RESTAGE (REpurposing STAtins to Improve Outcomes in GastroEsophageal Cancer) Trial (RESTAGE)

RESTAGE (REpurposing STAtins to Improve Outcomes in GastroEsophageal Cancer) Trial: A Phase II Randomized Open-Label Trial of Perioperative Simvastatin Plus Standard-of-Care Systemic Therapy in Gastroesophageal Adenocarcinoma

Esophageal and gastroesophageal junction cancers are serious diseases with limited cure rates, even when patients receive chemotherapy and surgery. New ways to improve treatment are urgently needed.

This study will test whether adding a commonly used cholesterol-lowering medication, simvastatin, to standard cancer treatment can improve outcomes. Simvastatin is widely used, safe, and inexpensive. Research suggests that it may also slow cancer growth by blocking pathways that cancer cells rely on for survival.

In this trial, patients will receive standard chemotherapy (with or without immunotherapy) before surgery. Half of the patients will also take simvastatin daily for up to two years. Researchers will compare how well tumors respond to treatment and whether patients remain cancer-free longer.

If successful, this approach could offer a simple and accessible way to improve survival for patients with these cancers without adding significant side effects or cost.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastroesophageal Adenocarcinoma
• Intervention / Treatment: Drug: SOC neoadjuvant FLOT (or FLOT-D); Drug: SOC neoadjuvant FLOT (or FLOT-D) + simvastatin

• Study Type: Interventional
• Enrollment (Estimated): 184
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lorenzo Edwin Ferri, MD, PhD; Phone Number: 42835 514-934-1934; Email: lorenzo.ferri@mcgill.ca

Study Locations

• Canada
  • Montreal, Canada
    • McGill University Health Center
    • Contact: Lorenzo Edwin Ferri, MD, PhD; Phone Number: 42835 514-934-1934; Email: lorenzo.ferri@mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed, informed consent.
2. Age, 18 years or older.
3. Histological diagnosis of adenocarcinoma or poorly differentiated carcinoma of the esophagus or EGJ.
4. The tumour must be deemed potentially resectable by the surgical team. This assessment is based on complete staging imaging studies (detailed below) - clinical staging of the tumor and ruling out metastatic disease.
5. Locally advanced disease as defined per AJCC/UICC 8th edition37: stage IIA, IIB, III, IVA (T1-4a N2-3).
6. Eligibility for standard-of-care perioperative systemic therapy with FLOT+/-D.
7. Life expectancy greater than 3 months.
8. ECOG performance status < 2.

Exclusion Criteria:

1. Prior esophageal or gastric malignancy.
2. History of allergic reactions to simvastatin or atorvastatin or similar chemical or biological compounds.
3. Ongoing cholesterol-lowering therapy (statins, fibrates, ezetimibe, PCSK9 inhibitors), in which case the patient is offered enrollment in the observational arm.
4. Hepatic dysfunction (alanine aminotransferase level more than three times the upper limit of the normal range) or renal dysfunction (creatinine level more than three times the upper limit of the normal range).
5. Predisposing factors for rhabdomyolysis: hypothyroidism, reduced renal function, muscle disease, or excessive alcohol consumption AND creatine kinase up to less than five times the upper limit (measured in the presence of predisposing factors).
6. Concurrent medication with potent CYP3A4-inhibitors, e.g. ketokonazole, erythromycin, gemfibrozil, cyclosporine, or danazol.
7. Pre-existing medical conditions precluding treatment, including any contraindication systemic chemotherapy or major surgery.
8. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, discussed before registration in the trial.
9. Pregnant and breastfeeding women.
10. Unwillingness to undergo per-protocol investigations or treatments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; SOC neoadjuvant FLOT (or FLOT-D)	Drug: SOC neoadjuvant FLOT (or FLOT-D); Standard of care neoadjuvant FLOT (or FLOT-D).
Experimental: Experimental; SOC neoadjuvant FLOT (or FLOT-D) + simvastatin	Drug: SOC neoadjuvant FLOT (or FLOT-D) + simvastatin; Standard of care neoadjuvant FLOT (or FLOT-D) + simvastatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MPR	Major Pathological Response	From enrolment to surgical pathology assessment, 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Statin-enhanced toxicity of standard-of-care regimen, specifically grade 3 or 4 adverse events	Statin-enhanced toxicity of standard-of-care regimen, specifically grade 3 or 4 adverse events (as per CTCAE v6.0 36) warranting dosage modification or stoppage of interventional drug or chemotherapy.	Start of neoadjuvant therapy to the end of adjuvant therapy (weeks 2-28)
2-year EFS	2-year EFS, defined as elapsed time from date of randomization to date of recurrence (local or distant) or death, occurring after resection	Elapsed time from date of randomization to date of recurrence or death, within 2 years from resection

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2031

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: May 29, 2026
• First Posted (Actual): June 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Statin; Gastroesophageal junction cancer; Esophageal cancer; Gastroesophageal Adenocarcinoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Lovastatin; Simvastatin
• Other Study ID Numbers: THOR-ESO-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No