Prophylaxis of Diarrhea in Adult Cancer Patients Receiving Targeted Cancer Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Crofelemer 125 MG [Mytesi]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects randomized to the placebo arm, will receive oral doses of matching placebo tablets twice daily with or without food. | Drug: Placebo<br>* Matching placebo tablets<br>|
| Experimental: Crofelemer<br>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]<br>* Randomized, Double-blind, Placebo-controlled, two arm trial<br>|

What is the study measuring?
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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. |