AU2011213847A1 - Prevention, treatment, and amelioration of radiation induced enteritis - Google Patents

Abstract

The present invention provides a new method of ameliorating and/or treating enteritis induced by radiation therapy, alone or in combination with other therapies, for the treatment of, for example, gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, ladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endometrial, ovarian, vaginal, or vulvar cancers; or osteogenic and other sarcomatous malignancies in which pelvic structures are involved, comprising the administration of a therapeutically effective amount of balsalazide to a patient in need thereof.

Description

AUSTRALIA Regulation 3.2 Patents Act 1990 Complete Specification Standard Patent APPLICANT: Salix Pharmaceuticals, Inc. Invention Title: PREVENTION, TREATMENT, AND AMELIORATION OF RADIATION INDUCED ENTERITIS The following statement is a full description of this invention, including the best method of performing it known to me: 1 PREVENTION, TREATMENT, AND AMELIORATION OF RADIATION INDUCED ENTERITIS RELATED APPLICATIONS This application claims priority from U.S. Application No. 10/856,348; filed on 5 May 28, 2004, which was converted into U.S. Provisional Application No. 60/608,951 on October 26, 2004, both of which are incorporated herein by reference in their entirety. In the specification and the claims the term "comprising" shall be understood to have a broad meaning similar to the term "including" and will be understood to 10 imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. This definition also applies to variations on the term "comprising" such as "comprise" and "comprises". FIELD OF THE INVETNION 15 This invention relates to the use of balsalazide to treat, prevent, or ameliorate enteritis. More specifically, this invention relates to the use of balsalazide to treat radiation induced enteritis caused by radiation therapy, alone or in combination with other therapies. BACKGROUND OF THE INVENTION 20 The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that the referenced prior art forms part of the common general knowledge in Australia.

1A Various pelvic therapies, including radiation therapy, chemotherapy, and surgical procedures, (sometimes referred to as "pelvic therapies"), which are used in a wide variety of clinical settings as either adjuvant, or primary treatment for subjects with pelvic disorders, e.g., tumors, may cause bowel toxicity and other side effects 5 such as acute radiation enteritis. For example, approximately 80% of patients undergoing pelvic radiotherapy experience acute radiation enteritis. Side effects of these various pelvic therapies cause discomfort and may lead to a decrease in the therapeutic benefit of treatments because of the need for unscheduled breaks in therapy. Thus, it would be beneficial to have a treatment that 10 prevents, ameliorates, or otherwise treats the side effects of pelvic therapies, SUMMARY OF THE INVENTION Disclosed herein are methods of preventing, ameliorating and/or treating radiation induced enteritis. Also disclosed are methods of treating radiation induced enteritis caused by a combination of radiation therapy with chemotherapy and/or surgical procedures. In general, subjects who may benefit from treatment with balasalazide include those who are scheduled to begin or those who are in the process of undergoing radiation therapy, particularly in the pelvic region. Subjects who may particularly benefit from this treatment include those who are or may be susceptible to enteritis. For example, the subjects maybe about to undergo, may be undergoing, or may have undergone radiation therapy. The subjects may have also had a combination of pelvic therapies. Subjects may be suffering from, for example, gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, bladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endometrial, ovarian, vaginal, or vulvar cancers; or osteogenic and other sarcomatous malignancies in which pelvic structures are involved. The present invention provides a new treatment for radiation induced enteritis. According to one aspect of the present invention, the method of treating radiation induced enteritis comprises administering to a subject in need of such treatment a therapeutically effective amount of balsalazide. In certain embodiments, the balsalazide is administered at least one day prior to the subject's first dose of radiotherapy. In a related embodiment, the balsalazide is administered at least five days prior to the subject's first dose of radiotherapy. In certain other embodiments, the balsalazide is administered from at least one day prior to the first dose of radiotherapy until at least one day after the cessation of radiation therapy. According to certain preferred embodiments, the balsalazide is administered twice daily to the subject. In another embodiment, from between about 3,000 mg to about 5000 mg of balsalazide is administered daily to a subject. In certain embodiments, the balsalazide is administered at least one day prior to a subject's first dose of radiotherapy, chemotherapy, or prior to undergoing a surgical procedure. 2 WO 2005117851 PCTUS2005/018757 Certain other embodiment include the balsalazide being administered at least five days prior to a subject's first dose of radiotherapy, chemotherapy, and/or prior to undergoing a surgical procedure. Other embodiments include balsalazide being administered during radiation therapy, chemotherapy, or the surgical procedure. In certain preferred embodiments, the balsalazide is administered from.at least one day prior to the administration of a pelvic therapy, until at least one day after the pelvic therapy. For example, prior to the first dose of radiotherapy, chemotherapy, and/or prior to undergoing the surgical procedure According to another aspect, the method of protecting against radiation induced enteritis includes administering to a subject in need thereof a therapeutically effective amount of balsalazide. In another aspect, the method of protecting against radiation induced injury to the mucosa of the colon includes administering to a subject in need thereof a therapeutically effective amount of balsalazide. In yet another aspect, the method of protecting against radiation induced colorectal inflammation includes administering to a subject in need thereof a therapeutically effective amount of balsalazide. Other embodiments of the invention are disclosed infra. DERSCRTPTION OF THE DRAWTNAS Fig. 1 shows the symptom index for balsalazide treated patients in accordance with one embodiment of the present invention and placebo treated patients. DRTA TT ED DESCRIPTTON OF THE INVENTOR Disclosed herein are methods of treating radiation induced enteritis. Radiation therapy and radiotherapy are used interchangeably herein and include external irradiation and internal irradiation, also referred to as brachytherapy, intracavitary brachytherapy, or interstitial brachytherapy. Radiation sources contemplated include pure Gamma, pure Beta and mixed irradiations. As used herein, the terms "chemotherapy" and chemotherapeuticc agents" are used interchangeably and refer to chemotherapeutic agents or drugs exhibiting anti-cancer effects and used in the treatment of malignancies. We have surprisingly found that the administration of balsalazide to a patient experiencing radiation induced enteritis, reduces symptoms of the condition. The success of balsalazide in the treatment of radiation enteritis is surprising because of the failure of other related 5-ASA drugs, such as osalazine and mesalamine, in clinical trials. Balsalazide is the generic name for a 2-hydtoxy-5-phenylazobenzOic acid derivative in which an aminosalicylate moiety, 5-aminosalicylic acid (5 ASA) (mesalamine), is linked to a carrier molecule, 4-aninobenzoyl-*-alanine (4-ABA), through an azo-bond. Disodium balsalazide is highly water-soluble and is cleaved in the colon to release mesalamine, which is the therapeutically active portion of the molecule, as well as 4-aminobenzol alamine, which is the carrier moiety. Mesalamine is 5-aminosaliacylic acid and appears to act topically. The use of balsalazide to treat radiation induced enteritis is especially beneficial because is metabolized by intestinal microflora to the active form, 5-ASA, thus ensuring optimal delivery of the active drug to the bowel without loss via absorption more proximally in the intestinal tract. Balsalazide also exhibits fewer side effects than other 5-ASA prodrugs and it may be administered to subjects with sulpha allergies. Balsalazide is also beneficial because the active component has been demonstrated to directly scavenge free radicals, which may reduce subsequent inflammatory response. Without wishing to be bound by any particular theory, we believe that balsalazide may protect against radiation-induced enteritis by blocdng the mediators of inflammation and the release of free radicals in the rectal mucosa. As used herein radiation induced enteritis includes radiation induced injury to the pelvic area from irradiation of the pelvic region. Irradiation often causes acute radiation enteritis or colorectal toxicity. Symptoms may include diarrhea, proctitis, stool incontinence, loose stool, increased defecations per day, tenesmus, mucous production, abdoninopelvic pain, and peri-rectal discomfort. Acute radiation enteritis results largely from irritation 4 WO 2005/117851 PCTIUS2005/018757 of the sigmoid colon and rectum. Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) with balsalzaide who is in need thereof. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). Balsalazide may be used in various treatment regimes. These regimes may vary depending upon the subject and the type of treatment. Balsalazide may be administered prior to, during, and/or after the treatment therapies. Balsalazide may be administered, for example, twice a day, three times a day, or four times a day. Balsalazide may be administered in doses, for example of from about between 2000 mg BID to about 2500 mg TIL:- Another example is administering balsalazide from between about 4.0 g/ day to about 7.25 g/day. The balsalazide may be administered, for example, in tablet form, powered form, liquid for or in capsules. Subjects in need thereof include subjects that will undergo radiation therapy, either alone or in combination with other pelvic therapies that could induce enteritis. This need may be apparent prior to undergoing radiation therapy, chemotherapy, a pelvic surgical procedure or a combination of therapies; subjects undergoing radiation therapy, chemotherapy, a pelvic surgical procedure or a combination of therapies; and subjects post radiation therapy, chemotherapy, a pelvic surgical procedure,- or a combination of therapies. For example, subjects may be about to undergo, may be undergoing, or have undergone radiation therapy in combination with chemotherapy or a surgical procedure. Also included are subjects who are or who may be susceptible to enteritis. Subjects may be suffering from, for example, gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, bladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endometrial, ovarian, vaginal, or vulvar cancers; or osteogenic and other sarcomatous malignancies in which pelvic structures are involved.. As used herein, a therapeutically effective amount means an amount effective, when administered to a human or non-human subject, to provide a 5 therapeutic benefit such as an amelioration of symptoms,- e.g., an amount effective to decrease the -symptoms of acute radiation enteritis. According to certain embodiments, balsalazide may be administered prior to radiotherapy. Balsalazide may be administered, for example, at least one day prior to the subject's first dose of radiotherapy, at least five days prior to the subject's first dose of radiotherapy, during radiation therapy, for at least one day after the cessation of radiation therapy, for fourteen days after the cessation of radiation therapy. Administration at least five days prior to the therapy includes administration daily, every day prior to the pelvic therapy, administration on a majority of 'days prior the therapy, administration on the day of treatment or no administration on the day of treatment Certain preferred embodiments include administering balsalazide from at least one day prior to the first dose of radiotherapy until at least one day after the cessation of radiation therapy. Treatment prior to the radiation therapy allows for the 5-ASA to be present at its site of action during the cause of the injury. In certain embodiments, the balsalazide is administered to a subject from between about 2 weeks to about 6 weeks in duration, from between about 8 weeks to about 12 weeks in duration, or from between 1 day to about 7 days. The balsalazide may be administered intermittently or conritinuously during the course of treatment. Length of treatment may vary depending of the type and length of radiotherapy, chemotherapy, and/or type of surgical procedure and the proper length of treatment may be easily determined by one of skill in the art having the benefit of this disclosure. For any bf the embodiments, balsalazide may be administered, for; example, once daily, twice daily, three times daily, or four times daily to a subject. In some particularly preferred methods of the present invention comprise administering the balsalazide twice daily to the subject because it may, for example, minimize the side effects and increase patient compliance. Dosages, according to certain preferred embodiments, range from between about 3,000 mg to about 5000 mg of balsalazide administered daily. For example, a dose of 2250 mg may be administered to a subject twice daily. Other appropriate dosages for methods according to this invention 6 WO 2005/117851 PCT/US2005/018757 may be determined bf health care professionals or by the subject. The amount of balsalazide administered daily may be increased or decreased based on the weight, age, health, sex or medical condition of the subject. One of skill in the art would be able to determine the proper dose for a subject based on this disclosure. For subjects undergoing multiple therapies, balsalazide may be administered, for example, at least one day prior to the subject's first dose of radiotherapy, chemotherapy, and/or prior to undergoing a surgical procedure;. at least five days prior to the subject's first dose of radiotherapy, chemotherapy, and/or prior to undergoing a surgical procedure; during radiation therapy, chemotherapy,. and/or the surgical procedure; at least one day after the cessation of radiation therapy, chemotherapy, or after the surgical procedure; for fourteen days after the cessation of radiation therapy, chemotherapy, or after the surgical procedure. It is often preferable to administer the balsalazide to a subject prior to treatment, during treatment, as well as after the cessation of treatment. For example, balsalazide may be administered from at least one day prior to the first dose of radiotherapy, chemotherapy, and/or prior to undergoing the surgical procedure until at least one day after the cessation of radiation therapy, chemotherapy, or the surgical procedure. Indications include a subject receiving radiotherapy, chemotherapy, and/or surgical procedure as a result of treatment for cancer of the cervix, prostate, appendix, colon, intestine, rectum, or other gastrointestinal malignancy, or prostatectomy. According to certain embodiments, balsalazide may be administered in corribination with other compounds, including for example, chemotherapeutic agents, anti-inflammatory agents, anti-pyretic agents radio sensitizing agents, radioprotective agents, urologic agents, anti-emetic agents, and/or anti-diarrheal agents. for example, cisplatin, carboplatin, docetaxel, paclitaxel, flurouracil, capecitabine, gemcitabine, irinotecan, topotecan, etoposide, mitomycin, gefitinib, vincristine, vinblastine, doxorubicin, cyclophosphamide, celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, ketoprofen, dexamethasone, prednisone, prednisolone, hydrocortisone, acetaminophen, misonidazole, amifostine, tamsulosin, phenazopyridine, ondansetron, granisetron, alosetron, palonosetron, promethazine, prochlorperazine, trimethobenzamide, aprepitant, diphenoxylate with atropine, and/or loperamide. The methods disclosed herein are also useful for protecting a subject against radiation induced enteritis by administering to a subject in need thereof a therapeutically effective amount of balsalazide, For example, prophylactic doses may be administered prior to a patient undergoing radiation. The methods disclosed herein are useful for protecting a subject against radiation induced injury to the mucosa of the colon, as well as against radiation induced colorectal inflammation by administering to a subject in need thereof a therapeutically effective amount of balsalazide. It should be appreciated that the invention should not be construed to be limited to the example, which is now described; rather, the invention should be construed to include any and all applications provided herein and all equivalent variations within the skill of the ordinary artisan. . Clinic Trial f Balsnlnzde tn Treat Raidiatinn Enferitis Subjects included patients treated for FIGO stage IB2-IVA cervical cancer, AJCC Stage TI-3 MO prostate cancer, or biochemical failure after prostatectomy. Radiotherapy was delivered to the subjects in a 4-field technique to at least 40 Gy, and tumor dose was at least 64 Gy for prostate patients, and 75 Gy for cervical patients. Brachytherapy boost was permitted. Patients were given 2250 mg of BSZ or an identical-appearing placebo twice daily beginning 5 days prior to radiotherapy, and continuing for 2 weeks after completion. Toxicities were graded weeldy according to NCI Common Toxicity Criteria for each of the following: proctitis, diarrhea, dysuria, weight loss, fatigue, nausea, and vomiting. A symptom index was formulated for each toxicity consisting of the toxicity's numeric grade multiplied by the number of days it was experienced, and summed for each 8 WO 2005/117851 PCT/US2005/018757 grade. Thus, a patient with 7 days of grade 1 proctitis, 14 days of grade 2 proctitis, and 7 days of grade 3 proctitis H(1*7)+ (2*14)+(3*7)] would have a proctitis index of 56. A higher Index indicates worse toxicity. Patients were randomized by sealed envelope decision, with only the protocol coordinator aware of the results of randomization. After randomization, the study drug or identical-appearing placebo was given to the study subject with instructions concerning dosage and administration schedule. As stated above, the toxicity was assessed weekly during the course of radiation treatment, then for a period of at least-six months after completion of radiotherapy. National Cancer Institute (NCI) common toxicity criteria were used to grade the severity of radiation-induced acute bowel toxicity. Diarrhea was used as the primary endpoint and was assessed as follows: Grade 0 - no diarrhea or increased stool frequency Grade 1 - increase of 2-3 stools/day Grade 2 - increase of 4-6 stools/day or nocturnal stool Grade 3 - increase of 7-9 stools/day or incontinence Grade 4 - increase of > 10 stools/day or grossly bloody diarrhea Documented baseline hemorrhoidal bleeding was not considered grade 4. A secondary endpoint included proctitis, which was assessed using guidelines outlined by the NCI Comnon Toxicity Criteria, including: Grade 0 - None Grade I - increased stool frequency, occasional blood-streaked stools or rectal discomfort, not requiring medication Grade 2 - increased stool frequency, bleeding, mucous discharge or rectal discomfort requiring medication Grade 3 - increased stool frequency/diarrhea requiring parenteral support, rectal bleeding requiring transfusion, or persistent mucus discharge necessitating the use of pads Grade 4 - perforation, bleeding or necrosis, or other life-threatening complications requiring surgical intervention Clinical experience indicated that the only statistically significant side effect of balsalazide disodium was abdominal pain, which is seen in 11% of patients receiving the drug versus 0% in those receiving placebo. Adverse events reported in trials of balsalazide were comparable to those seen in patients receiving placebo, which included headache, nausea, diarrhea, flatulence, and fatigue. Except for the nausea/vomiting seen in 2 patients on balsalazide and 1 on placebo, all toxicities were appreciably lower in patients taking balsalazide. Proctitis was prevented most effectively, with a mean index of 35 in balsalazide patients vs. 77 in placebo patients (p=0.04). No patient on balsalazide experienced grade 4 diarrhea, while 2 placebo patients did. Average weight loss in placebo patients was greater than 3 pounds, whereas average balsalazide patients gained weight. Fatigue index in balsalazide patients was 20, while placebo patients averaged 49. Unexpectedly, dysuria was appreciably lower in balsalazide patients as well. Figure 1 is a bar graph presenting the symptom indices comparing subjects administered balsalazide and those given placebo. 10

Claims (27)

1. A method of treating radiation induced enteritis comprising, administering to a subject in need thereof a therapeutically effective amount of balsalazide. 5

2. The method of claim 1. wherein the balsalazide is administered at least one day prior to the subject's first dose of radiotherapy.

3. The method of claim 1, wherein the balsalazide is administered at least five 10 days prior to the subject's first dose of radiotherapy.

4. The method of claim 1, wherein the balsalazide is administered during radiation therapy. 15

5. The method of claim 1, wherein the balsalazide is administered for at least one day after the cessation of radiation therapy.

6. The method of claim 1, wherein the balsalazide is administered for fourteen days after the cessation of radiation therapy. 20

7. The method of claim 1, wherein the balsalazide is administered from at least one day prior to the first dose of radiotherapy until at least one day after the cessation of radiation therapy. 25

8. The method of any one of claims 1 to 7, wherein the subject received radiotherapy as a result of treatment for gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, bladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endometrial, ovarian, vaginal, or vulvar cancers; or osteogenic and 30 other sarcomatous malignancies in which pelvic structures are involved. 12

) 9. The method of any one of claims 1 to 8, wherein the balsalazide is administered twice daily to the subject.

10 The method of any one of claims 1 to 9, wherein from between about 3,000mg 5 to about 5000mg of balsalazide is administered to the subject daily.

11. The method of any one of claims 1 to 10, wherein the balsalazide is administered to the subject from between about 8 weeks to about 12 weeks. 0

12. The method of any one of claims 1 to 11, wherein the subject has acute radiation enteritis.

13. The method of claim 1, wherein the radiation induced enteritis is caused by radiation therapy in combination with chemotherapy or a surgical procedure. 15

14. The method of claim 13, wherein the balsalazide is administered at least one day prior to the subject's first dose of radiotherapy, chemotherapy, or prior to undergoing a surgical procedure. 20

15. The method of claim 13, wherein the balsalazide is administered at least five days prior to the subject's first dose of radiotherapy, chemotherapy, or prior to undergoing a surgical procedure.

16. The method of claim 13, wherein the balsalazide is administered during 25 radiation therapy, chemotherapy, or the surgical procedure.

17. The method of claim 13, wherein the balsalazide is administered for at least one day after the cessation of radiation therapy, chemotherapy, or after the surgical procedure. 30 13

18. The method of claim 13, wherein the balsalazide is administered for fourteen days after the cessation of radiation therapy, chemotherapy, or after the surgical procedure. 5

19. The method of claim 13, wherein the balsalazide is administered from at least one day prior to the first dose of radiotherapy, chemotherapy, or prior to undergoing the surgical procedure until at least one day after the cessation of radiation therapy, chemotherapy, or the surgical procedure. l0

20. The method of claim 13, wherein the subject received radiotherapy, chemotherapy, or surgical procedure as a result of treatment for gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, bladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endothqtrial, ovarian, vaginal, or vulvar 15 cancers; or osteogenic and other sarcomatous malignancies in which pelvicstructures are involved.

21. The method of claim 13, wherein the balsalazide is administered twice daily to the subject. 20

22. The method of claim 13, wherein from between about 3,000mg to about 5000mg of balsalazide is administered to the subject daily.

23. The method of claim 13, wherein the balsalazide is administered to the subject 25 from between about 8 weeks to about 12 weeks.

24. A method of protecting against radiation induced enteritis comprising, administering to a subject before, during, and/or after undergoing radiation therapy a therapeutically effective amount of balsalazide. 30 14

) 25 A method of protecting against radiation induced injury to the mucosa of the colon comprising, administering to a subject before, during, and/or after undergoing radiation therapy a therapeutically effective amount of balsalazide. 5

26. A method of protecting against radiation induced colorectal inflammation comprising, administering to a subject before, during, and/or after undergoing radiation therapy a therapeutically effective amount of balsalazide.

27. Use of balsalazide in the preparation of a medicament for the treatment or 10 prophylaxis of radiation induced enteritis.