Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy (OnTARGET)

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

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.

Study Overview

• Status: Completed
• Conditions: Adult Solid Tumor; Cancer Therapy-Related Diarrhea; Chemotherapy-related Diarrhea; Prophylaxis of Diarrhea; Symptomatic Relief of Diarrhea; Targeted Therapy-related Diarrhea
• Intervention / Treatment: Drug: Placebo; Drug: Crofelemer 125 MG [Mytesi]

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 287
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1414
    • Fleischer Medical Center
  • Buenos Aires, Argentina, C1019ABS
    • Medical Center Austral
  • Buenos Aires, Argentina
    • Buenos Aires British Hospital
  • Córdoba, Argentina
    • Cordoba Oncology Institute (IONC)
  • Paraná, Argentina, 3100
    • Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)
  • Salta, Argentina
    • CEDIT Diagnostic and treatment center
  • Santa Fe, Argentina, S3000FFV
    • Isis Specialized Clinic
  • Tucuman, Argentina, 4000
    • 9 of July Sanatorium
• Georgia
  • Tbilisi, Georgia, 0159
    • JSC K. Eristavi National Center of Experimental and Clinical Surgery
  • Tbilisi, Georgia, 0186
    • LTD Caucasus Medical Centre
  • Tbilisi, Georgia, 0112
    • LLC "Todua Clinic"
  • Tbilisi, Georgia, 0159
    • Archangel St. Michael Multiprofile Clinical Hospital LTD
  • Tbilisi, Georgia, 0172
    • Malkhaz Katsiashvili Multiprofile Emergency Medicine Center LLC
• Serbia
  • Belgrade, Serbia, 11000
    • National Cancer Research Center
  • Belgrade, Serbia, 11 080
    • Clinical Hospital Center Bezanijska Kosa
  • Kragujevac, Serbia, 34 000
    • University Clinical Center Kragujevac
  • Nis, Serbia, 18 000
    • University Clinical Center Nis
  • Sremska Kamenica, Serbia, 21204
    • Institute of Pulmonary Diseases of Vojvodina
  • Sremska Kamenica, Serbia, 21204
    • Oncology Institute of Vojvodina (IOV)
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan
    • Kaohsiung Chang Gung Memorial Hospital
  • Taichung, Taiwan, 404332
    • China Medical University Hospital
  • Tainan, Taiwan, 736402
    • Chi Mei Medical Center - Liouying Branch
  • Taipei, Taiwan, 100226
    • National Taiwan University Hospital
  • Taipei, Taiwan, 112201
    • Taipei Veterans General Hospital
• United States
  • Arizona
    • Prescott, Arizona, United States, 86314
      • Arizona Oncology Associates PC - HAL
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center INC
    • Corona, California, United States, 92882
      • The Oncology Institute of Hope and Innovation
    • Glendale, California, United States, 91204
      • The Oncology Institute of Hope and Innovation
    • Whittier, California, United States, 90602
      • Pih Health Whittier Hospital
  • Colorado
    • Lafayette, Colorado, United States, 80218
      • SCL Health Research Institute
  • Florida
    • Aventura, Florida, United States, 33180
      • GenesisCare USA
    • Palm Bay, Florida, United States, 32909
      • Cancer Care Centers of Brevard, Inc.
    • Plantation, Florida, United States, 33322
      • BRCR Global
    • Saint Petersburg, Florida, United States, 33710
      • Advanced Research Institute
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology, P.A.
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • Port Jefferson Station, New York, United States, 11776
      • North Shore Hematology Oncology Associates Dba New York Cancer and Blood Specialists
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Research
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU) Knight Cancer Institute
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The West Clinic Research
  • Texas
    • Denison, Texas, United States, 75020
      • Texas Oncology - Denison
    • Flower Mound, Texas, United States, 75028
      • Texas Oncology, P.A. - Flower Mound
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • New Braunfels, Texas, United States, 78130
      • Texas Oncology - New Braunfels
    • Plano, Texas, United States, 75075-7787
      • Texas Oncology - Plano East
    • Webster, Texas, United States, 77598
      • Texas Oncology - Gulf Coast
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
    • Winchester, Virginia, United States, 22601
      • Shenandoah Oncology Associates
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research and Innovation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects randomized to the placebo arm, will receive oral doses of matching placebo tablets twice daily with or without food.	Drug: Placebo; Matching placebo tablets
Experimental: Crofelemer; Subjects randomized to the crofelemer arm, will receive oral doses of crofelemer 125mg delayed-release tablets twice daily with or without food.	Drug: Crofelemer 125 MG [Mytesi]; Randomized, Double-blind, Placebo-controlled, two arm trial

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
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.

Collaborators and Investigators

• Sponsor: Napo Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Pablo Okhuysen, MD, M.D. Anderson Cancer Center; Study Chair: Pravin Chaturvedi, PhD, Napo Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2020
• Primary Completion (Actual): August 7, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: August 28, 2020
• First Submitted That Met QC Criteria: September 3, 2020
• First Posted (Actual): September 4, 2020

Study Record Updates

• Last Update Posted (Actual): July 26, 2024
• Last Update Submitted That Met QC Criteria: July 24, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: NP 303-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No