Search

EP-3509584-B1 - GLUCOCORTICOID RECEPTOR MODULATORS TO TREAT PANCREATIC CANCER

EP3509584B1EP 3509584 B1EP3509584 B1EP 3509584B1EP-3509584-B1

Inventors

  • HUNT, HAZEL
  • BLOCK, Thaddeus S.

Dates

Publication Date
20260513
Application Date
20170908

Claims (7)

  1. A combination for use in the treatment of a subject hosting a non-adrenocorticotropin-(ACTH)-secreting pancreatic tumor to reduce the tumor load of the pancreatic tumor, wherein tumor load refers to the size of the tumor, wherein the combination comprises a chemotherapeutic agent and a nonsteroidal selective glucocorticoid receptor modulator (SGRM), wherein said nonsteroidal SGRM comprises a heteroaryl ketone fused azadecalin structure or an octahydro fused azadecalin structure, wherein the nonsteroidal SGRM comprising a heteroaryl ketone fused azadecalin structure has the formula: wherein the nonsteroidal SGRM comprising an octahydro fused azadecalin structure has the formula: wherein the nonsteroidal selective glucocorticoid receptor modulator preferentially binds to the glucocorticoid receptor rather than the progesterone receptor (PR), the mineralocorticoid receptor (MR) or the androgen receptor (AR); wherein the chemotherapeutic agent is a taxane, wherein the taxane is preferably selected from the group consisting of nab-paclitaxel, paclitaxel, and docetaxel.
  2. The combination for use of claim 1, wherein non-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor.
  3. The combination for use of claim 1, wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl ketone fused azadecalin structure having the formula:
  4. The combination for use of claim 1, wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising an octahydro fused azadecalin structure having the formula:
  5. A pharmaceutical composition for use in treating a non-ACTH-secreting pancreatic tumor comprising a pharmaceutically acceptable excipient and a nonsteroidal selective glucocorticoid receptor modulator compound (SGRM), wherein said nonsteroidal SGRM comprises a heteroaryl ketone fused azadecalin structure or an octahydro fused azadecalin structure, wherein the nonsteroidal SGRM comprising a heteroaryl ketone fused azadecalin structure has the formula: wherein the nonsteroidal SGRM comprising an octahydro fused azadecalin structure has the formula: wherein the pharmaceutical composition is to be used in a combination therapy with a chemotherapeutic agent, wherein the nonsteroidal selective glucocorticoid receptor modulator preferentially binds to the glucocorticoid receptor rather than the progesterone receptor (PR), the mineralocorticoid receptor (MR) or the androgen receptor (AR); wherein the chemotherapeutic agent is a taxane, wherein the taxane is preferably selected from the group consisting of nab-paclitaxel, paclitaxel, and docetaxel.
  6. The pharmaceutical composition for use of claim 5, wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a heteroaryl ketone fused azadecalin having the formula:
  7. The pharmaceutical composition for use of claim 5, wherein the nonsteroidal selective glucocorticoid receptor modulator is the compound comprising an octahydro fused azadecalin having the formula:

Description

CROSS-REFERENCES TO RELATED APPLICATIONS This application claims benefit of US provisional application no. 62/385,590, filed September 9, 2016. BACKGROUND Pancreatic cancer is the fifth leading cause of cancer death in the United States. It is more common among men, and men between the ages of 60 and 70 are most at risk. Pancreatic cancer usually begins in the ducts of the pancreas when abnormal cells within the pancreas grow out of control and form a tumor. More than 95% of pancreatic cancers are classified as exocrine pancreatic tumors. These tumors start in the exocrine cells that make pancreatic enzymes that help in digestion. Neuroendocrine pancreatic tumors account for less than 5% of all pancreatic tumors and they tend to grow slower than exocrine tumors. Pancreatic neuroendocrine tumors develop from the abnormal growth of endocrine (hormone-producing) cells in the pancreas called islet cells and thus are often referred to as "islet cell tumors." Pancreatic cancer often has a poor prognosis, even when diagnosed early, and signs and symptoms may not appear until the cancer is quite advanced and complete surgical removal is not possible. Conventional treatment options for pancreatic cancer include surgery, radiation therapy (also termed "radiotherapy") and chemotherapy. For the reasons stated above, only 15-25% of tumors are resectable at the time of diagnosis and regrettably only 10-20% of patients resected will survive more than two years. Pancreatic tumors that are at an advanced stage often require radiotherapy or chemotherapy treatment. Radiotherapy requires maximized exposure of the affected tissues while sparing normal surrounding tissues. Interstitial therapy, where needles containing a radioactive source are embedded in the tumor, has become a valuable new approach. In this way, large doses of radiation can be delivered locally while sparing the surrounding normal structures. Intraoperative radiotherapy, where the beam is placed directly onto the tumor during surgery while normal structures are moved safely away from the beam, is another specialized radiation technique. Again, this achieves effective irradiation of the tumor while limiting exposure to surrounding structures. Despite the obvious advantage of approaches predicated upon local control of the irradiation, patient survival rate is still very low. Chemotherapy relies upon a generalized damage to DNA and destabilization of chromosomal structure which eventually leads to destruction of cancer cells. The non-selective nature of these treatments, however, often results in severe and debilitating side effects. The systemic use of these drugs may result in damage to normally healthy organs and tissues, and compromise the long-term health of the patient. The effects of glucocorticoid receptor ("GR") mediated signaling pathway on cancer cells in general are controversial. On one hand, it is believed that activating the GR signaling pathways advantageously induces apoptosis in malignant lymphoid cancers (see Schlossmacher, J. Endocrinol. (2011) 211(1):17-25). On the other hand, it has been reported that agents blocking the GR signaling pathway can potentiate chemotherapy in killing breast cancer cells (see U.S. Pat. No. 9,149,485). It has been suggested that the combination of neoplasia-treating agents and certain GR antagonists may be used for treating over 30 types of neoplasia (cancer), including pancreatic cancer (Altschul et al., U.S. Patent 8,658,128). It has also been suggested that GR inhibitors can be used in combination with a somatostatin receptor-binding agent to treat an adrenocorticotropin ("ACTH")-secreting, islet cell tumor of the pancreas (see WO 2013/039916, Niemann et al., "Compositions for and Methods of Treatment and Enhanced Detection of Non-Pituitary Tumors"). In terms of the effect on pancreatic cancer, however, the prevailing view is that glucocorticoid, e.g., dexamethasone, can relieve side effects of the chemotherapeutic agent and should be co-administered with chemotherapeutic agents in treating pancreatic cancer (see Zhang et al., BMC Cancer, 2006 March 15 6: 61). Further, it has been reported that dexamethasone inhibits pancreatic cancer cell growth. See, Norman et al., J. Surg. Res. 1994 Jul; 57(1): 33-8. Von Hoff et al. (The New England Journal of Medicine (NEJM), vol. 369, no. 18, 31 October 2013, pages 1691-1703, DOI: 10.1056/NEJMoal304369) disclose a treatment of pancreatic cancer with a combination of nab-paclitaxel and gemcitabine. WO2013177559 and WO2015077530 disclose the compounds CORT 125134 and CORT125281 as specific glucocorticoid receptor modulators. The present application, in contrast to the prevailing view that activation of GR signaling benefits pancreatic cancer patients, provides a novel and surprising combination therapy that employs compounds that inhibit GR signaling to treat patients suffering from certain types of pancreatic cancer. BRIEF SUMMARY Disclosed herein are novel methods for tre