Evaluate REC-4881 in Patients With FAP

Phase 1

Recruiting

• Conditions: Familial Adenomatous Polyposis
• Interventions: Drug: REC-4881; Drug: Placebo

• Registration Number: NCT05552755
• Lead Sponsor: Recursion Pharmaceuticals Inc.

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. Participates in Cohort Expansion will be treated with a dose(s) to determine the RP2D.

Study Timeline

• Study First Submitted: 2022-09-14
• Study First Submitted QC: 2022-09-20
• Study First Posted: 2022-09-23
• Study Start: 2023-07-10
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-01
• Last Update Posted: 2024-08-05
• Primary Completion: 2026-07
• Study Completion: 2026-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 73

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. No significant cardiovascular abnormalities
7. Left ventricular ejection fraction of >50% as determined by echocardiogram
8. No significant hematopoietic abnormalities
9. No significant hepatic abnormalities
10. No significant renal abnormalities
11. Female participants must have a negative serum pregnancy test prior to Study Day 1
12. All participants must be willing to follow the contraceptive guidance in the protocol
13. Absence of gross blood in stool at Screening
14. Participant must be willing to discontinue use of non-steroidal anti-inflammatory agents (NSAIDs) prior to Study Day 1

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Exclusion Criteria

1. No clinically significant laboratory abnormality, medical or psychiatric illness
2. Has had prior pelvic irradiation.
3. Has gastrointestinal disease or recent gastrointestinal procedure that could interfere with oral absorption of REC-4881
4. Has received treatment with other investigational agents prior to Study Day 1
5. Treatment with other FAP-directed drug therapy within 8 weeks of screening endoscopy (Part 2 only).
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.
10. 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 the study
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. History of alcohol or substance abuse.
19. Received treatment with another MEK inhibitor prior to Screening
20. Active or known HIV, hepatitis B or hepatitis C infections
21. Has a severe or uncontrolled medical condition
22. Use of strong BCRP or MRP2 inhibitors prior to Study Day 1
23. Has clinically significant cardiovascular disease within 6 months of Day 1 including myocardial infarction or unstable angina, cardiac arrhythmias, uncontrolled hypertension, pulmonary embolism, QTcF prolongation, Congestive heart failure, Myocarditis or clinically significant pericarditis

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
REC-4881 12mg (Part 2)	REC-4881	Participants will receive REC-4881 12mg PO dosed once daily
Placebo (Part 1)	Placebo	Participants will receive placebo PO dosed once daily
REC-4881 4mg (Part 1)	REC-4881	Participants will receive REC-4881 4mg PO dosed once daily
REC-4881 4mg (Part 2)	REC-4881	Participants will receive REC-4881 4mg PO dosed once daily
REC-4881 8mg (Part 2)	REC-4881	Participants will receive REC-4881 8mg PO dosed once daily

Primary Outcome Measures

Name	Time	Method
Characterize plasma pharmacokinetic (PK) parameters of REC-4881	Assessed at multiple timepoints from Day 1 through 43 days in Part 1	Maximum (peak) plasma drug concentration (Cmax), time to reach maximum (peak) plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC)
Incidence of Treatment-Emergent Adverse Events	16 weeks (Part 2)	Treatment Emergent Adverse Events, Serious Adverse Events, and treatment discontinuation and dose modification due to toxicity
Evaluate totality of data to determine the Recommended Phase 2 Dose (RP2D)	16 weeks (Part 2)	Determination of the RP2D
Percent change from baseline in polyp burden	12 weeks (Part 2)	Effect of REC-4881 on duodenal adenomas and rectal/pouch adenomas

Secondary Outcome Measures

Name	Time	Method
Characterize plasma pharmacokinetic (PK) parameters of REC-4881	Assessed at multiple timepoints from Day 1 through Week 3 (Part 2)	Maximum (peak) plasma drug concentration (Cmax), time to reach maximum (peak) plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC)
Assess the effect of REC-4881 on polyp number, histological grade and disease score	12 weeks (Part 2)	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
Assess the pharmacodynamic (PD) effect of REC-4881, and correlation between PD and clinical outcome	Day 1 through Week 3 (Part 2)	Percent inhibition of pERK at multiple timepoints
Incidence of Treatment-Emergent Adverse Events	43 days (Part 1)	Treatment Emergent Adverse Events, Serious Adverse Events, and treatment discontinuation and dose modification due to toxicity

Trial Locations

Locations (12)

Medical Associates Research Group; 🇺🇸 San Diego, California, United States

GI Pros; 🇺🇸 Naples, Florida, United States

Gastroenterology Health Partners, PLLC; 🇺🇸 New Albany, Indiana, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Benaroya Research Institute at Virginia Mason; 🇺🇸 Seattle, Washington, United States

Vanderbilt Digestive Center; 🇺🇸 Nashville, Tennessee, United States

Huntsman Cancer Institute and University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Gastro One-8110 Walnut Rs; 🇺🇸 Cordova, Tennessee, United States

Del Sol Research Management; 🇺🇸 Tucson, Arizona, United States

Tandem Clinical Research; 🇺🇸 Marrero, Louisiana, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Digestive and Liver Center of Florida; 🇺🇸 Orlando, Florida, United States