Safety and Efficacy of Oral HRX215 in Patients Undergoing Hepatectomy for Colorectal Carcinoma Liver Metastases: A Randomized, Placebo-Controlled Study

Trial ID: 2025-523630-59-00
Protocol: HRX215-CR03-LR01
Sponsor: HepaRegeniX GmbH

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Diseases & Conditions

Colon cancer

Objectives

The primary objective is to evaluate the safety and tolerability of oral HRX215 in patients following minor or major hepatectomy due to colorectal cancer metastases. Additionally, the study aims to characterize the pharmacokinetics of the investigational product by assessing its absorption, metabolism, and excretion in comparison to healthy individuals. The secondary objective is to evaluate the potential for liver regeneration following surgical intervention.

Participants

The study includes 39 participants diagnosed with colorectal liver metastases. The population consists of both male and female patients aged 18 to 75 years. Eligible individuals must have a general health status corresponding to World Health Organization score 0 or 1 or an Eastern Cooperative Oncology Group status of 0 or 1, with an estimated life expectancy exceeding 6 months. Participants undergo minor or major liver surgery, specifically an R0-resection intended hepatectomy. Inclusion is contingent upon specific remnant liver volume or estimated future liver remnant requirements determined by preoperative imaging. Additionally, subjects must demonstrate stable preoperative biological parameters, including specific levels of platelets, neutrophils, hemoglobin, creatinine, bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase, and international normalized ratio. The study objectives are:

To assess the safety and tolerability of oral HRX215.
To evaluate the pharmacokinetics of HRX215 regarding its absorption, metabolism, and excretion.

Plans and Procedures

This Phase 1/2 clinical trial is a double-blind, randomized, placebo-controlled study designed to evaluate the safety, tolerability, and efficacy of darizmetinib hydrochloride (HRX215) in participants following hepatectomy for colorectal liver metastases. The research methodology includes two open pilot parts involving participants after minor and major liver resection, followed by a main study component. The primary objectives are to assess the incidence and severity of adverse events, monitor changes in vital signs and clinical laboratory parameters, and evaluate the pharmacokinetics of the investigational product. Secondary endpoints involve assessing changes in liver volume. The study procedures involve a screening phase to ensure eligibility based on remnant liver volume, preoperative biological parameters, and general health status, followed by the administration of either HRX215 or a placebo via oral capsules. Participants are monitored through scheduled visits to track safety and efficacy, including assessments of postoperative liver failure risk and histopathology of non-tumor liver tissue. The total duration of the trial, including recruitment, is estimated to span from June 2026 to September 2027.

Treatment

The investigational product is HRX215, which contains the active substance darizmetinib hydrochloride. This medication is administered in capsule form via the oral route.

The control group receives a placebo consisting of white opaque, size 1 capsules.

Efficacy

Efficacy assessment in this study focuses on the evaluation of liver volume. The primary efficacy parameter is the absolute change in liver volume from postoperative day 1 (POD1) to postoperative day 7 (POD7), as determined by computed tomography (CT) imaging.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants aged 18 to 75 years (inclusive)
Participants with liver metastases originating from a colon carcinoma planned for R0-intended hepatectomy for colorectal liver metastases. a. For pilot part 1 only: stable within 1-3 days after minor liver resection, otherwise normal nontumor liver parenchyma proven by histopathology assessment of a liver biopsy within 3 months before surgery
Participants with remnant liver volume (RLV) or estimated future liver remnant (FLR) after resection: a. For participants in pilot Part 1, after minor liver resection (RLV > 69%) by preoperative magnetic resonance imaging (MRI).b. For participants in pilot Part 2 and main study Part 3: participants with an estimated FLR of 30% - 50% (inclusive) prior to resection, calculated from preoperative CT or MRI after subtraction of tumor volume.
Preoperative assessment indicating that the participant is at low risk for PHLF (estimated <3–5%) based on surgeon’s standard practice and consistent with E-AHPBA-ESSO-ESSR Innsbruck Consensus guidelines for preoperative liver function assessment before hepatectomy
General health status World Health Organization (WHO) 0 or 1 or ECOG status 0 or 1
Estimated life expectancy > 6 months
Patients whose preoperative biological parameters are: a. Platelets ≥ 100,000/mm3, b. Polynuclear neutrophils ≥ 1000/mm3 c. Hemoglobin ≥ 9 g/dL (Posttransfusion patients can be included) d. Creatinine < 1.5 × upper limit of normal (ULN) e. Bilirubin ≤ ULN f. Albumin > LLN g. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ ULN h. INR ≤ 1.5
Must agree to use highly effective contraception specified in the Appendix A of the protocol from the time of informed consent until at least 36 days (5 half-lives + 30 days) after the last dose of study drug.
Participants must have adequate non-tumor liver tissue available for baseline histology for safety assessment purposes, either from planned resection or archival tissue collection within 3 months
Written signed informed consent

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Exclusion Criteria

Liver cirrhosis
Preoperative presence of clinical ascites
Any other hepatobiliary cancer
Body mass index > 35 kg/m2
American Society of Anesthesiologists (ASA) Score ≥ 4
Peritoneal disease or findings indicating unresectability •Part 1: A Completeness of Cytoreduction (CC) Score greater than 0 identified: preoperatively or intraoperatively. Any preoperative or intraoperative findings indicating that curative resection is not achievable •Part 2 and main study part 3; Any preoperative radiologic finding consistent with peritoneal carcinomatosis. Any preoperative finding indicating that curative resection is not achievable
Ongoing participation or participation within the 28 days prior to inclusion in the study in another therapeutic trial with an experimental drug and during 6 month follow-up period post-hepatectomy.
Serious non-stabilized disease, active uncontrolled infection, or other serious underlying disorder likely to prevent the patient from receiving the treatment
Pregnancy (βHCG positive), breastfeeding
Contraindication to iodine contrast agents
Current treatment with anticoagulants (including DOACs, heparin,antivitamin K) that cannot be safety interrupted for at least 48 hrs before study treatment (Part 2 and 3).
Chemotherapy within the last 30 days preoperatively
More than 12 cycles or more than 6 months of preoperative chemotherapy
Anticipated need to start adjuvant chemotherapy prior to completion of 28 day treatment period including chemotherapy via intrahepatic arterial pump
Positive test at screening for active hepatitis B virus (HBV)/hepatitis C virus (HCV) or autoimmune hepatitis
Incomplete liver metastasis resection (recognized at time of surgery) (part 1).
Portal vein and/or hepatic vein embolization procedure (pilot part 2 and main study part) or surgical hepatic augmentation procedure e.g. ALPPS
Presence of high-grade dysplastic lesions which cannot be completely resected at the time of liver resection or a history of malignancy within the past five years prior to screening, except for subjects with completely resected basal cell carcinoma of the skin or carcinoma in situ of the cervix
Legal incapacity (persons in custody or under guardianship)
Deprived of liberty Subject (by judicial or administrative decision)
Impossibility to sign the informed consent document or to adhere to the medical follow-up of the trial for geographical, social or psychological reasons
Contraindications against MRI or CT exams (according to local medical practice)
Inability to discontinue a concomitant medication which is primarily cleared by CYP2D6 from initiation of study treatment through day 28.