Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy

Adult Solid Tumor Clinical Trial

— OnTARGET  

Official title:

A Phase 3 Multicenter, Randomized, Double-blind Placebo-controlled Trial Evaluating Crofelemer for the Prophylaxis of Diarrhea in Adult Patients With Solid Tumors Receiving Targeted-cancer Therapies With or Without Standard Chemotherapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04538625
• Other study ID #: NP 303-102
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 7, 2020
• Est. completion date: June 2024

Study information

• Verified date: November 2023
• Source: Napo Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A 24-week, (two 12-week stages), randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of crofelemer in providing prophylaxis of diarrhea in adult patients with solid tumors treated with targeted cancer therapy-containing treatment regimens. Diarrhea grading will be done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Patients will be randomized 1:1 to placebo or crofelemer and will be stratified by the type of targeted cancer therapy and the tumor type. Placebo and/or crofelemer will be dispensed at Visit 1/Day 1 with the concurrent start of the targeted cancer therapy regimen. The initial Stage I double-blind placebo-controlled primary treatment phase will occur over a 12-week period to accommodate approximately 3 cycle chemotherapy cancer treatment dosing-cycles. The Primary and Secondary Endpoints will be analyzed after the last patient last visit (LPLV) of Stage I. After completing the Stage I double-blind, placebo-controlled primary treatment phase, the subjects will have the option to remain on their assigned treatment arm and reconsented to enter into the Stage II extension phase. Reconsent will be required to enter into Stage II. For subjects who do not reconsent, visit 5 will be the last study visit.

Description:

A randomized, placebo controlled, double blind study to evaluate the safety and efficacy of crofelemer in providing prophylaxis of diarrhea in adult patients with solid tumors receiving targeted cancer therapy containing regimens. Diarrhea grading will be done according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE Ver. 5.0). Randomization will be at a 1:1 ratio with subjects randomized either to crofelemer 125 mg delayed-release tablets or matching placebo tablets administered orally twice daily with or without food. Randomization will be stratified by the type of targeted cancer therapy and by tumor type. Placebo and crofelemer treatment will be initiated concomitantly with the administration of targeted cancer therapy-containing regimens. The Stage I double-blind placebo-controlled primary treatment phase will be the first 12-week period to accommodate targeted cancer therapy with approximately three (3) cycle chemotherapy regimens (if needed) over the inclusive 12-week period after initiation of crofelemer or placebo treatment in Stage I. After completing the Stage I treatment phase (12 weeks), and after the LPLV of the primary Stage I treatment phase, the primary and secondary endpoints will be analyzed. The subjects will have the option to remain on their assigned treatment arm and reconsented to enter into the Stage II extension phase. Reconsent will be required to enter into Stage II. For subjects who do not reconsent, Visit 5 will be the last study visit. Subjects who enter into the Stage II extension phase will continue on their originally assigned study treatment commenced at the beginning of Stage I.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 256
• Est. completion date: June 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 1. Patients to receive targeted cancer therapy drugs that have a reported an all grade diarrhea incidence of 50% or higher (e.g., tyrosine kinase inhibitors, cdk inhibitors, anti-EGFR, etc., for treatment of solid tumors.

2. Patients able to provide written informed consent.

3. Men and women = 18 years of age.

4. Pathologically and/or radiologically confirmed diagnosis of solid tumors scheduled to receive targeted cancer therapy.

5. Patients eligible to receive targeted cancer therapy per NCCN (National Comprehensive Cancer Network) guidelines and/or standard-of-care practice, with or without cycle chemotherapy.

6. Patient can receive concomitant cycle [standard] chemotherapy agents together with their targeted cancer therapy treatment regimens.

7. ECOG (Eastern Cooperative Oncology Group) performance status 0-2 and expected to survive a 12-week course of targeted therapy with or without chemotherapy

8. Negative urine pregnancy test at time of informed consent for women of childbearing potential.

Exclusion Criteria:

• 1. Patients receiving any type of immunotherapy including but not limited to immune checkpoint inhibitors that inhibit negative regulatory components of immune response such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programmed cell death protein-1 and its ligand (PD1/ PDL1) and IL-2 cancer immunotherapy.

2. Any cancer therapy for which antidiarrheal (antimotility) medications in the prophylaxis setting is mandatory, including but not limited to patients receiving neratinib and irinotecan.

3. Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.).

4. Ongoing diarrhea and/or diarrheal episodes within the previous 7 days prior to randomization into the study.

5. Laxative use within 7 days prior to randomization or a history of constipation requiring the use of laxatives for more than = 30 consecutive days.

6. Inadequate organ function, which may include, but is not limited to, the following laboratory results within 28 days prior to signing consent: Total bilirubin > upper limit of normal (ULN), AST (SGOT) and ALT (SPGT) > 2.5 ULN (unless the participant has documented Gilbert's syndrome, hepatocellular carcinoma or hepatic metastases), serum creatinine > 2.0 mg/dL or 177 µmol/L.

1. NOTE: Investigator discretion will determine continued eligibility after randomization occurs, in the event the liver function test results are greater than (>) the proposed upper limit of normal.

7. Use of other investigational drugs within 4 weeks of signed informed consent or foreseen use during the study.

8. Use of antibiotics within the past 7 days (up to 2 prophylactic doses of antibiotic for procedures, including but not limited to port placement, is permitted) prior to randomization.

9. Total colectomy and/or any type of gastrointestinal ostomy.

10. Major abdominal or pelvic surgery within the past 3 months.

11. Previous (within 1 month) or planned abdominal and/or pelvic radiation.

12. Fecal incontinence from ongoing radiation-induced diarrhea or constipation

13. Active systemic infection requiring ongoing intervention, including but not limited to oral and intravenous antibiotics, anti-fungals, anti-parasitics, and anti-viral drugs.

14. Inability to comply with study requirements as judged by the Investigator.

15. Pregnant and/or breastfeeding.

Related Conditions & MeSH terms

• Adult Solid Tumor
• Cancer Therapy-Related Diarrhea
• Chemotherapy-related Diarrhea
• Diarrhea
• Prophylaxis of Diarrhea
• Symptomatic Relief of Diarrhea
• Targeted Therapy-related Diarrhea

Intervention

Drug:
• Crofelemer 125 MG [Mytesi]
Randomized, Double-blind, Placebo-controlled, two arm trial
• Placebo
Matching placebo tablets

Locations

Country	Name	City	State
Argentina	Buenos Aires British Hospital	Buenos Aires
Argentina	Fleischer Medical Center	Buenos Aires
Argentina	Medical Center Austral	Buenos Aires
Argentina	Cordoba Oncology Institute (IONC)	Córdoba
Argentina	Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)	Paraná
Argentina	CEDIT Diagnostic and Treatment Center	Salta
Argentina	Isis Specialized Clinic	Santa Fe
Argentina	9 of July Sanatorium	Tucuman
Georgia	Archangel St. Michael Multiprofile Clinical Hospital LTD	Tbilisi
Georgia	JSC K. Eristavi National Center of Experimental and Clinical Surgery	Tbilisi
Georgia	LLC "Todua Clinic"	Tbilisi
Georgia	LTD Caucasus Medical Centre	Tbilisi
Georgia	Malkhaz Katsiashvili Multiprofile Emergency Medicine Center LLC	Tbilisi
Serbia	Clinical Hospital Center Bezanijska Kosa	Belgrade
Serbia	National Cancer Research Center	Belgrade
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center Nis	Nis
Serbia	Institute of Pulmonary Diseases of Vojvodina	Sremska Kamenica
Serbia	Oncology Institute of Vojvodina (IOV)	Sremska Kamenica
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chi Mei Medical Center - LiouYing Branch	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
United States	Pacific Cancer Medical Center Inc	Anaheim	California
United States	GenesisCare USA	Aventura	Florida
United States	American Oncology Partners of Maryland	Bethesda	Maryland
United States	Jacobi Medical Center	Bronx	New York
United States	Gabrail Cancer Research	Canton	Ohio
United States	The Oncology Institute of Hope and Innovation	Corona	California
United States	Texas Oncology - Denison	Denison	Texas
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Texas Oncology, P.A. - Flower Mound	Flower Mound	Texas
United States	The West Clinic Research	Germantown	Tennessee
United States	The Oncology Institute of Hope and Innovation	Glendale	California
United States	MD Anderson Cancer Center	Houston	Texas
United States	SCL Health Research Institute	Lafayette	Colorado
United States	Minnesota Oncology Hematology, P.A.	Minneapolis	Minnesota
United States	Texas Oncology - New Braunfels	New Braunfels	Texas
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Cancer Care Centers of Brevard, Inc.	Palm Bay	Florida
United States	Texas Oncology - Plano East	Plano	Texas
United States	BRCR Global	Plantation	Florida
United States	North Shore Hematology Oncology Associates dba New York Cancer and Blood Specialists	Port Jefferson Station	New York
United States	Oregon Health & Science University (OHSU) Knight Cancer Institute	Portland	Oregon
United States	Arizona Oncology Associates PC - HAL	Prescott	Arizona
United States	Advanced Research Institute	Saint Petersburg	Florida
United States	MultiCare Institute for Research and Innovation	Tacoma	Washington
United States	Texas Oncology - Gulf Coast	Webster	Texas
United States	PIH Health Whittier Hospital	Whittier	California
United States	Shenandoah Oncology Associates	Winchester	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Napo Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Georgia,  Serbia,  Taiwan, 

References & Publications (18)

Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, McCallum R, Mitchell EP, O'Dorisio TM, Vokes EE, Wadler S. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004 Jul 15;22(14):2918-26. doi: 10.1200/JCO.2004.04.132. — View Citation

Bowen JM. Mechanisms of TKI-induced diarrhea in cancer patients. Curr Opin Support Palliat Care. 2013 Jun;7(2):162-7. doi: 10.1097/SPC.0b013e32835ec861. — View Citation

Carlotto A, Hogsett VL, Maiorini EM, Razulis JG, Sonis ST. The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. Pharmacoeconomics. 2013 Sep;31(9):753-66. doi: 10.1007/s40273-013-0081-2. — View Citation

Cottreau J, Tucker A, Crutchley R, Garey KW. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. 2012 Feb;6(1):17-23. doi: 10.1586/egh.11.87. — View Citation

Crutchley RD, Miller J, Garey KW. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. 2010 May;44(5):878-84. doi: 10.1345/aph.1M658. Epub 2010 Apr 13. — View Citation

Davila M, Bresalier RS. Gastrointestinal complications of oncologic therapy. Nat Clin Pract Gastroenterol Hepatol. 2008 Dec;5(12):682-96. doi: 10.1038/ncpgasthep1277. Epub 2008 Oct 21. — View Citation

Di Fiore F, Van Cutsem E. Acute and long-term gastrointestinal consequences of chemotherapy. Best Pract Res Clin Gastroenterol. 2009;23(1):113-24. doi: 10.1016/j.bpg.2008.11.016. — View Citation

DiCesare D, DuPont HL, Mathewson JJ, Ashley D, Martinez-Sandoval F, Pennington JE, Porter SB. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol. 2002 Oct;97(10):2585-8. doi: 10.1111/j.1572-0241.2002.06027.x. — View Citation

Engelking C, Rutledge DN, Ippoliti C, Neumann J, Hogan CM. Cancer-related diarrhea: a neglected cause of cancer-related symptom distress. Oncol Nurs Forum. 1998 Jun;25(5):859-60. No abstract available. — View Citation

Gibson RJ, Keefe DM. Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies. Support Care Cancer. 2006 Sep;14(9):890-900. doi: 10.1007/s00520-006-0040-y. Epub 2006 Apr 8. — View Citation

Hirsh V, Blais N, Burkes R, Verma S, Croitoru K. Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Curr Oncol. 2014 Dec;21(6):329-36. doi: 10.3747/co.21.2241. — View Citation

Holodniy M, Koch J, Mistal M, Schmidt JM, Khandwala A, Pennington JE, Porter SB. A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol. 1999 Nov;94(11):3267-73. doi: 10.1111/j.1572-0241.1999.01535.x. — View Citation

Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013 Nov-Dec;14(6):261-73. doi: 10.1310/hct1406-261. — View Citation

Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78(4):180-6. doi: 10.1159/000185719. Epub 2008 Dec 18. — View Citation

Nee J, Salley K, Ludwig AG, Sommers T, Ballou S, Takazawa E, Duehren S, Singh P, Iturrino J, Katon J, Lee HN, Rangan V, Lembo AJ. Randomized Clinical Trial: Crofelemer Treatment in Women With Diarrhea-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2019 Dec;10(12):e00110. doi: 10.14309/ctg.0000000000000110. — View Citation

Pessi MA, Zilembo N, Haspinger ER, Molino L, Di Cosimo S, Garassino M, Ripamonti CI. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol Hematol. 2014 May;90(2):165-79. doi: 10.1016/j.critrevonc.2013.11.008. Epub 2013 Dec 5. — View Citation

Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010 Jan;2(1):51-63. doi: 10.1177/1758834009355164. — View Citation

Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of Number of Loose/watery Stools	The frequency of diarrhea as measured by the average number of loose/watery stools per week will be evaluated as a continuous endpoint.	For the entire 12-week double-blind placebo-controlled treatment period (The Stage 1 Primary Treatment Phase).
Secondary	Proportion of Durable, Clinical Responders	Proportion of "durable responders" defined as the proportion of subjects with =7 loose and/or watery bowel movements per week for at least 50% of the time over the Stage 1 double-blind placebo-controlled primary treatment period (Stage 1).	Initial 12-week (Stage 1) period of the study.
Secondary	Maximum Number of Weekly Loose/Watery Stools	Maximum number of weekly unformed (loose and/or watery) bowel movements from Week 1 through end of Week 12.	Initial 12-week (Stage 1) period of the study.
Secondary	Fecal Incontinence	Mean number of fecal incontinence episodes from Week 1 through end of Week 12	Initial 12-week (Stage 1) period of the study.