Evaluate REC-4881 in Patients With FAP

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, two-part trial in participants with Familial Adenomatous Polyposis (FAP).

Detailed Description
-----------------
This is a Phase 2, trial to evaluate efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of REC-4881 in participants with FAP. This two-part study is designed to characterize the safety, tolerability, PK, PD, and preliminary activity of REC-4881 administered orally (PO) at multiple doses on a once daily schedule in participants with phenotypic classical FAP with disease involvement of the duodenum or the residual colon/rectum/pouch as the primary disease site.

Official Title
-----------------
A Phase 2, Multicenter, Trial to Evaluate Efficacy, Safety, and Pharmacokinetics, and Pharmacodynamics of REC-4881 in Patients With Familial Adenomatous Polyposis (FAP)

Conditions
-----------------
Familial Adenomatous Polyposis

Intervention / Treatment
-----------------
* Drug: REC-4881
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female and ≥ 18 years of age' Have provided written informed consent to participate in the study Diagnosis of phenotypic classical FAP with disease involvement of the duodenum or the residual colon/rectum/pouch as the primary disease site. Genetic diagnosis of FAP with APC gene mutation (Part 2 only). Has undergone colectomy or subtotal colectomy No significant cardiovascular abnormalities No significant hematopoietic abnormalities No significant hepatic abnormalities No significant renal abnormalities Female participants must have a negative serum pregnancy test prior to Study Day 1 All participants must be willing to follow the contraceptive guidance in the protocol Absence of gross blood in stool at Screening Participant must be willing to discontinue use of non-steroidal anti-inflammatory agents (NSAIDs) prior to Study Day 1 Exclusion Criteria: No clinically significant laboratory abnormality, medical or psychiatric illness Has had prior pelvic irradiation. Has gastrointestinal disease or recent gastrointestinal procedure that could interfere with oral absorption of REC-4881 Has received treatment with other investigational agents prior to Study Day 1 Treatment with other FAP-directed drug therapy within 8 weeks of screening endoscopy (Part 2 only). Is currently under treatment for desmoid tumors. Use of omega-3 fatty acids or oral corticosteroids prior to Study Day 1 Use of strong CYP3A inhibitors or inducers prior to Study Day 1 History of an ongoing or newly diagnosed eye abnormality. Cancer on biopsy at screening endoscopy in GI tract (including stomach, duodenum, and colon/rectum/pouch) (Part 2 only). Has a large polyp (>1 cm) not amenable to complete removal Has active pancreatitis secondary to pancreatic duct obstruction Has active gall bladder disease Is pregnant, lactating or is planning to attempt to become pregnant during the study Has had major surgery prior to Study Day 1 Has an active infection requiring systemic therapy. Has known hypersensitivity to the study drug or its excipients. History of alcohol or substance abuse. Received treatment with another MEK inhibitor prior to Screening Active or known HIV, hepatitis B or hepatitis C infections Has a severe or uncontrolled medical condition Use of strong BCRP or MRP2 inhibitors prior to Study Day 1

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Part 1)<br>Participants will receive placebo PO dosed QD | Drug: Placebo<br>* Placebo capsules<br>|
| Experimental: REC-4881 4mg (Part 1)<br>Participants will receive REC-4881 4mg PO dosed QD | Drug: REC-4881<br>* REC-4881 4mg capsules<br>|
| Experimental: REC-4881 8mg (Part 2)<br>Participants will receive REC-4881 8mg PO dosed QD | Drug: REC-4881<br>* REC-4881 4mg capsules<br>|
| Experimental: REC-4881 12mg (Part 2)<br>Participants will receive REC-4881 12mg PO dosed QD | Drug: REC-4881<br>* REC-4881 4mg capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize plasma pharmacokinetic (PK) parameters of REC-4881 | Maximum (peak) plasma drug concentration (Cmax), time to reach maximum (peak) plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) | Assessed at multiple timepoints from Day 1 through 43 days in Part 1 | 
| Incidence of Treatment-Emergent Adverse Events | Treatment Emergent Adverse Events, Serious Adverse Events, and treatment discontinuation and dose modification due to toxicity | 30 weeks (Part 2) | 
| Percent change from baseline in polyp burden | Effect of REC-4881 on duodenal adenomas and rectal/pouch adenomas | 24 weeks (Part 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Treatment Emergent Adverse Events, Serious Adverse Events, and treatment discontinuation and dose modification due to toxicity | 43 days (Part 1) | 
| Characterize plasma pharmacokinetic (PK) parameters of REC-4881 | Maximum (peak) plasma drug concentration (Cmax), time to reach maximum (peak) plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) | Assessed at multiple timepoints from Day 1 through Week 3 (Part 2) | 
| Assess the effect of REC-4881 on the change of polyp number by size and histological grade | Change from baseline in polyp number, polyp number >5 mm, highest histological grade, spigelman stage classification for duodenal polyps, and inSiGHT stage for rectal/pouch polyps | 24 weeks (Part 2) | 
| Assess the pharmacodynamic (PD) effect of REC-4881, and correlation between PD and clinical outcome | Percent inhibition of pERK at multiple timepoints | Day 1 through Week 3 (Part 2) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FAP, familial adenomatous polyposis, APC mutation, adenomatous polyposis coli, desmoid disease