A Study to Evaluate the Safety of Fenretinide in Healthy Volunteers

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about a single dose of fenretinide in healthy volunteers, in both a fasted and fed state. The main questions it aims to answer are: •How well is a single dose of fenretinide tolerated? AND •How is a single dose of fenretinide metabolized in healthy volunteers? Participants will be asked to: Remain confined in a clinical research unit for 5 days after dosing. Provide blood samples for intense PK sampling and safety labs. Fast for 10 hours prior to administration of study drug (fasted cohorts). Consume a high fat meal prior to administration of study drug (fed cohort). Return to the clinic for a single follow-up visit for safety assessments. Researchers will compare active fenretinide to placebo to see if fenretinide is more or less tolerable than placebo.

Detailed Description
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This study is a randomized, double-blind, placebo-controlled single ascending dose study. There are 3 planned dose-level cohorts (Cohorts 1-3). Each dose-level cohort will consist of 8 subjects (6 active + 2 placebo), who will be treated under fasted conditions. The subjects in the highest tolerated dose-level cohort will also be administered ISLA101 under fed conditions, in a cross-over manner (Cohort 4). Proposed doses are 300, 600, and 900 mg/m2 (equivalent to 8.1, 16.2, and 24.3 mg/kg). Each subject will be allocated to 1 dose level only. The study will include a 5-day stay in the clinical research unit followed by a final safety follow-up visit at Day 8.

Official Title
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A Phase 1a, Randomized, Double-blind Placebo-controlled Study to Evaluate Safety and Tolerability and to Characterize the Pharmacokinetic Profile of Single Ascending Doses of Fenretinide Oral Capsules in Healthy Adult Volunteers

Conditions
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Safety and Tolerability

Intervention / Treatment
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* Drug: Fenretinide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Healthy male or female volunteers not of childbearing potential, who are 18 years to 65 years of age (inclusive) at the time of signing the informed consent form (ICF). 2. Females not of childbearing potential, as defined in the following criteria: a. History of hysterectomy. b. Post-menopausal. i. Natural post-menopausal females with at least 12 months from natural spontaneous amenorrhea and a serum follicle-stimulating hormone (FSH) concentration ≥ 40 IU/L. ii. Post-surgical females must have undergone bilateral oophorectomy at least 6 weeks prior to study. 3. Male subjects with female partners of childbearing potential must agree to practice abstinence or use a combination of 2 of the following acceptable birth control methods during the study and for at least 90 days after dosing: Partners have an intrauterine device (IUD) without hormones in place for at least 3 months. Barrier method (condom or diaphragm) for at least 14 days prior to screening and 90 days after dosing with study drug. Partners using stable hormonal contraceptive for at least 3 months prior to screening and for 90 days after dosing with study drug. History of vasectomy at least 3 months prior to signing the ICF. 4. Must be able to understand and provide signed informed consent for study participation. 5. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. 6. Body mass index (BMI) 18.0 to 32.0 kg/m2 (inclusive), and a body weight ≥ 50 kg. 7. Normal renal function, defined as estimated glomerular filtration rate (eGFR) ≥ 70 mL/min/1.73 m2 at screening and Day -1. 8. Clinical laboratory values should be within the laboratory's stated normal range. If not within this range, they must be without clinical significance, as determined by the Investigator. 9. No history of clinically relevant medical disorders, as determined by the Investigator. Exclusion Criteria: 1. Known or suspected pregnancy (confirmed via a positive serum human chorionic gonadotropin [hCG] pregnancy test at screening), planned pregnancy during the study period, nursing, or lactation. 2. Women of childbearing potential or men who intend to father a child or donate sperm during the study period and for 3 months after study drug administration. 3. Known allergy to fenretinide or any of the components of ISLA101. 4. Evidence or history of clinically significant medical conditions, such as hematological, renal, endocrine (e.g., polycystic ovarian syndrome or other anovulatory states), immunologic, pulmonary, metabolic, gastrointestinal (e.g., Crohn's disease, acute or chronic pancreatitis, and others) and surgery (except for simple appendectomy or repair of a hernia), which all can influence the absorption of study drug; cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), or any other illness that the Investigator considers exclusionary or that could interfere with the interpretation of the study results. 5. History of severe infectious disease or recurrent infections. 6. Aspartate transaminase (AST), alanine aminotransferase (ALT), or total bilirubin above the 1.5 x upper limit of normal (ULN) at screening and Day -1. 7. Clinically significant electrocardiogram (ECG) abnormalities or vital sign abnormalities at screening and Day -1, long QT syndrome, or a history of cardiac disease. 8. Abnormal diet that may affect absorption, distribution, metabolism, or excretion of drugs, for example, lacking standard nutrients (e.g, cleansing diet 2 weeks before or during the study). 9. Positive result for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening. 10. History of positive test for tuberculosis (TB) at screening. 11. A subject who has donated 1 unit of blood of over 500 mL within 56 days prior to the study drug administration, or donated plasma within 14 days prior to study drug administration. 12. Use of systemic antibiotics within 30 days prior to dosing. 13. Any use of drugs that inhibit or induce CYP enzymes within 30 days prior to administration of study drug and for the duration of study participation. 14. Use of any tobacco products, e-cigarettes, and/or nicotine replacement products in the 3 months preceding screening. 15. Any food allergy, intolerance, or restriction that, in the opinion of the Investigator, could contraindicate the subject's participation in this study. 16. Recent history of (within the past 12 months), or strong potential for, alcohol or substance abuse. Alcohol abuse will be defined as > 14 drinks per week (1 drink = 10g of ethanol). 17. History of drug or alcohol abuse within 5 years before screening or positive result of UDS (e.g, amphetamines, benzodiazepines, cannabinoids, cocaine, hallucinogens, opiates) or alcohol breath test at screening. 18. Exposure to any investigational agent or used an invasive investigational medical device within 30 days or within a period less than 5 drug half-lives prior to study entry (whichever is longer). 19. Study site employees, Sponsor's employees, or immediate family members of a study site or Sponsor employee. 20. Previously enrolled in this study. 21. Vaccination 14 days from screening or plans to get a vaccine within 30 days after dosing. 22. Acute infection (such as influenza) or relevant lesion at the time of Screening or Day -1. Subjects can be rescreened once they have recovered. 23. Criteria at the discretion of the Investigator: a. Chronic medical condition that impacts subject safety. b. Clinically significant abnormal physical examination or vital signs at screening. c. Condition believed to interfere with the subject's ability to provide informed consent or comply with study instructions, or that might confound the interpretation of the study results or put the subject at undue risk. d. History or evidence of a clinically significant disorder, condition, or disease that that is believed to significantly impair pain perception (e.g., history of stroke, history of neuropathy), would pose a risk to subject safety or interfere with evaluation, procedures, or study completion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fenretinide 300 mg/m2<br>Single oral dose of fenretinide, 300 mg/m2 | Drug: Fenretinide<br>* Ascending single doses of oral fenretinide<br>|
| Active Comparator: Fenretinide 600 mg/m2<br>Single oral dose of fenretinide, 600 mg/m2 | Drug: Fenretinide<br>* Ascending single doses of oral fenretinide<br>|
| Active Comparator: Fenretinide 900 mg/m2<br>Single oral dose of fenretinide, 900 mg/m2 | Drug: Fenretinide<br>* Ascending single doses of oral fenretinide<br>|
| Placebo Comparator: Placebo<br>Single oral dose of placebo capsules | Drug: Placebo<br>* Single oral dose of matching placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and % of subjects experiencing adverse events following a single oral dose of fenretinide | Primary objective | Day 1 to Day 8 | 
| Number and % of subjects experiencing serious adverse events following a single oral dose of fenretinide | Primary objective | Day 1 to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the CMax - observed maximum plasma concentration following a single oral dose of fenretinide in the fasted state | Secondary objective | Day 1 to Day 8 | 
| Assess the TMax - time to reach maximum concentration curve following a single oral dose of fenretinide in the fasted state | Secondary objective | Day 1 to Day 8 | 
| Assess the AUC-∞ Area under the concentration curve from zero to infinite time following a single oral dose of fenretinide in the fasted state | Secondary objective | Day 1 to Day 8 | 
| Assess the AUC(last) - Area under the curve up to the last quantifiable timepoint after a single oral dose of fenretinide in the fasted state | Secondary objective | Day 1 to Day 8 | 
| Assess the half life of a single oral dose of fenretinide in the fasted state | Secondary objective | Day 1 to Day 8 |