FIELD OF THE INVENTION

The present invention is directed to methods of preventing, ameliorating and/or treating diarrhea. More specifically, the methods presented herein prevent, ameliorate or treat chemotherapy-induced diarrhea (CID) using a proanthocyanidin such as crofelemer in combination with a chemotherapy agent.

BACKGROUND

Diarrhea is a common occurrence in human cancer patients that can result from radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections or a combination thereof. In particular, chemotherapy-induced diarrhea (CID) is common, especially in patients with advanced cancer, and has to be assessed for etiologies associated with the chemotherapeutic regimen or not [Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-35, 2009]. Careful analysis can result in better management of the diarrheal symptoms to prevent severe complications that may be irreversible [Davila, M. and Bresalier, R., Nat Clin Pract Gastroenterol Hepatol 5: 682-696, 2008; Vincenzi, B. et al. Nat Clin Pract Oncol 5: 455-465, 2008]. Sequelae can include dehydration, malnutrition, cardiovascular issues, and even death.

CID is very prevalent depending on the chemotherapy regime with an estimated prevalence of between about 50-80% in patients [Benson, A. et al. J Clin Oncol 22: 2918-2926, 2004; Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-35, 2009] especially those treated with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation.

Therapeutic agents commonly causing diarrhea include 5-fluorouracil (5-FU), capecitabine and irinotecan (CPT-11) [Benson, A. et al. J Clin Oncol 22: 2918-2926, 2004; Keefe, D. et al. Semin Oncol Nurs 20: 38-47, 2004]. It is often a dose-related adverse effect and may be associated with other features of toxicity. CID appears to be a multifactorial process whereby acute damage to the intestinal mucosa (including loss of intestinal epithelium, superficial necrosis and inflammation of the bowel wall) causes an imbalance between absorption and secretion in the small bowel [Keefe, D. et al. Gut 47: 632-637, 2000; Keefe, D. Support Care Cancer 15: 483-490, 2007; Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-35, 2009].

Left untreated, life-threatening gastrointestinal syndrome is recognized by two National Cancer Institute-sponsored cooperative group trials as a serious complication. These trials reviewed early toxic deaths occurring in irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication [Conti, J. et al. J Clin Oncol 14: 709-715, 1996; Arbuckle, R. et al. Oncologist 5: 250-259, 2000; Saltz L. et al. N Engl J Med 343: 905-914, 2000]. In addition, diarrhea can hinder chemotherapy and other treatments for cancer by causing dosing delays, reductions, or use of alternative agents which may have an ultimate impact on survival [Engelking, C. et al., Oncol Nurs Forum 25: 859-860 1998; Ippoliti, A., Am J Health Syst Pharm 55: 1573-1580, 1998].

Therefore, drug-related diarrhea in human subjects undergoing chemotherapy represents an important and unmet clinical need requiring more effective management. Currently prescribed therapies are only partially effective or are plagued by unacceptable side effects such as constipation and the potential for addiction. The development of a drug for the treatment of chemotherapy-associated diarrhea with a low potential for drug-drug interactions, effects on drug metabolism, or abuse potential would provide an important benefit for subjects undergoing chemotherapy.

SUMMARY

Disclosed herein are methods of preventing, ameliorating and/or treating diarrhea in human subjects being administered or having been administered a chemotherapy regimen. In one embodiment, the methods presented herein prevent, ameliorate or treat chemotherapy-induced diarrhea (CID).

In one aspect, provided herein are methods of treating CID in a human subject undergoing chemotherapy, particularly for cancer treatment, comprising administering to a subject in need thereof a composition comprising an effective amount of a proanthocyanidin polymer composition fromC. lechleri, preferably crofelemer, to treat, ameliorate or prevent CID. In certain embodiments, the crofelemer is an enterically protected formulation. In certain embodiments the chemotherapy is administered to treat, ameliorate, manage or prevent cancer.

According to certain embodiments, crofelemer may be administered in combination with other chemotherapy agents.

In one embodiment, the crofelemer is administered at the same time as administration of chemotherapy to reduce or delay the onset of CID.

In certain embodiments, the subject exhibits Grade 1, Grade 2, Grade 3 or Grade 4 diarrhea in accordance with the Common Toxicity Criteria from the National Cancer Institute.

In one embodiment, the crofelemer is administered before administration of chemotherapy to reduce or delay the onset of CID.

In one embodiment, the crofelemer is administered after administration of chemotherapy to reduce the onset of or treat CID.

In certain embodiments, the crofelemer is administered to reduce the risk, incidence or severity of CID so that the human subject can tolerate a particular chemotherapy agent with CID as a side effect or a higher dose of a chemotherapy agent that has CID as a side effect.

In one embodiment, the chemotherapy agent is selected from alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II, kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based agents and retinoids

In one embodiment, the chemotherapy agent comprises one or more tyrosine kinase inhibitors.

In one embodiment, the tyrosine kinase inhibitor is selected from lapatinib, sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib, dasatinib, cabozantinib, ruxolitinib, neratinib, bosutinib and valatinib.

In one embodiment, the chemotherapy comprises one or more HER of hEGFR (Human epidermal growth factor receptor) inhibitors.

In one embodiment, the HER inhibitor is selected from RG7116, RG1273 (pertuzumab, Perjeta®), RG3502 (trastuzumab emantasine, T-DMI), RG597 (trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarceva®), dacomitinib (PF-00299804), PF-05280014 (Pfizer's biosimilar mAB to RG597).

In various embodiments, the chemotherapy regiment comprises two or more HER inhibitors, such as trastuzumab and pertuzumab, and one or more chemotherapy agents, such as, a taxane like docetaxel or paclitaxel. In various embodiments, the chemotherapy regiment further comprises a platinum-based antineoplastic such as carboplatin.

In various embodiments, the chemotherapy regiment comprises a HER inhibitors, such as trastuzumab or pertuzumab, a tyrosine kinase inhibitor, such as neratinib, and a taxane, such as, docetaxel or paclitaxel. In various embodiments, the chemotherapy regiment further comprises a platinum-based antineoplastic such as carboplatin.

In various embodiments, the chemotherapy regiment is administered once every three weeks.

In various embodiments, the crofelemer is administered after a subject begins to exhibit symptoms of CID.

In certain embodiments, the crofelemer is administered for the duration of treatment with the chemotherapy.

In certain embodiments, the subject is undergoing chemotherapy to treat one or more forms of cancer, such as breast cancer.

In certain embodiments, the crofelemer is administered until symptoms of CID are ameliorated and then crofelemer is discontinued.

In various embodiments, the administration comprises: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof. In other embodiments, the crofelemer is formulated for oral administration but is not enterically protected, e.g., does not have an enteric coating. In other embodiments, the dosage of the proanthocyanidin polymer composition is bioequivalent to about 250 mg to about 1000 mg per day; about 250 mg per day; about 500 mg per day; about 1000 mg per day; about 125 mg two times per day; about 250 mg two times per day; or about 500 mg two times per day of an oral dosage form of crofelemer that enterically protected.

In one aspect, presented herein are methods of treating stool consistency in a subject undergoing chemotherapy, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

In one aspect, presented herein are methods of improving stool consistency in a subject undergoing chemotherapy, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

In one aspect, presented herein are methods of alleviating watery diarrhea in a subject undergoing chemotherapy, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

In one aspect, presented herein are methods of decreasing the number of bowel movements per day in a subject undergoing chemotherapy, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

The dosages may be the amount of a composition containing a proanthocyanidin polymer composition fromC. lechlerithat is bioequivalent to the dose of an enteric protected formulation of crofelemer.

In one embodiment, a human subject is considered treated if the subject demonstrates one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily or weekly abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in stool consistency score (from watery to formed), a decrease in the number of days per week that subjects experienced urgency, a decrease in the number of days per week that the subject experienced fecal incontinence.

In one embodiment, a human subject is considered treated if the subject demonstrates an improvement in the score for daily stool consistency.

In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in stool consistency.

In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in the number of watery bowel movements per day.

In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in the number of bowel movements per day.

In one embodiment, symptoms increased or decreased are measured from a baseline.

In one embodiment, the administering is for the duration of the chemotherapy.

In one embodiment, the administering occurs for about 1 to about 6 weeks longer than the chemotherapy cycle.

In one embodiment, the administering occurs for about 3 to 12 weeks.

Other embodiments are disclosed below.

