Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy

NCT04538625 | Completed Phase 3 FDA Drug

• 1 other identifier: NP 303-102
• Study Type: interventional
• Target: 287
• Locations: 5 countries
• Sites: 52

Brief 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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Proportion of Durable, Clinical Responders

  Initial 12-week (Stage 1) period of the study.

• Maximum Number of Weekly Loose/Watery Stools

  Initial 12-week (Stage 1) period of the study.

• Fecal Incontinence

  Initial 12-week (Stage 1) period of the study.

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Subjects randomized to the placebo arm, will receive oral doses of matching placebo tablets twice daily with or without food.

Drug: Placebo

Crofelemer

EXPERIMENTAL

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]

Interventions

Crofelemer 125 MG [Mytesi] DRUG

Randomized, Double-blind, Placebo-controlled, two arm trial

Crofelemer

Placebo DRUG

Matching placebo tablets

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.
• \. Patients able to provide written informed consent.
• \. Men and women ≥ 18 years of age.
• \. Pathologically and/or radiologically confirmed diagnosis of solid tumors scheduled to receive targeted cancer therapy.
• \. 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.
• \. Patient can receive concomitant cycle \[standard\] chemotherapy agents together with their targeted cancer therapy treatment regimens.
• \. ECOG (Eastern Cooperative Oncology Group) performance status 0-2 and expected to survive a 12-week course of targeted therapy with or without chemotherapy
• \. Negative urine pregnancy test at time of informed consent for women of childbearing potential.

You may not qualify if:

• \. 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.
• \. Any cancer therapy for which antidiarrheal (antimotility) medications in the prophylaxis setting is mandatory, including but not limited to patients receiving neratinib and irinotecan.
• \. Ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.).
• \. Ongoing diarrhea and/or diarrheal episodes within the previous 7 days prior to randomization into the study.
• \. Laxative use within 7 days prior to randomization or a history of constipation requiring the use of laxatives for more than ≥ 30 consecutive days.
• \. 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.
• 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.
• \. Use of other investigational drugs within 4 weeks of signed informed consent or foreseen use during the study.
• \. 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.
• \. Total colectomy and/or any type of gastrointestinal ostomy.
• \. Major abdominal or pelvic surgery within the past 3 months.
• \. Previous (within 1 month) or planned abdominal and/or pelvic radiation.
• \. Fecal incontinence from ongoing radiation-induced diarrhea or constipation
• \. Active systemic infection requiring ongoing intervention, including but not limited to oral and intravenous antibiotics, anti-fungals, anti-parasitics, and anti-viral drugs.
• \. Inability to comply with study requirements as judged by the Investigator.

Sponsors & Collaborators

• Napo Pharmaceuticals, Inc.: lead

Study Sites (52)

Arizona Oncology Associates PC - HAL

Prescott, Arizona, 86314, United States

Location

Pacific Cancer Medical Center Inc

Anaheim, California, 92801, United States

Location

The Oncology Institute of Hope and Innovation

Corona, California, 92882, United States

Location

The Oncology Institute of Hope and Innovation

Glendale, California, 91204, United States

Location

PIH Health Whittier Hospital

Whittier, California, 90602, United States

Location

SCL Health Research Institute

Lafayette, Colorado, 80218, United States

Location

GenesisCare USA

Aventura, Florida, 33180, United States

Location

Cancer Care Centers of Brevard, Inc.

Palm Bay, Florida, 32909, United States

Location

BRCR Global

Plantation, Florida, 33322, United States

Location

Advanced Research Institute

St. Petersburg, Florida, 33710, United States

Location

American Oncology Partners of Maryland

Bethesda, Maryland, 20817, United States

Location

Minnesota Oncology Hematology, P.A.

Minneapolis, Minnesota, 55404, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

North Shore Hematology Oncology Associates dba New York Cancer and Blood Specialists

Port Jefferson Station, New York, 11776, United States

Location

Jacobi Medical Center

The Bronx, New York, 10461, United States

Location

Gabrail Cancer Research

Canton, Ohio, 44718, United States

Location

Oregon Health & Science University (OHSU) Knight Cancer Institute

Portland, Oregon, 97239, United States

Location

The West Clinic Research

Germantown, Tennessee, 38138, United States

Location

Texas Oncology - Denison

Denison, Texas, 75020, United States

Location

Texas Oncology, P.A. - Flower Mound

Flower Mound, Texas, 75028, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Texas Oncology - New Braunfels

New Braunfels, Texas, 78130, United States

Location

Texas Oncology - Plano East

Plano, Texas, 75075-7787, United States

Location

Texas Oncology - Gulf Coast

Webster, Texas, 77598, United States

Location

Inova Schar Cancer Institute

Fairfax, Virginia, 22031, United States

Location

Shenandoah Oncology Associates

Winchester, Virginia, 22601, United States

Location

MultiCare Institute for Research and Innovation

Tacoma, Washington, 98405, United States

Location

Fleischer Medical Center

Buenos Aires, 1414, Argentina

Location

Medical Center Austral

Buenos Aires, C1019ABS, Argentina

Location

Buenos Aires British Hospital

Buenos Aires, Argentina

Location

Cordoba Oncology Institute (IONC)

Córdoba, Argentina

Location

Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)

Paraná, 3100, Argentina

Location

CEDIT Diagnostic and Treatment Center

Salta, Argentina

Location

9 of July Sanatorium

San Miguel de Tucumán, 4000, Argentina

Location

Isis Specialized Clinic

Santa Fe, S3000FFV, Argentina

Location

LLC "Todua Clinic"

Tbilisi, 0112, Georgia

Location

Archangel St. Michael Multiprofile Clinical Hospital LTD

Tbilisi, 0159, Georgia

Location

JSC K. Eristavi National Center of Experimental and Clinical Surgery

Tbilisi, 0159, Georgia

Location

Malkhaz Katsiashvili Multiprofile Emergency Medicine Center LLC

Tbilisi, 0172, Georgia

Location

LTD Caucasus Medical Centre

Tbilisi, 0186, Georgia

Location

Clinical Hospital Center Bezanijska Kosa

Belgrade, 11 080, Serbia

Location

National Cancer Research Center

Belgrade, 11000, Serbia

Location

Institute of Pulmonary Diseases of Vojvodina

Kamenitz, 21204, Serbia

Location

Oncology Institute of Vojvodina (IOV)

Kamenitz, 21204, Serbia

Location

University Clinical Center Kragujevac

Kragujevac, 34 000, Serbia

Location

University Clinical Center Nis

Niš, 18 000, Serbia

Location

Changhua Christian Hospital

Changhua, 500, Taiwan

Location

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, Taiwan

Location

China Medical University Hospital

Taichung, 404332, Taiwan

Location

Chi Mei Medical Center - LiouYing Branch

Tainan, 736402, Taiwan

Location

National Taiwan University Hospital

Taipei, 100226, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112201, Taiwan

Location

Related Publications (18)

• 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.

  PMID: 25489260 BACKGROUND

• 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.

  PMID: 18941434 BACKGROUND

• 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.

  PMID: 16604351 BACKGROUND

• 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.

  PMID: 21789126 BACKGROUND

• 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.

  PMID: 9644701 BACKGROUND

• 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.

  PMID: 15254061 BACKGROUND

• 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.

  PMID: 19258191 BACKGROUND

• 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.

  PMID: 23963867 BACKGROUND

• 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.

  PMID: 23399616 BACKGROUND

• 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.

  PMID: 20388859 BACKGROUND

• 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.

  PMID: 22149578 BACKGROUND

• 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.

  PMID: 19808995 BACKGROUND

• 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.

  PMID: 10566728 BACKGROUND

• 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.

  PMID: 12385443 BACKGROUND

• 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.

  PMID: 19092244 BACKGROUND

• 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.

  PMID: 24373918 BACKGROUND

• 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.

  PMID: 24334179 BACKGROUND

• 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.

  PMID: 31800542 BACKGROUND

MeSH Terms

Interventions

crofelemer

Study Officials

• Pablo Okhuysen, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

• Pravin Chaturvedi, PhD

  Napo Pharmaceuticals

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind, placebo controlled
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: August 28, 2020
• First Posted: September 4, 2020
• Study Start: October 7, 2020
• Primary Completion: August 7, 2023
• Study Completion: October 30, 2023
• Last Updated: July 26, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (27); SE (6); GE (5); AR (8); TW (6)