Clinical trial NCT04538625: Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cancer Therapy-Related Diarrhea
Chemotherapy-related Diarrhea
Adult Solid Tumor
Prophylaxis of Diarrhea
Symptomatic Relief of Diarrhea
Targeted Therapy-related Diarrhea
Lead sponsor: Napo Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-09-04
Enrollment: 287
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model 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).
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Frequency of Number of Loose/watery Stools
timeFrame: For the entire 12-week double-blind placebo-controlled treatment period (The Stage 1 Primary Treatment Phase).
Secondary outcomes:
measure: Proportion of Durable, Clinical Responders
timeFrame: Initial 12-week (Stage 1) period of the study.
measure: Maximum Number of Weekly Loose/Watery Stools
timeFrame: Initial 12-week (Stage 1) period of the study.
measure: Fecal Incontinence
timeFrame: Initial 12-week (Stage 1) period of the study.
Other outcomes:
Locations:
city: Prescott
country: United States
facility: Arizona Oncology Associates PC - HAL
state: Arizona
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center Inc
state: California
city: Corona
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Glendale
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Whittier
country: United States
facility: PIH Health Whittier Hospital
state: California
city: Lafayette
country: United States
facility: SCL Health Research Institute
state: Colorado
city: Aventura
country: United States
facility: GenesisCare USA
state: Florida
city: Palm Bay
country: United States
facility: Cancer Care Centers of Brevard, Inc.
state: Florida
city: Plantation
country: United States
facility: BRCR Global
state: Florida
city: Saint Petersburg
country: United States
facility: Advanced Research Institute
state: Florida
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland
state: Maryland
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Port Jefferson Station
country: United States
facility: North Shore Hematology Oncology Associates dba New York Cancer and Blood Specialists
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Research
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU) Knight Cancer Institute
state: Oregon
city: Germantown
country: United States
facility: The West Clinic Research
state: Tennessee
city: Denison
country: United States
facility: Texas Oncology - Denison
state: Texas
city: Flower Mound
country: United States
facility: Texas Oncology, P.A. - Flower Mound
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: New Braunfels
country: United States
facility: Texas Oncology - New Braunfels
state: Texas
city: Plano
country: United States
facility: Texas Oncology - Plano East
state: Texas
city: Webster
country: United States
facility: Texas Oncology - Gulf Coast
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Winchester
country: United States
facility: Shenandoah Oncology Associates
state: Virginia
city: Tacoma
country: United States
facility: MultiCare Institute for Research and Innovation
state: Washington
city: Buenos Aires
country: Argentina
facility: Fleischer Medical Center
city: Buenos Aires
country: Argentina
facility: Medical Center Austral
city: Buenos Aires
country: Argentina
facility: Buenos Aires British Hospital
city: Córdoba
country: Argentina
facility: Cordoba Oncology Institute (IONC)
city: Paraná
country: Argentina
facility: Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)
city: Salta
country: Argentina
facility: CEDIT Diagnostic and Treatment Center
city: Santa Fe
country: Argentina
facility: Isis Specialized Clinic
city: Tucuman
country: Argentina
facility: 9 of July Sanatorium
city: Tbilisi
country: Georgia
facility: LLC "Todua Clinic"
city: Tbilisi
country: Georgia
facility: Archangel St. Michael Multiprofile Clinical Hospital LTD
city: Tbilisi
country: Georgia
facility: JSC K. Eristavi National Center of Experimental and Clinical Surgery
city: Tbilisi
country: Georgia
facility: Malkhaz Katsiashvili Multiprofile Emergency Medicine Center LLC
city: Tbilisi
country: Georgia
facility: LTD Caucasus Medical Centre
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Bezanijska Kosa
city: Belgrade
country: Serbia
facility: National Cancer Research Center
city: Kragujevac
country: Serbia
facility: University Clinical Center Kragujevac
city: Nis
country: Serbia
facility: University Clinical Center Nis
city: Sremska Kamenica
country: Serbia
facility: Institute of Pulmonary Diseases of Vojvodina
city: Sremska Kamenica
country: Serbia
facility: Oncology Institute of Vojvodina (IOV)
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: Chi Mei Medical Center - LiouYing Branch
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Pablo Okhuysen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Napo Pharmaceuticals
name: Pravin Chaturvedi, PhD
role: STUDY_CHAIR
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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.
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.
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.
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.
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