate, teniposide, doxorubicin, daunorubicin and pemetrexed. In one aspect, the CTA is one or more of nab-paclitaxel, gemcitabine and cisplatin. In one aspect, the CTA is one or more of nab-paclitaxel and gemcitabine. In one aspect, the route of administration of the HHI is selected from intravenous, oral and topical. In one aspect, the route of administration of the additional cancer therapy is selected from intravenous, oral and topical. In one aspect, the doses of the HHI and the additional cancer therapy are administered between the biologically effective dose and the maximum tolerated dose. In one aspect, the patient receives treatment cycles, and the additional cancer therapy is a CTA administered in all or substantially all treatment cycles. In one aspect, the patient receives additional cancer therapy treatment cycles and the HHI is administered in less than all treatment cycles. In one aspect, the patient receives additional cancer therapy treatment in multiple cycles and one or more doses of the HHI are administered only before and during earlier treatment cycles. In one aspect, one or more doses of the HHI are administered only 1-10 days before chemotherapy for 1-5 cycles. In one aspect, one or more doses of the HHI administered are administered no later than the third cycle. In one aspect, each cycle is 28 days and the HHI is administered on days -4 to -1 and days 10 to 13 of each cycle of cycles 1-3 and CTA is administered on days 1, 8 and 15 every 28 days. In one aspect, the HHI is TAK 441 at a dose of 800 mg. In one aspect, the CTA is selected from one or more of 1000 mg / m. 2 Gemcitabine and 125 mg / m 2Albumin-bound paclitaxel. In one aspect, one or more doses of additional cancer therapy are followed by one or more doses of a checkpoint inhibitor (CI). In one aspect, the CTA is a checkpoint inhibitor (CI) administered in one or more doses. In one aspect, the route of administration of the CI is selected from intravenous, oral or topical. In one aspect, one or more doses of the CI are administered between the biologically effective dose and the maximum tolerated dose. In one aspect, the CI is a CTLA 4 inhibitor, a PD1 inhibitor or a PDL1 inhibitor. In one aspect, the CI is Tremelimumab, Ipilimumab, Durvalumab, Nivolumab, Pembrolizumab, Atezolizumab, Cemiplimab, AGEN1884, AGEN2034 or AGEN1181. In one aspect, the CI is Ipilimumab. In one aspect, the patient is treated in multiple cycles, and one or more doses of the CI are administered only near the end or start of the treatment cycle. In one aspect, one or more doses of CI are administered only within 7 days of the end of a treatment cycle. In one aspect, one or more doses of CI are administered only after at least 1, 2, or 3 treatment cycles. In one aspect, the cycle is 28 days, and CI is administered on days 1 and 21 of each cycle starting with cycle 4. In one aspect, the CI dose is a 3 mg / kg intravenous dose of ipilimumab.

[0018] One embodiment of the present disclosure includes a method of treating or ameliorating cancer or the effects of cancer in a subject in need thereof, comprising administering to the subject an effective amount of a hedgehog inhibitor (HHI) or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent (CTA).

[0019] In one aspect, the HHI is TAK 441. In one aspect, the CTA is nab-paclitaxel. In one aspect, the CTA is a checkpoint inhibitor (CI). In one aspect, the method further comprises administering a checkpoint inhibitor (CI). In one aspect, the cancer has a fibrotic stroma. In one aspect, the cancer is pancreatic cancer, esophageal cancer, squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, hepatocellular carcinoma, renal cancer, or bile duct cancer. In one aspect, the cancer is pancreatic adenocarcinoma (PDAC). In one aspect, the cancer is hepatocellular carcinoma. In one aspect, the therapeutic effect is measured by tumor regression. In one aspect, the therapeutic effect is measured by a tumor growth inhibitor in a tumor growth inhibition model selected from one or more of the following: metabolic response as measured by fluorodeoxyglucose (FDG), PET according to EORTC criteria, objective response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, progression-free survival, overall survival, response based on the level of tumor markers (e.g., CA 19.9), toxicity (e.g., according to Common Toxicity Criteria for Adverse Events Terminology, National Cancer Institute, version 4.03 (NCI CTCAE v4.03)), and tumor resilience.

[0020] One embodiment of the present disclosure includes the methods described herein, as the use of the listed agents for treating the listed diseases or disorders.

[0021] One embodiment of the present disclosure includes the methods described herein as use of the listed agents in the preparation of a medicament for treating the listed diseases or disorders.

[0022] One embodiment of the present disclosure includes the use of a listed agent for treating a listed disease or disorder.

[0023] One embodiment of the present disclosure includes the use of a listed agent as a medicament for treating a listed disease or disorder.

[0024] One embodiment of the present disclosure includes pharmaceutical compositions comprising the listed agents for use in treating the listed diseases or disorders.

[0025] One embodiment of the present disclosure includes the listed agents, which are suitable for use in treating the listed diseases or disorders.

[0026] Although not specifically described, one or more aspects and embodiments may be combined in different embodiments. That is, all aspects and embodiments may be combined in any manner or combination. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Shown are tumor growth (percentage relative to initial tumor volume) of the Panc163 model treated with the indicated regimens. Tumors were implanted s.c.

[0029] Figure 2 Shown are tumor growth (percentage relative to initial tumor volume) of the JH051 model treated with the indicated regimens. Tumors were implanted s.c.

[0030] Figure 3 . Shown is the tumor growth (percentage relative to the initial tumor volume) of the Panc025 model treated with the indicated regimens. Tumors were implanted s.c.

[0031] Figure 4 Representative images of Masson's staining of Panc 163 tumor samples obtained from all experimental arms.

[0032] Figure 5 Representative images of Masson's staining of Panc 025 tumor samples obtained from all experimental groups. In the first column, the staining pattern at the day of treatment initiation is shown.

[0033] Figure 6 Scenario 1 is shown. Figure 7 Scenario 2 is shown, Figure 8 Scheme 3 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0035] definition

[0036] As used herein, "treat" (also referred to as "treatment") refers to any medical intervention or administration of a substance that partially or completely alleviates, ameliorates, relieves, suppresses, delays the onset of, reduces the severity of, or reduces the incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition.

[0037] As used herein, "transient administration of an agent" means administration that is interrupted either permanently or for a set period of time, such that administration does not continue throughout all cycles of treatment.

[0038] As used herein, "cancer," "malignancy," "neoplasm," "tumor," and "cancer" are used interchangeably and refer to cells that exhibit abnormal, uncontrolled or autonomous growth.

[0039] As used herein, "chemotherapeutic agent" means one or more of a pro-apoptotic agent, a cytostatic agent, or a cytotoxic agent.

[0040] As used herein, "clinically significant" refers to, but is not limited to, worthy of consideration or having an impact in clinical decision making.

[0041] As used herein, the term "clinical" refers to information related to or based on the actual observation and treatment of patients, as distinguished from theoretical or basic science.

[0042] As used herein, the phrase "administration regimen" or alternatively "treatment regimen" refers to a set of unit dosages, usually more than one, which are administered separately to a subject, usually at intervals of time.

[0043] As used herein, "time to disease progression" ("TTP") means the time from the time of initial treatment to the progression or worsening of cancer, usually measured in weeks or months. Such progression can be determined by testing or observation, such as evaluation by a skilled clinician.

[0044] As used herein, "prolonging TTP" means increasing the time before disease progression in treated patients relative to untreated patients.

[0045] As used herein, "survival" means that the patient remains alive, and includes overall survival as well as progression-free survival.

[0046] As used herein, "overall survival" means that a patient remains alive for a defined period of time (such as 1 year, 5 years or longer) from the time of diagnosis or treatment.

[0047] As used herein, "progression-free survival" means that the patient remains alive without the cancer progressing or getting worse. Such progression can be determined by testing or observation, such as by evaluation by a skilled clinician.

[0048] As used herein, "prolonging survival" means increasing overall survival or progression-free survival in treated patients relative to untreated patients.

[0049] As used herein, relative terms of treatment achievement, such as "improvement," "increase," or "decrease," or grammatical equivalents thereof, indicate a value or condition compared to a baseline measurement or condition, such as a measurement in the same individual before initiation of a treatment described herein, or a measurement in a control individual (or multiple control individuals) in the absence of a treatment described herein.

[0050] As used herein, "biologically effective dose" refers to the amount of an absorbed compound that reaches a target or site of action in the body to cause a biological effect.

[0051] As used herein, "maximum tolerated dose" (or MTD) means the highest dose of a drug or treatment that does not cause unacceptable side effects.

[0052] As used herein, a "cycle" refers to a treatment regimen administered over a period of time.

[0053] As used herein, a "fibrotic response to a malignancy" refers to an increase or decrease in the progression and / or persistence of fibroids in a tumor.

[0054] As used herein, "tumor regression" refers to the cessation of growth or a decrease in size, mass, or number of tumor mass or tissue.

[0055] As described above, TAK-441 is an investigational small molecule that is orally administered and inhibits Smo. In an in vitro model, TAK-441 inhibits the binding of cyclopamine, a human Smo inhibitor, to a 50% inhibitory concentration (IC 50 ). In a mouse model of castration-resistant prostate cancer, TAK-441 was demonstrated to inhibit paracrine signaling of Hh ligands and thereby suppress tumor progression.

[0056] TAK-441 was studied in a Phase I trial at participating Spanish sites. This recently published trial studied the safety, tolerability, pharmacokinetics, and preliminary clinical activity of single and multiple doses of TAK-441. A total of 34 patients with advanced solid tumors (colorectal cancer (26%), basal cell carcinoma (21%), and pancreatic cancer (9%)) were included (median age: 59 years, range: 28-82 years). Patients received daily doses of oral TAK-441 (PO) in the range of 50-1600 mg. The daily dose was then doubled in each cohort until the maximum tolerated dose (MTD) was reached. Blood samples were collected to evaluate the plasma concentration of TAK-441 after administration, as well as skin biopsies to determine the inhibition of Gli1 gene expression.

[0057] Based on the size of the tablet and its potency, the MTD was established at 1600 mg / day. Dose-limiting toxicities included muscle cramps and fatigue. Oral absorption was fairly rapid, with a mean maximum time (T max ) is 1.8-4.2 hours after a single dose, and 2.4-4.0 hours after multiple doses. The median elimination half-life is 12.9-18.3 hours. The pharmacokinetics of TAK-441 based on the area under the plasma concentration-time curve (AUC) are linear over the entire dose range. Inhibition of Gli1 gene expression in skin biopsies was observed at all doses analyzed.

[0058] As noted, the present disclosure includes a method for treating a subject having a cancerous tumor. The method includes transiently administering a hedgehog inhibitor (HHI) to the subject in combination with one or more additional cancer therapies. The additional cancer therapies may be selected from, but are not limited to, chemotherapy, immunotherapy, and targeted therapy. The present disclosure further includes a method of transiently administering the HHI to a cancer patient in combination with one or more additional cancer therapies, wherein administration of the HHI is interrupted prior to the onset of clinically significant deleterious fibroblast depletion, including, but not limited to, systemic side effects such as the development of cachexia, anemia, and other paraneoplastic syndromes, as well as the induction of immunosuppression and acceleration of cancer.

[0059] In this regard, the reduction of stroma and the induction of angiogenesis can be considered positive because they allow for better delivery of chemotherapeutic agents. Fibrotic tumors have low vascular density and are hypovascular. For these reasons, drugs cannot penetrate fibrotic tumors. Therefore, the induction of angiogenesis will improve the uptake of drugs. However, there is a fine balance between the positivity of this effect and then becoming harmful. When fibrosis is eliminated or overly restricted, the tumor becomes overvascularized, and this leads to higher metastasis and shorter patient survival.

[0060] TAK-441 is being developed for oral use to treat advanced hematologic and non-hematologic malignancies. Preclinical studies have determined that TAK-441 is orally bioavailable in multiple species. It produced a 50% inhibition (IC ) of 4.4 nM in a luciferase-Gli-sensitive (Gli-luc) promoter assay using cells / Gli-luc NIH3T3. 50 ) concentration, TAK-441 inhibited Gli transcriptional activity. In MRC5 human embryonic fibroblasts, an IC of 1.9 nM was produced 50 TAK-441 also inhibited the expression of Gli1 mRNA at concentrations of 1.5 nM. In addition, TAK-441 inhibited the binding of cyclopamine to human Smo (hSmo) in 293T cells overexpressing hSmo with an IC of 8.6 nM. 50 These data suggest that TAK-441 inhibits the Hh signaling pathway through its binding to Smo.

[0061] Administration of TAK-441 in an allograft model of medulloblastoma or a mouse xenograft model PAN-04 primary human pancreas with mutations in Ptch1(+ / -) (Ptch1 heterozygotes) and p53(- / -) (no (null) p53) resulted in dose-dependent inhibition of mouse or stromal tumors, respectively, associated with expression of Gli1 mRNA in vivo. TAK-441 exhibited significant dose-dependent tumor activity in these models (p<0.025). In addition, the combination of TAK-441 and rapamycin, an inhibitor of mTOR (mammalian rapamycin target), showed better combined antitumor activity than the activity of any agent alone in the PAN-04 mouse model of pancreatic cancer.

[0062] In vivo pharmacokinetics

[0063] TAK-441 is characterized by a low CL (161.3 and 397.9 ml / h / kg), a moderate volume of distribution (Vss) in steady-state plasma (681.6 and 2181.3 ml / kg), and a moderate t1 / 2 (1.7 and 9.8 hours), with oral bioavailability of 31.7% and 90.3% in rats and dogs, respectively. There were no differences in plasma exposure between the sexes in rats or dogs. Regarding the effect of food, in dogs, an approximately 2-fold increase in the extent of absorption was observed when TAK-441 was administered to fed dogs (compared to fasted dogs), resulting in a C max and the increase in the area under the 0-24 hour plasma concentration versus time curve (AUC0-24h).

[0064] At a concentration of 1.73 mM, TAK-441 has high binding to plasma proteins in mice (99.7%) and rats (96.2%), and low binding in dogs (79.6%) and humans (87.7%). TAK-441 is metabolized to unidentified metabolites by cytochrome P450 (CYP) isozymes CYP3A4 / 5 after oral administration to rats and dogs. When liver microsomes were incubated, no human-specific metabolites were detected. TAK-441 is a weak inhibitor of CYP2C8 and has no inhibitory effect on other CYP isozymes. TAK-441 is not a time-dependent inhibitor of CYP isozymes in human liver microsomes. Therefore, the possibility of TAK-441 affecting the pharmacokinetics of other CYP3A4 / 5 substrates administered concomitantly is low. However, concomitant administration of CYP3A inhibitors and / or inducers may affect the pharmacokinetics of TAK-441. TAK-441 has high permeability in Caco-2 cells (Papp,A-to-B 19.6'10 -6 cm / sec; Papp,B-to-Un 37.8'10-6 cm / sec), is a poor substrate for the P-glycoprotein (P-gp) flow pump, and is a weak inhibitor of P-gp (IC 50 is 6.59mM).

[0065] Safety Pharmacology

[0066] The biochemical activity of TAK-441 (at a concentration of 10 mM) was performed in a total of 126 experiments. Of the enzymes, receptors, and transporters included in the TAK-441 assay, it inhibited one enzyme, human PDE4 phosphodiesterase, and one transporter, the human neurotransmitter dopamine, by more than 50% (67% and 75%, respectively).

[0067] Toxicology studies

[0068] In a toxicology study conducted under Good Laboratory Practice (GLP), TAK-441 was administered to rats and dogs at exposures exceeding the expected concentration to achieve efficacy associated with a variety of changes attributable to pharmacological inhibition of the Hh signaling pathway. These changes include: weight loss; atrophy of growth plates in the ribs and hair follicles; erosion or ulceration of the gastric mucosa; anemia; necrosis and hematopoiesis of the bone marrow and inflammation and hemorrhage of the lungs. Dose-limiting toxicities observed in dogs include: weight loss; decreased food consumption; gastrointestinal damage (vomiting, diarrhea, anorexia, weight loss, ulceration, and bleeding). Each of these effects is considered to be easy to follow up clinically and through laboratory tests.

[0069] The results of studies conducted with TAK-441 indicate that the observed clinically relevant changes, including changes in hematological parameters, gastrointestinal disorders, decreased appetite and weight loss, are reversible. Isolated changes for which reversibility has not been confirmed include atrophy of growth plates in hair follicles and bones and changes in incisors. In the case of clinical administration of TAK-441 to adult patients with cancer, atrophy of growth plates and changes in incisors are not considered relevant toxicological findings because in adult patients, the growth plates have closed and the incisors have matured. On the other hand, the relevance of gait changes and tremors observed in rats to humans is unknown and clinical follow-up is easy.

[0070] TAK-441 Phase 1 Trial

[0071] As described above, TAK-441 has been evaluated in a Phase 1 study in patients with advanced cancer. A total of 34 patients (median age: 59 years, range: 28-82 years) with advanced solid tumors (colorectal cancer (26%), basal cell carcinoma (21%), and pancreatic cancer (9%)) were included. Patients received daily doses of TAK-441 oral (PO) in the range of 50-1600 mg. The daily dose was subsequently doubled in each cohort until the maximum tolerated dose (MTD) was reached. Blood samples were collected to evaluate the plasma concentration of TAK-441 after administration, as well as skin biopsies to determine the inhibition of Gli1 gene expression. The MTD was established at 1,600 mg / day (based on the size of the tablet and its potency). The adverse effects observed are detailed in Table 2. Dose-limiting toxicities include muscle cramps and fatigue. Oral absorption is quite rapid; the average T max The median elimination half-life was 12.9-18.3 hours. The pharmacokinetics of TAK-441 based on plasma concentration-time AUC were linear across the entire dose range. Inhibition of Gli1 gene expression in skin biopsies was observed at all doses analyzed.

[0072] Partial responses were observed in 1 patient with basal cell carcinoma, and stable disease was observed in 7 patients with various solid tumors.TAK-441 was well tolerated, exhibiting an MTD of 1600 mg / day, with evidence of antitumor activity.

[0073] Chemotherapeutic agents (CTA)

[0074] Two exemplary CTAs include cytostatics, specifically gemcitabine ("Gem") and nab-paclitaxel ("nab-P"). Gem has marketing authorization for use in patients with locally advanced or metastatic pancreatic adenocarcinoma. It is a nanoparticle formulation of paclitaxel bound to albumin, and its performance may be very different from other paclitaxel formulations. Nab-P is approved by the European Medicines Agency (EMA) for commercialization in combination with Gem for the treatment of patients with advanced pancreatic cancer.

[0075] Both cytotoxins are prepared by the pharmacy service and administered intravenously according to the specifications described in their respective technical data sheets. Where possible, treatment should be administered during the day in the hospital (to enable the patient to be ambulatory) and at home. Nab-P can be administered as a 30-minute intravenous infusion followed by a 30-minute intravenous infusion of Gem.

[0076] A typical dose and administration schedule is nab-P 125 mg / m 2 Intravenous (IV), then Gem 1,000 mg / m on days 1, 8, and 15 of a 28-day cycle 2 Intravenous (IV).

[0077] Other CTAs include, but are not limited to, taxol, irinotecan, temozolomide, capecitabine, topotecan, cisplatin, oxaliplatin, carboplatin, camptothecin, cytarabine, fluorouracil, cyclophosphamide, etoposide phosphate, teniposide, doxorubicin, daunorubicin, and pemetrexed. Example

[0078] Example 1 Targeting pancreatic cancer stroma with TAK441

[0079] To determine whether the combination of TAK441 and nab-paclitaxel would result in antitumor synergy and to evaluate the sequential promotion and inhibition of angiogenesis, three (3) different pancreatic ductal adenocarcinoma (PDAC) tumors (Panc163, JH051, and Panc025) from the PancXenoBank were treated with a combination of nab-paclitaxel (ABI) and TAK-441, a hedgehog inhibitor.

[0080] After several dose-finding studies to determine the most feasible dose of nab-paclitaxel, a dose of 50 mg / kg 1dq4 x 3 was used. TAK-441 was selected and administered daily at the recommended dose (25 mg / kg orally daily). The study was conducted for 21 days.

[0081] As in Figure 1-3 As shown in , the combination of the two agents resulted in synergistic tumor regression in all models analyzed compared to either agent alone.

[0082] Based on the tumor volume values ​​at day 21 of the experiment, the tumor growth inhibition (TGI) factors were estimated as shown in Table 1. In all three pancreatic cancer models, the greatest inhibition was observed when mice were treated with a combination of nab-paclitaxel and the antistromal agent TAK-441.

[0083] Table 1

[0084]

[0085] To evaluate the histological status of the stroma after treatment, Masson's Trichrome stained slides from the Panc 163 and Panc025 models were analyzed.

[0086] like Figure 4 and 5 As shown, samples from the ABI-treated group showed more tumor shrinkage and increased presence of fibrosis (based on collagen staining).

[0087] Example 2 (prophetic)

[0088] A Phase I / II clinical trial (which may be one or more of open, multicenter, and non-randomized) includes a number of patients with advanced pancreatic cancer selected to have adequate power, e.g., twenty-five (25), who meet the protocol-specified inclusion criteria (without exclusion), or who are subsequently withdrawn based on relevant criteria and / or protocol.

[0089] According to the conventional treatment regimen, patients received gemcitabine (1000 mg / m2) on days 1, 8, and 15 of each cycle (every 28 days). 2 IV)(G) and nab-P (125 mg / m 2 IV) (A) conventional chemotherapy. In cycles 1-3, TAK-441 (also known as NLM-001) is administered at a dose of 800 mg / day orally (PO) for 4 days prior to treatment on days 1 and 15, followed by a day of rest before treatment with chemotherapy. Initially, a subset, such as six (6) patients, is included and the toxicity of one treatment cycle is observed. If more than two ≥ grade 3 toxic events associated with TAK-441 occur, the drug dose is reduced to 400 mg / day.

[0090] Tumor elasticity was measured by endoscopic ultrasound and elastography at baseline and on days -1 and 13 of cycle 1. Biopsies of the primary tumor were performed simultaneously at baseline and on day 13 of cycle 1. After the first cycle, patients continued treatment until disease progression or unacceptable toxicity. Figure 6 Option 1.

[0091] Patients were treated for four (4) cycles of four days on and four days off.

[0092] Treated patients are considered to show improvements over control patients, including, but not limited to, improvements in one or more of the following:

[0093] Metabolic response, by FGDPET (according to EORTC criteria).

[0094] Objective response according to RECIST criteria.

[0095] Objective response determined by Response and Evaluation Criteria in Solid Tumors (RECIST) v 1.1. These criteria are a set of published criteria that define when a cancer patient improves, stabilizes, or worsens during treatment. Results are tabulated according to different response categories.

[0096] Progression-free survival, overall survival: Progression-free survival (PFS) at 3 and 6 months (% PFS-3m; % PFS-6m) is defined as the percentage of patients who have no cancer progression (growth or spread) after 3 or 6 months of recruitment recorded from the start of randomization. Estimation was performed by constructing a survival table using the Kaplan-Meier method. For the purpose of statistical analysis, the date corresponding to disease progression was:

[0097] i. Planned response review when progression is documented by CT and / or physical examination.

[0098] ii. Death from any cause in the absence of previously documented progression.

[0099] iii. Initiation of second-line therapy following a decision to interrupt protocol treatment for any reason, either for reasons of toxicity or tolerability.

[0100] iv. Record of progression when no second-line therapy was given after protocol treatment was suspended.

[0101] v. Overall survival was determined from the start of treatment until the patient's death due to any cause. It was estimated by constructing a survival table using the Kaplan-Meier method.

[0102] Response based on tumor marker CA 19.9 levels

[0103] CA 19.9 response was calculated as the maximum percent change from baseline in those patients whose baseline was above 1.25 times the upper limit of normal of the local laboratory at each center. In addition, the results were tabulated according to categorical responders and non-responders, for which three different response criteria were used: a reduction of more than 50%, more than 75%, and more than 90%, respectively.

[0104] Toxicity according to CTCAE NCI v4.03

[0105] The safety of treatment is described by tabulating all observed adverse effects, including clinical events and laboratory data. They are classified, and their severity is quantified according to Common Terminology Criteria for Adverse Events, National Cancer Institute 4.3 versions (CTCAE-NCI v.4.3) of adverse events. Disease progression is considered to be the result of the natural course of disease, so it is collected in patient CRF, and is not considered as adverse events in this study. Therefore, disease progression is not communicated according to the pharmacovigilance program, but must be recorded in the response category according to the measures specified in the scheme.

[0106] Tumor elasticity

[0107] The second variable of the study is the measurement of tumor elasticity by elastography, which is defined as the "quotient strain ratio" between tumor tissue and normal tissue as described previously. The Pentax linear echoendoscope and the Hitachi EUB900 device will be used for its measurement. Areas representing tumor and normal surrounding tissue will be selected. The results of elastography are expressed by the "quotient strain ratio" between tumor tissue and normal tissue. In previous studies, the average value of this index was 32. We hope to reduce it by at least 50% with TAK-441 treatment.

[0108] Biomarkers

[0109] Expression of Gli-1 mRNA, smooth muscle actin-positive cancer-associated fibroblasts (SMA+CAFs), collagen structure, and lymphocyte infiltration (CD3, CD4, and CD8).

[0110] Example 3 (prophetic)

[0111] Phase I / II clinical trials (which can be one or more of open, multicenter, and non-randomized as in Example 2) that additionally add administration of checkpoint inhibitors, such as PD1 or CTLA4 inhibitors. An example is ipilimumab.

[0112] As an example, starting with cycle 4, ipilimumab is administered at a 3 mg / kg intravenous dose on days 1 and 21 of each cycle, as in regimen 2 (see Figure 7 Otherwise, the dosage and improvement endpoints remained as described in Example 2.

[0113] As another example, a treatment regimen may include: NLM-001: 800 mg / day orally on days -4 to -1 and days 10 to 13 of each cycle of cycles 1-3; gemcitabine (G): 1,000 mg / m orally on days 1, 8, and 15 every 28 days. 2 Intravenous; Abraxane (A): 125 mg / m on days 1, 8, and 15 every 28 days 2 Intravenous; and CTLA-4 inhibitor (CTLA-4): 1 mg / kg on Day 15 of Cycle 1 and Days 1 and 15 of subsequent cycles. Figure 8 Scheme 3 shown is exemplary.

[0114] As in Example 2 above, tumor elasticity was measured by endoscopic ultrasound and elastography at baseline and on days -1 and 13 of cycle 1. Biopsies of primary tumors were performed simultaneously at baseline and on day 13 of cycle 1. After the first cycle, patients continued treatment until disease progression or unacceptable toxicity. In addition, the improvement endpoints remained as described in Example 2.

[0115] Prophetic Examples 2 and 3 together provide direction to demonstrate that brief, so-called "shock" administration of TAK 441 transiently reduces pancreatic cancer stroma in advanced pancreatic cancer patients, thereby facilitating the action of chemotherapy treatment.

[0116] Example 4 (prophetic)

[0117] Hepatocellular carcinoma (HCC) is a lethal tumor whose incidence is increasing in the United States, primarily due to the prevalence of hepatitis C infection. HCC is the most common primary liver cancer and the second leading cause of cancer death worldwide. See, Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancerincidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5): E359-E386. doi: 10.1002 / ijc.29210. Despite major advances in the diagnosis and treatment of HCC, its prognosis remains extremely poor, with a 5-year overall survival (OS) rate of 12% for all stages combined (supra). Most HCC (80-90%) develop from underlying chronic liver disease (with or without cirrhosis); major causes include chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcohol consumption, nonalcoholic steatohepatitis, or other less common causes such as hemochromatosis, tobacco, and aflatoxin B 1. The highest incidence of HCC is observed in Southeast Asia and Central Africa, where endemic chronic HBV infection accounts for 70% of cases.See, e.g., Pawlotsky JM. Pathophysiology of hepatitis C virus infection and related liverdisease. Trends Microbiol. 2004; 12(2):96-102; Trepo C, et al., Hepatitis B virus infection. Lancet. 2014; 384(9959):2053-2063; Morgan TR, et al., Alcohol and hepatocellular carcinoma.Gastroenterology, 2004;127(5Suppl 1):S87-S96; ZhangDY, et al., Fibrosis-dependent mechanisms of hepatocarcinogenesis.Hepatology.2012;56(2):769-775; Bugianesi E, et al., NASH and the risk of cirrhosis and hepatocellular carcinoma in type 2diabetes.Curr Diab Rep. 2007; 7(3): 175-180; Forner A, et al., Hepatocellular carcinoma. Lancet. 2012; 379(9822): 1245-1255; and Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Prime. 2016, each of which is incorporated by reference for background on HCC.

[0118] The "Barcelona Clinic Liver Cancer" (BCLC) classification is currently recommended to assess prognosis and select the most appropriate treatment for patients with HCC (available online at https: / / www.esmo.org / Guidelines / Gastrointestinal-Cancers / Hepatocellular-Carcinoma). There are five BCLC grades (0, A, B, C, and D), which take into account both the underlying liver function assessed by the Child-Pugh score and the patient's general condition according to the Eastern Collaborative Oncology Group Performance Status (ECOGPS). The only curative treatment for HCC, reserved for patients with early-stage HCC (BCLC stage 0, stage A), is surgical resection, thermal ablation, radiotherapy, and / or liver transplantation. Adjuvant therapy for HCC has not yet been validated.

[0119] Hedgehog signaling promotes tumor-associated macrophage polarization to inhibit CD8+T cell recruitment in tumors. See, Petty et al., Journal of Clinical Investigation (2019), which is incorporated herein by reference for such a test protocol. The compound TAK-441 of the present disclosure can be co-administered with PD-1 blockade to provide synergistic efficacy. Also refer to the article: Scientists discover reasons why targeted immuno-oncology drugs sometimes fail (October 23, 2019), from https: / / medicalxpress.com / news / 2019-10-scientistsimmuno-oncology-drugs.html, which is incorporated herein by reference for such a test protocol. This synergy may be particularly suitable for treating HCC.

[0120] PD-1 is a checkpoint protein on T cells, a type of immune cell that helps the body recognize abnormal cells and diseases in the body. PD-1 normally acts as a "shutdown switch" that helps prevent T cells from attacking other cells. PD-1 inhibitors are used to selectively block this protein and enhance the immune response to attack cancer cells. Previously reported data have shown that one of the main reasons why some cancer patients do not respond to PD-1 therapy is that fighting T cells (called CD8 T cells) cannot invade the tumor microenvironment, a state also known as "cold tumors." In their study, Yang et al. reported data showing a specific cellular mechanism that limits the ability of CD8 T cells to infiltrate the tumor microenvironment. They showed that Hedgehog signaling shuts off chemokine secretion by tumor-associated macrophages—which is critical for CD8 T-cell infiltration. By blocking (inhibiting) the hedgehog pathway, the researchers were able to reverse the process and promote CD8 T cell infiltration into the tumor microenvironment. The data showed that hedgehog inhibitors administered in combination with PD-1 blockade were more effective in killing cancer cells than single agents alone in preclinical models including liver and lung cancer.

[0121] The hedgehog (HH) pathway is involved in the embryonic development of the liver, and its reactivation plays an important role in maintaining cancer cell growth and progression in hepatocellular carcinoma (HCC). In liver carcinogenesis, HH signaling is required for the differentiation, proliferation, and polarity of hepatoembryonic cells. High expression levels of HH components in HCC tissue are associated with mesenchymal properties and maintain the proliferation of cancer stem cells, which is a dynamic source of malignant cells in HCC progression. Current data on HH inhibition in preclinical models further confirm the role of HH and deserve future study in the clinical setting. See, e.g., Implication of the Hedgehog pathway in hepatocellular carcinoma, Della Corte, et al., World J Gastroenterol. 2017 Jun 28; 23(24): 4330-4340. Published online June 28, 2017.

[0122] Examples of checkpoint inhibitors may include one or more of the following: PD-1 inhibitors such as pembrolizumab Nivolumab and cimiprilimab PD-L1 inhibitors such as atezolizumab Avelumab Durvalumab and CTLA-4 inhibitors such as ipilimumab Additional checkpoint inhibitors include tremelimumab, AGEN1884, AGEN2034, or AGEN1181.

[0123] Study Description

[0124] A Phase I / II clinical trial (which is one or more of open, multicenter, and non-randomized as in Example 2) additionally adds administration of a checkpoint inhibitor, such as a PD1 or CTLA4 inhibitor, as noted herein.

[0125] The Hedgehog inhibitor TAK-441 (which may also be referred to as NLM001) can be administered at a dose of 800 mg / day (a dose lower than the maximum previously administered) for 4 cycles for 5 days. At the end of each cycle, the administration is followed by the administration of the checkpoint inhibitor. It is believed that the effect shown by this combination is higher than that shown by any single agent alone.

[0126] In one aspect of the embodiments provided herein, the improvement in the patient is demonstrated by one or more of:

[0127] Metabolic response,

[0128] Positron emission tomography,

[0129] According to the standard objective response,

[0130] Progression-free survival,

[0131] Total survival,

[0132] Response based on tumor marker levels,

[0133] Toxicity, and

[0134] Tumor elasticity.

[0135] In this regard, metabolic response can be measured by fluorodeoxyglucose (FDG), PET can be evaluated according to EORTC criteria, objective response can be evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, progression-free survival is as defined herein, overall survival is as defined herein, response based on the level of tumor markers can be evaluated for, for example, CA 19.9, toxicity can be evaluated according to, for example, Common Toxicity Criteria for Adverse Events Terminology (National Cancer Institute) version 4.03 (NCI CTCAE v4.03)), and the elasticity of the tumor can be evaluated by elastography, which is defined as the quotient strain ratio between tumor tissue and normal tissue.

[0136] All subjects will be included in the efficacy analysis according to the principle of "by treatment intention". All subjects who have received at least the first dose of the first treatment cycle will be included in the toxicity analysis.

[0137] The elasticity index will be graphically represented for each subject and measurement time. For each patient, the change in this parameter will be calculated for each measurement point. The values ​​at different points will be compared with the aid of a nonparametric test for paired samples. The changes in CA 19.9 will be analyzed in the same way.

[0138] Objective responses by CT and / or MRI will be analyzed according to RECIST criteria, with responses attributed to each subject. Descriptive statistics will be used to summarize the overall data of the study. Responses by PET will also be analyzed using EORTC criteria.

[0139] Biomarker analyses for each subject will be presented graphically. Data will be summarized using descriptive statistics for each collection point, including calculations of proportional changes before and after treatment and comparisons of nonparametric methods for paired samples. Overall, we will use methods previously published in GA studies.

[0140] Likewise, pharmacokinetic parameters will be represented and visualized graphically and summarized using descriptive statistics.

[0141] Descriptive statistics will be used to describe adverse events characterized by type, frequency, severity (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03), timing, severity, and relationship to study treatment.

[0142] Overall survival is defined as the time elapsed between the inclusion date and the date of death. Progression-free survival is defined as the time elapsed between the inclusion date and the date of progression (i.e., the start of second-line treatment without recorded progression or death). Both variables will be studied using survival curves according to the Kaplan-Meier method.

[0143] Given the exploratory nature of the study design, correction for the diversity of tests used was not considered necessary.

[0144] The significance level used in all statistical tests will be a value of p = 0.05, two-sided.

[0145] Details of the analysis will be reflected in a statistical analysis plan, which will be prepared before the study database is closed.

[0146] All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the purposes of the teachings of such references.

[0147] The test compounds used in the experiments described herein were used in free or salt form.

[0148] The specific responses observed may vary according to and depending on the particular active compound selected or the presence or absence of carrier and the type of formulation employed and the mode of administration, and such expected variations or differences in results are encompassed by the practice of the present invention.

[0149] Although specific embodiments of the present invention are described and described in detail herein, the present invention is not limited thereto. The above detailed description is provided as an example of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not deviate from the spirit of the present invention are intended to be included within the scope of the appended claims.

[0150] In summary, this application includes but is not limited to the following items:

[0151] 1. A method of treating a subject having a cancerous tumor, the method comprising transiently administering to the subject a hedgehog inhibitor (HHI) in combination with one or more additional cancer therapies.

[0152] 2. A method of transiently administering a hedgehog inhibitor (HHI) to a cancer patient in combination with one or more additional cancer therapies, wherein administration of the HHI is discontinued prior to initiation of clinically significant depletion of deleterious fibroblasts.

[0153] 3. The method according to item 1 or 2, wherein the HHI is administered prior to administration of at least one additional cancer therapy.

[0154] 4. The method according to any one of items 1 to 3, wherein administration of the HHI is discontinued prior to discontinuation of at least one additional cancer therapy.

[0155] 5. The method of any one of items 1-4, wherein at least one additional cancer therapy is a systemically delivered therapy.

[0156] 6. The method of claim 5, wherein the systemically delivered therapy is chemotherapy, targeted therapy or immunotherapy.

[0157] 7. The method according to item 5, wherein the additional cancer therapy is administration of a chemotherapeutic agent (CTA) and the HHI is administered prior to administration of the CTA.

[0158] 8. The method according to item 7, wherein the administration of HHI is interrupted before the CTA is interrupted.

[0159] 9. The method according to any one of items 1-8, wherein the tumor is a fibrotic tumor.

[0160] 10. The method according to any one of items 1-9, wherein the tumor is a solid tumor.

[0161] 11. The method of any one of items 1-10, wherein the tumor has a high stromal content.

[0162] 12. The method of any one of items 1-11, wherein the HHI reduces interstitial content.

[0163] 13. The method according to any one of items 1 to 12, wherein the HHI induces angiogenesis in or around a tumor.

[0164] 14. The method of any one of items 1-13, wherein the HHI improves tumor uptake of a subsequently administered CTA.

[0165] 15. The method according to any one of items 1 to 14, wherein the administration of the HHI is interrupted such that further reduction of the interstitial is stopped or is clinically insignificant.

[0166] 16. The method according to any one of items 1 to 15, wherein administration of the HHI is interrupted such that further depletion of tumor fibroblasts is stopped or is clinically insignificant.

[0167] 17. The method according to any one of items 1-16, wherein administration of the HHI improves the effect of the additional cancer therapy but is discontinued prior to promoting clinically significant tumor growth.

[0168] 18. The method according to any one of items 1 to 17, wherein the administration of the HHI is interrupted such that the administration of the HHI does not subsequently initiate clinically significant, HHI-induced metastasis.

[0169] 19. The method according to any one of items 1 to 18, wherein the administration of the HHI is interrupted such that the administration of the HHI does not significantly increase the likelihood of subsequent tumor metastasis.

[0170] 20. The method of any one of items 1-19, wherein administration of the HHI improves the effectiveness of a subsequently administered cancer therapy.

[0171] 21. The method of claim 20, wherein the improvement is confirmed by one or more of the following:

[0172] A) metabolic response,

[0173] B) Positron emission tomography,

[0174] C) Objective response according to criteria,

[0175] D) progression-free survival,

[0176] E) Overall survival,

[0177] F) Response based on tumor marker levels,

[0178] G) toxicity, and

[0179] H) Tumor elasticity.

[0180] 22. A method according to claim 20, wherein the improvement is confirmed by prolonged survival or prolonged time to disease progression.

[0181] 23. A method according to claim 20, wherein the improvement is confirmed by progression-free survival.

[0182] 24. The method of any one of items 1-23, wherein the cancer is pancreatic cancer, esophageal cancer, squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, hepatocellular carcinoma, renal cancer, or bile duct cancer.

[0183] 25. The method of any one of items 1-24, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0184] 26. The method of any one of items 1-24, wherein the cancer is hepatocellular carcinoma.

[0185] 27. The method according to any one of items 1-25, wherein the HHI is a Smo antagonist.

[0186] 28. The method of claim 27, wherein the Smo antagonist is selected from TAK 441, glagib, taladegib, sonidegib, saridegib, patidegib, BMS833923, LEQ506, and combinations thereof.

[0187] 29. The method according to any one of items 1-28, wherein the HHI is TAK 441.

[0188] 30. The method of any one of items 26-29, wherein the CTA is selected from gemcitabine, albumin-bound paclitaxel, taxol, irinotecan, temozolomide, capecitabine, topotecan, cisplatin, oxaliplatin, carboplatin, camptothecin, cytarabine, fluorouracil, cyclophosphamide, etoposide phosphate, teniposide, doxorubicin, daunorubicin and pemetrexed.

[0189] 31. A method according to claim 30, wherein the CTA is one or more of nab-paclitaxel, gemcitabine and cisplatin.

[0190] 32. A method according to claim 30, wherein the CTA is one or more of nab-paclitaxel and gemcitabine.

[0191] 33. The method according to any one of items 1 to 32, wherein the route of administration of the HHI is selected from intravenous, oral and topical.

[0192] 34. The method of any one of items 1-33, wherein the route of administration of the additional cancer therapy is selected from intravenous, oral and topical.

[0193] 35. The method of any one of items 1-34, wherein the HHI and the additional cancer therapy are administered at a dose between the biologically effective dose and the maximum tolerated dose.

[0194] 36. The method of any one of items 1-35, wherein the patient receives treatment cycles and the additional cancer therapy is a CTA administered during all or substantially all of the treatment cycles.

[0195] 37. The method of item 36, wherein the patient receives additional treatment cycles of cancer therapy and the HHI is administered in less than all treatment cycles.

[0196] 38. The method according to any one of items 1-37, wherein the patient is treated with additional cancer therapy in multiple cycles, and one or more doses of HHI are administered only before and during earlier treatment cycles.

[0197] 39. The method of item 37 or 38, wherein one or more doses of HHI are administered only 1-10 days prior to chemotherapy for 1-5 cycles.

[0198] 40. The method of item 39, wherein the one or more doses of HHI are administered no later than the third cycle.

[0199] 41. The method of any one of items 37-40, wherein each cycle is 28 days, and HHI is administered on days -4 to -1 and days 10 to 13 of each cycle of cycles 1-3 and CTA is administered on days 1, 8 and 15 every 28 days.

[0200] 42. The method of claim 41, wherein the HHI is TAK 441 at a dose of 800 mg.

[0201] 43. The method according to item 41 or 42, wherein the CTA is selected from one or more of 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Albumin-bound paclitaxel.

[0202] 44. The method of any one of items 1-43, wherein one or more doses of the additional cancer therapy are followed by one or more doses of a checkpoint inhibitor (CI).

[0203] 45. A method according to any one of items 1-29, wherein the CTA is a checkpoint inhibitor (CI) administered in one or more doses.

[0204] 46. ​​A method according to item 44 or 45, wherein the route of administration of the CI is selected from intravenous, oral or topical.

[0205] 47. A method according to any one of items 44-46, wherein one or more doses of the CI are administered between the biologically effective dose and the maximum tolerated dose.

[0206] 48. A method according to any one of items 44-47, wherein the CI is a CTLA 4 inhibitor, a PD1 inhibitor or a PDL1 inhibitor.

[0207] 49. The method of claim 48, wherein the CI is tremelimumab, ipilimumab, durvalumab, nivolumab, pembrolizumab, atezolizumab, cemiplizumab, AGEN1884, AGEN2034 or AGEN1181.

[0208] 50. The method of claim 49, wherein the CI is ipilimumab.

[0209] 51. A method according to any one of items 44-50, wherein the patient is treated in multiple cycles and one or more doses of the CI are administered only at the end or near the beginning of a treatment cycle.

[0210] 52. A method according to claim 51, wherein one or more doses of CI are administered only within 7 days of the end of the treatment cycle.

[0211] 53. A method according to claim 51, wherein one or more doses of CI are administered only after at least 1, 2 or 3 treatment cycles.

[0212] 54. A method according to claim 51, wherein the cycle is 28 days and CI is administered on days 1 and 21 of each cycle starting from cycle 4.

[0213] 55. A method according to claim 54, wherein the CI dose is a 3 mg / kg intravenous dose of ipilimumab.

[0214] 56. A method of treating or ameliorating cancer or the effects of cancer in a subject in need thereof, comprising administering to the subject an effective amount of a hedgehog inhibitor (HHI) or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent (CTA).

[0215] 57. A method according to item 56, wherein the HHI is TAK 441.

[0216] 58. A method according to item 56 or 57, wherein the CTA is nab-paclitaxel.

[0217] 59. A method according to claim 57, wherein the CTA is a checkpoint inhibitor (CI).

[0218] 60. The method according to claim 58 further comprises administering a checkpoint inhibitor (CI).

[0219] 61. The method of any one of items 56-60, wherein the cancer has a fibrotic stroma.

[0220] 62. A method according to any one of items 56-61, wherein the cancer is pancreatic cancer, esophageal cancer, squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, hepatocellular carcinoma, renal cancer or bile duct cancer.

[0221] 63. A method according to any one of items 56-62, wherein the cancer is pancreatic adenocarcinoma (PDAC).

[0222] 64. A method according to any one of items 56-62, wherein the cancer is hepatocellular carcinoma.

[0223] 65. A method according to any one of items 56-64, wherein the therapeutic effect is measured by tumor regression.

[0224] 66. The method according to any one of items 56-65, wherein the therapeutic effect is measured by a tumor growth inhibitory factor in a tumor growth inhibition model, the tumor growth inhibition model being selected from one or more of the following:

[0225] A) metabolic response as measured by fluorodeoxyglucose (FDG),

[0226] B) PET according to EORTC criteria,

[0227] C) objective response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria,

[0228] D) progression-free survival,

[0229] E) Overall survival,

[0230] F) Response based on levels of tumor markers (e.g. CA 19.9),

[0231] G) toxicity (e.g. according to Common Toxicity Criteria for Adverse Events Terminology, National Cancer Institute, version 4.03 (NCI CTCAE v4.03)), and

[0232] H) Tumor elasticity.

Claims

1. A method of treating a subject having a cancerous tumor, the method comprising transiently administering to the subject a hedgehog inhibitor (HHI) in combination with one or more additional cancer therapies.

2. A method of transiently administering a hedgehog inhibitor (HHI) to a cancer patient in combination with one or more additional cancer therapies, wherein administration of the HHI is discontinued prior to initiation of clinically significant depletion of deleterious fibroblasts.

3. The method of claim 1 or 2, wherein the HHI is administered prior to administration of at least one additional cancer therapy.

4. The method of any one of claims 1-3, wherein administration of the HHI is discontinued prior to discontinuation of at least one additional cancer therapy.

5. The method of any one of claims 1-4, wherein at least one additional cancer therapy is a systemically delivered therapy.

6. The method of claim 5, wherein the systemically delivered therapy is chemotherapy, targeted therapy, or immunotherapy.

7. The method of claim 5, wherein the additional cancer therapy is administration of a chemotherapeutic agent (CTA) and the HHI is administered prior to administration of the CTA.

8. The method of claim 7, wherein administration of HHI is discontinued prior to discontinuing CTA.

9. The method according to any one of claims 1-8, wherein the tumor is a fibrotic tumor.

10. The method of any one of claims 1-9, wherein the tumor is a solid tumor.

Images