Clinical trial NCT05552755: Evaluate REC-4881 in Patients With FAP
Official title: A Phase 1b-2, Multicenter, Trial To Evaluate The Efficacy, Safety, Pharmacokintetics, And Pharmacodynamics Of REC-4881 in Patients With Familial Adenomatous Polyposis (FAP)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Familial Adenomatous Polyposis
Keywords: FAP
familial adenomatous polyposis
APC mutation
adenomatous polyposis coli
desmoid disease
Lead sponsor: Recursion Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2022-09-23
Enrollment: 67
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, two-part trial in participants with Familial Adenomatous Polyposis (FAP).

Detailed description: This is a Phase 1b/2, trial to evaluate efficacy, safety, pharmacokinetics and pharmacodynamics of REC-4881 in participants with Familial Adenomatous Polyposis (FAP). This two-part study will treat participants with phenotypic classical FAP with disease involvement of the duodenum or the residual colon/rectum/pouch as the primary disease site.

Part 1 of the study enrolled seven participants with FAP who are post-colectomy/proctocolectomy. Participants were randomized to Placebo or REC-4881.

Part 2 of the study will treat participants with escalating dose levels of REC-4881 during the Dose Finding. Participants in Cohort Expansion will be treated with a dose(s) to determine the RP2D.

Eligibility criteria: Inclusion Criteria:

1. Male or female and ≥ 55 years of age
2. Have provided written informed consent to participate in the study
3. Diagnosis of phenotypic classical FAP with disease involvement of the duodenum or the residual colon/rectum/pouch as the primary disease site.
4. Genetic diagnosis of FAP with APC gene mutation (Part 2 only).
5. Has undergone colectomy or subtotal colectomy
6. Spigelman Classification Stage II or higher.
7. Investigator/Participant agrees to leave polyps ≤10 mm unresected during endoscopies performed at Screening and while on study
8. Have no significant cardiovascular abnormalities at Screening:

   1. Left ventricular ejection fraction \>50% as determined on screening echocardiogram
   2. A QT interval corrected for heart rate using the Fridericia formula (QTcF) \< 450 msec in men and \<470 msec in women.
9. Have no significant hematopoietic abnormalities at Screening:

   1. White blood cell count (WBC) ≥ 3,000/mm3 (non-black populations); 2,700/mm3 (black populations)
   2. Platelet count ≥ 120,000/mm3
   3. Hemoglobin ≥ 10.0 g/dL
   4. No history of clinical coagulopathy.
10. Have no significant hepatic abnormalities at Screening:

    1. Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (individuals with Gilbert syndrome may be enrolled)
    2. AST, ALT, ALP ≤ 2.0 X ULN.
11. Have no significant renal abnormalities at Screening: serum creatinine ≤ 1.5 times X ULN.
12. Female participants who are women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours before the first dose of study drug. If the urine test is positive or cannot be confirmed negative, a serum pregnancy test will be required and must be negative for the participant to be eligible.
13. All participants must be willing to follow the contraceptive guidance in the protocol and must not be lactating or planning to attempt to become pregnant during the study or for a further period of 4 months after the last dose of study drug or impregnate someone during this study or for a further period of 14 weeks after the last dose of study drug (Appendix 1).
14. Absence of gross blood in stool at Screening; red blood on toilet paper only is acceptable.
15. Participant must be willing to discontinue use of non-steroidal anti-inflammatory agents (NSAIDs) 6 weeks prior to Study Day 1 and remain off NSAIDs throughout the treatment period of the study (use of aspirin ≤ 700 mg week is allowed.)

Exclusion Criteria:

1. Has any clinically significant laboratory abnormality, medical or psychiatric illness which, in the opinion of the Investigator, could interfere with the conduct or interpretation of the study or put the participant at risk.
2. Has had prior pelvic irradiation.
3. Has gastrointestinal disease or recent gastrointestinal procedure that could interfere with oral absorption of REC-4881, including difficulty swallowing capsules.
4. Has received treatment with other investigational agents within the 4 weeks prior to Study Day 1 or a period during which the investigational agent has not been cleared from the body (i.e., at least a period of 5 half-lives, if known), whichever is longer.
5. Treatment with other FAP-directed drug therapy within 8 weeks of screening endoscopy (Part 2 only) or had a Whipple procedure.
6. Is currently under treatment for desmoid tumors.
7. Use of omega-3 fatty acids or oral corticosteroids prior to Study Day 1
8. Use of strong CYP3A inhibitors or inducers prior to Study Day 1
9. History of an ongoing or newly diagnosed eye abnormality.

   1. Retinal pathologies such as diabetic retinopathy, veno-occlusion, or macular edema
   2. Corneal pathologies such as herpes keratitis, corneal dystrophy, corneal erosions, corneal degeneration, active or recurrent keratitis, or uveitis (intermittent, posterior, and/or panuveitis)
   3. Other clinically significant ophthalmologic abnormalities (e.g., retinal detachment) or has findings at Screening. \[Participants with corrected myopia may be enrolled.\]
10. Has cancer at screening endoscopy in GI tract (including stomach, duodenum, and colon/rectum/pouch) (Part 2 only).
11. Has a large polyp (\>1 cm) not amenable to complete removal
12. Has active pancreatitis secondary to pancreatic duct obstruction
13. Has active gall bladder disease
14. Is pregnant, lactating or is planning to attempt to become pregnant during this study or within 4 months after the last dose of study drug (women) or is planning to attempt to impregnate someone or donate sperm during the study or within 14 weeks after the last dose of study drug (men).
15. Has had major surgery prior to Study Day 1
16. Has an active infection requiring systemic therapy.
17. Has known hypersensitivity to the study drug or its excipients.
18. Has a history of alcohol or substance abuse within 1 year prior to screening for study participation, or is currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner which, in the opinion of the Investigator, indicates abuse .
19. Received treatment with another MEK inhibitor 8 weeks prior to Screening and throughout the treatment period of the study.
20. Any of the following known active infections:

    1. HIV not optimally controlled or treated. Participants with HIV who are on sustained stable antiretrovirals (for \>4 weeks) and have CD4+ counts ≥ 350 cells/μL may be enrolled. No HIV testing is required unless clinically indicated or mandated by local health authority.
    2. Chronic hepatitis B virus (HBV) infection with surface antigen positive: participants with a prior history of treated HBV infection who are hepatitis B surface antigen-negative may be enrolled. No testing is required for hepatitis B unless clinically indicated or mandated by local health authority
    3. Chronic hepatitis C virus (HCV) infection: untreated or on active treatment. Participants with a prior history of treated HCV infection who are HCV RNA-undetectable may be enrolled. No testing is required for hepatitis C unless clinically indicated or mandated by local health authority.
21. Has a severe or uncontrolled medical condition (e.g., dermatologic disease, etc.) that, in the opinion of the Investigator, would pose a significant clinical risk for the participant.
22. Use of strong BCRP or MRP2 inhibitors within 14 days of Study Day 1 and throughout the treatment period of the study.
23. Clinically significant cardiovascular disease ≤ 6 months before first dose

    1. Myocardial infarction or unstable angina
    2. Clinically significant cardiac arrhythmias
    3. Uncontrolled hypertension: systolic blood pressure (SBP) \> 180 mmHg, diastolic blood pressure (DBP) \> 100 mmHg
    4. Pulmonary embolism, symptomatic cerebrovascular events or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy)
    5. QTcF prolongation \>450 msec in males and \>470 msec in females at screening or history of long QTc syndrome
    6. Congestive heart failure (New York Heart Association class III-IV)
    7. Myocarditis / clinically significant pericarditis.

Primary outcomes:
measure: Characterize plasma pharmacokinetic (PK) parameters of REC-4881
timeFrame: Assessed at multiple timepoints from Day 1 through 43 days in Part 1
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 16 weeks (Part 2)
measure: Evaluate totality of data to determine the Recommended Phase 2 Dose (RP2D)
timeFrame: 27 months (Part 2)
measure: Percent change from baseline in polyp burden
timeFrame: 9 weeks (Part 2)
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 43 days (Part 1)
measure: Characterize plasma pharmacokinetic (PK) parameters of REC-4881
timeFrame: Assessed at multiple timepoints from Day 1 through Week 3 (Part 2)
measure: Assess the effect of REC-4881 on polyp number, histological grade and disease score
timeFrame: 12 weeks (Part 2)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Tucson
country: United States
facility: Del Sol Research Management
state: Arizona
city: San Diego
country: United States
facility: Medical Associates Research Group
state: California
city: Naples
country: United States
facility: GI Pros
state: Florida
city: Orlando
country: United States
facility: Digestive and Liver Center of Florida
state: Florida
city: New Albany
country: United States
facility: Gastroenterology Health Partners, PLLC
state: Indiana
city: Marrero
country: United States
facility: Tandem Clinical Research
state: Louisiana
city: Grand Rapids
country: United States
facility: Corewell Health (Spectrum Health Hospitals Colorectal Cancer Multis)
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Cordova
country: United States
facility: Gastro One-8110 Walnut Rs
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Digestive Center
state: Tennessee
city: Dallas
country: United States
facility: Genetic Cancer Prevention Clinic - UT Southwestern
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute and University of Utah
state: Utah
city: Seattle
country: United States
facility: Benaroya Research Institute at Virginia Mason
state: Washington
Study officials:
References: