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(12) Patent Application Publication (10) Pub. No.: US 2007/0105790 A1 Khodadoust Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0105790 A1 Khodadoust Et Al US 20070105790A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0105790 A1 Khodadoust et al. (43) Pub. Date: May 10, 2007 (54) PANCREATIC CANCER TREATMENT USING (60) Provisional application No. 60/606,684, filed on Sep. NA-fk-- ATPASE INHIBITORS 2, 2004. (75) Inventors: Mehran Khodadoust, Brookline, MA Publication Classification (US); Ajay Sharma, Sudbury, MA (US); Reimar Bruening, Fremont, CA (51) Int. Cl. (US) A6II 3 L/70 (2006.01) AOIN 43/04 (2006.01) Correspondence Address: (52) U.S. Cl. ................................................................ 514/34 FSH & NEAVE P GROUP ROPES & GRAY LLP (57) ABSTRACT ONE INTERNATIONAL PLACE BOSTON, MA 02110-2624 (US) The reagent, pharmaceutical formulation, kit, and methods of the invention provides a new approach for treating (73) Assignee: Bionaut Pharmaceuticals, Inc., Cam pancreatic cancers. The invention provides the use of Na'e/ bridge, MA K"-ATPase inhibitors, such as cardiac glycosides (e.g. oua bain and proscillaridin, etc.), either alone or in combination (21) Appl. No.: 11/441,397 with other standard therapeutic agents (chemo- or radio (22) Filed: May 24, 2006 therapies, etc.) for treating pancreatic cancers. The Subject Na/K-ATPase inhibitors, such as cardiac glycosides, Related U.S. Application Data including bufadieneolides or their corresponding aglycones (e.g., proscillaridin, Scillaren, and Scillarenin, etc.), espe (63) Continuation-in-part of application No. 1 1/219,638, cially in oral formulations and/or solid dosage forms con filed on Sep. 2, 2005. taining more than 1 mg of active ingredients. Patent Application Publication May 10, 2007 Sheet 1 of 19 US 2007/0105790 A1 |?un61-I Snoue6opuedelL(Z SJ??OUuOud Patent Application Publication May 10, 2007 Sheet 3 of 19 US 2007/0105790 A1 TuelpeN uelpeN 0 06 08 01 09 09 []; 09 0Z 0\, ºaun61-I OS2 OO2 O s ueoueo6un-?OTOSN so ?-Oued Patent Application Publication May 10, 2007 Sheet 4 of 19 (WnI'0)LON8 (SORI)6?SV OOE Ore OB O. s.r.o. yaun61 Patent Application Publication May 10, 2007 Sheet 5 of 19 US 2007/0105790 A1 O O O s 9 s Q N o e (u/6d) SA Patent Application Publication May 10, 2007 Sheet 6 of 19 US 2007/0105790 A1 10.I?u00 OO. O.8 O Otr O. O. OO O8 O OP DE O so so 9eun61-I OO OS Otto Oe O O). O8 O9 Otr ). sal too st-rho: Patent Application Publication May 10, 2007 Sheet 7 of 19 US 2007/0105790 A1 V O Z O) S O O E O) (D OO OB O Or O& O so O. O.8 s US 2007/0105790 A1 (Iuu/5u) -ONJO ouoo unueS US 2007/0105790 A1 quæuu?eau)?sodsÁed (fu) publeM Jouni US 2007/0105790 A1 ?ueuu?eauLjsodsÁed (fu) bufóleM Jouni uleeN Patent Application Publication May 10, 2007 Sheet 13 of 19 US 2007/0105790 A1 c),eun61 quau?eau1IsodsÁed Patent Application Publication May 10, 2007 Sheet 14 of 19 US 2007/0105790 A1 (lujõuG)DONEÆn-EG LO (Iuu/6uuG)L-ON CN ——————————————? #7||3infil ?uðu?eau1?sodsÁed (5u) u fleM Jouni uleeN Patent Application Publication May 10, 2007 Sheet 15 of 19 US 2007/0105790 A1 cond Winool dih dAH 78N9 Win 'O JON dAH ONE NIn O' ho ON 9. l dAH ONSW 'O JON dAH Ouluoto JON Patent Application Publication May 10, 2007 Sheet 16 of 19 US 2007/0105790 A1 H XS) Win 00 n H CY) 7:0NSWU 'O C ols O H . loN9 Wu O'O - n E. CD O Oluoo 8. as S v s C c. Patent Application Publication May 10, 2007 Sheet 17 of 19 US 2007/0105790 A1 ZLeun61-I LONE<!======>SSeloSseIOyoNg (Wn) uu (Meupy foc) eSelvy-en US 2007/0105790 A1 sÁed (6uu) buffenWuoun ueeW ———————————————————————————————+0°0 920Z9|,0!,90 Patent Application Publication May 10, 2007 Sheet 19 of 19 US 2007/0105790 A1 (uilibu) ouoo unues e6eleav US 2007/0105790 A1 May 10, 2007 PANCREATC CANCER TREATMENT USING several drugs) may be used before Surgery or following NA-AK-- ATPASE INHIBITORS Surgery. Often, chemotherapy combined with radiotherapy is used in the conventional treatment of pancreatic cancer REFERENCE TO RELATED APPLICATION (Klinkenbijl et al. 1999: Snady et al. 2000). 0001. This application is a continuation-in-part applica 0006 Radiation therapy alone can improve pain and may tion of U.S. Ser. No. 11/219,638, filed on Sep. 2, 2005, which claims the benefit of the filing date of U.S. Provisional prolong survival. The results are dose-related. Precision Application Ser. No. 60/606,684, entitled “PANCREATIC external-beam techniques are required. A radiation proce CANCER TREATMENTS USING CARDIAC GLYCO dure known as IMRT (intensity modulated radiation SIDES,” and filed on Sep. 2, 2004. The teachings of the therapy) combined with concurrent 5-fluoruracil (5-FU) referenced applications are incorporated herein by reference. chemotherapy can provide a definite palliative benefit (symptom relief) with tolerable acute radiation related tox BACKGROUND OF THE INVENTION icity for patients with advanced pancreatic cancer (Bai et al. 2003). 0002 The pancreas can be divided into two parts, the exocrine and endocrine pancreas. Each has a different func 0007. In a preliminary report, five patients diagnosed tion. The exocrine pancreas produces various pancreatic with locally advanced nonresectable pancreatic cancer enzymes that help break down and digest food. The endo achieved improved quality of life, delay of local progres crine pancreas produces hormones (such as insulin) that sion, and reduction of biomarker CA19-9 after infusion of regulate how the body stores and uses food. About 95% of colloidal phosphorus 32 ('P) and administration of com pancreatic cancers begin in the exocrine pancreas. The rest bined chemoradiotherapy. All five of these patients demon are cancers of the endocrine pancreas, which are also called strated cessation of local tumor growth or regression of islet cell cancers. disease on CT scans for a minimum of 10 months from completion of therapy. Three of these patients survived 0003. According to the National Pancreas Foundation, without local disease progression over 24 months from pancreatic cancer is 4th most common cause of all cancer initiation of therapy, with one patient approaching 36 deaths and the 10th most common malignancy in the United months. CA19-9 values for all patients declined within States. Conventional medicine’s inability to effectively treat weeks after completion of therapy. This new method of pancreatic cancer is evidenced by survival rates of only 18% isotope delivery has resulted in reduction of tumor volume, at 1 year and 4% at 5 years—one of the poorest 5-year normalization of the biomarker CA19-9, and improved Survival rates of any cancer. Pancreatic cancer results in the performance status in those patients who have localized death of more than 90% of afflicted patients within 12 nonresectable disease without dissemination (cancer spread) months. In 2002, about 28,000 Americans died from cancer (DeNittis et al. 1999). of the pancreas. The disease is not only common, but it is also extremely difficult to treat. For these and other reasons, 0008. The chemotherapeutic agent most commonly used cancer of the pancreas has been called “the challenge of the to treat cancer of the pancreas is GEMZAR(R) (Gemcitabin). twenty-first century.” GEMZARR) works by interfering with cell division and the repair functions, thus preventing the further growth of 0004 Surgical removal (“resection') of the cancer is at present the only chance for a cure for patients with cancer of cancer cells and leading to cell death. the pancreas. However, only some 10-15% of all pancreatic 0009 Clinical studies showed that GEMZARR) helped cancer cases are eligible for complete Surgical removal of improving Survival for some patients with cancer of the the tumor. The Surgical resection of most pancreas cancers pancreas. For example, in a study of GEMZAR(R) versus the is called a “Whipple procedure” or “pancreaticoduodenec drug 5-FU in previously untreated patients, nearly 1 in 5 tomy.” Although great Strides have been made in the Surgical patients was alive at 1 year after starting therapy with treatment of this disease, these operations are very complex, GEMZARR, compared with 1 in 50 who were given 5-FU. and unless performed by Surgeons specially trained and The typical patient survived about 6 months after starting experienced in this procedure, they can be associated with therapy with GEMZAR(R), which was 6 weeks longer than very high rates of operative morbidity and mortality. In those given 5-FU. general. Whipple resection is a high-risk procedure with a mortality rate of about 15%, and a 5-year survival rate of 0010. In a study of GEMZAR(R) in patients previously only 10% (Snady et al. 2000). The 5-year survival rate for treated with the drug 5-FU, after starting on GEMZAR(R), patients who do not receive treatment is only about 3%, about 1 in 25 patients was alive at 1 year. After starting on while for patients underwent a Whipple procedure for cancer GEMZARR, the typical patient lived for 4 months. Nearly of the pancreas is now approaching 25% in best case 1 in 4 patients had improvement in 1 or more of the scenario. following for at least 1 month, without any Sustained wors ening in any of the other symptoms. So far, GEMZAR(R) is 0005. Unfortunately, many cancers of the pancreas are indicated for the treatment of locally advanced or metastatic not resectable at the time of presentation. The median pancreatic cancer. In treating pancreatic cancer, GEMZAR(R) survival time for inoperable cases (the majority) is often is usually given alone, not in combination with other che only a few months.
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