HRX215, A First Generation MKK4 Inhibitor Drug, for the Treatment of Patients With Colorectal Liver Metastasis After Undergoing a Portal Vein Embolization

Phase 2B Study to Determine Efficacy of HRX215, a First Generation MKK4 Inhibitor Drug, in Improving Regeneration of the Remnant Liver After Portal Vein Embolization (PVE) of Colorectal Liver Metastasis (CRLM)

This phase IIb trial tests the effect of HRX215 in treating patients with colorectal cancer that has spread from where it first started to the liver (liver metastasis) after undergoing a portal vein embolization (PVE). Currently, surgery to remove the tumor (hepatectomy) remains the only potential treatment for cure. However, less than 30% of patients are considered resectable (can be removed by surgery) at the time of diagnosis. The risk of liver failure and other complications rise with larger areas liver that is removed during surgery. Therefore, the potential for surgery is determined by the amount of liver that will remain after resection. PVE is a standard strategy to increase the potential for resection. A PVE is a procedure that blocks the portal vein (a blood vessel that carries blood to the liver) to prevent flow of blood to the tumor. HRX215 targets and binds to MKK4, a protein found on liver cells plays a part in cellular growth and prevents liver repair and regrowth of cells and tissue. Blocking the activity of MKK4 may help prevent liver failure, protect liver cells and improve liver mass. Giving HRX215 after a PVE may help improve the rate of liver regrowth and increase the likelihood of hepatectomy in patients with colorectal liver metastasis.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Malignant Neoplasm in the Liver; Metastatic Colorectal Carcinoma; Stage IV Colorectal Cancer AJCC v8; Resectable Colorectal Carcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Drug: Placebo Administration; Procedure: Biopsy Procedure; Procedure: Computed Tomography; Drug: Darizmetinib; Drug: Embolization Therapy; Procedure: Hepatectomy; Procedure: Positron Emission Tomography

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
• Study Contact Backup: Name: Cancer Center Clinical Trials Referral Office; Phone Number: 507-293-6386

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Contact: Cancer Center Clinical Trials Referral Office; Phone Number: 507-293-6386
      • Principal Investigator: Scott L. Nyberg, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• REGISTRATION: Adults 18-90 years
• REGISTRATION: Individuals with metachronous colorectal carcinoma liver metastases (CRCLM) after resection of the primary OR synchronous CRCLM with planned simultaneous resection of primary and metastatic disease
• REGISTRATION: Measurable intrahepatic disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) and considered resectable by multidisciplinary tumor board with at least one senior hepatic surgeon
• REGISTRATION: Available CT suitable for volumetric studies on FLR ≤ 21 days
• REGISTRATION: Clinical indication for PVE prior to major hepatectomy as evaluated by at least one senior hepatic surgeon
• REGISTRATION: Estimated life expectancy ≥ 3 months as evaluated and approximated by a senior hepatic surgeon
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• REGISTRATION: Platelets ≥ 100,000/mm^3 (≤ 15 days prior to registration)
• REGISTRATION: Polynuclear neutrophils ≥ 1000/mm^3 (≤ 15 days prior to registration)
• REGISTRATION: Hemoglobin ≥ 9 g/dL (≤ 15 days prior to registration) (post-transfusion participants can be included)
• REGISTRATION: Creatinine ≤ 1.5 x upper limit of normal (ULN) (≤ 15 days prior to registration)
• REGISTRATION: Bilirubin ≤ ULN (≤ 15 days prior to registration)
• REGISTRATION: Albumin ≥ 3 g/dL (≤ 15 days prior to registration)
• REGISTRATION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (≤ 15 days prior to registration)
• REGISTRATION: International normalized ratio ≤ 1.5 (≤ 15 days prior to registration)
• REGISTRATION: Of note, a slight deviation from normal ranges of liver function tests, circulating cell counts, and kidney function can be assumed after systemic neoadjuvant chemotherapy prior to PVE (Field et al., 2008; Takamoto et al., 2010; Lock et al., 2017), which is accounted for in the above list. These parameters at inclusion will then serve as patient baseline
• REGISTRATION: Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. Serum or urine human chorionic gonadotropin test is suitable. Can be done with a home test and results reported by participant to the site
• REGISTRATION: Provide written informed consent
• REGISTRATION: Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• RANDOMIZATION: Adults 18-90 years
• RANDOMIZATION: Individuals with metachronous CRCLM after resection of the primary OR synchronous CRCLM with planned simultaneous resection of primary and metastatic disease
• RANDOMIZATION: Estimated life expectancy ≥ 3 months as evaluated and approximated by a senior hepatic surgeon
• RANDOMIZATION: Measurable intrahepatic disease as defined by RECIST and considered resectable by multidisciplinary tumor board with at least one senior hepatic surgeon
• RANDOMIZATION: Available CT suitable for volumetric studies on FLR ≤ 21 days
• RANDOMIZATION: Scheduled for PVE prior to major hepatectomy

Exclusion Criteria:

• REGISTRATION: Cirrhosis or clinical ascites
• REGISTRATION: Patients with synchronous CRCLM and scheduled staged approach (i.e., resection of metastatic hepatic disease after PVE followed by resection of the colorectal primary in a second operation)
• REGISTRATION: Any liver cancer other than CRLM

• REGISTRATION: Contraindications to imaging or perioperative management:

  • Allergy/contraindication to iodine contrast
  • Anticoagulation with heparin/antivitamin K (AVK) that cannot be interrupted for 48 hours
  • Antiplatelet therapy (e.g., clopidogrel) that cannot be interrupted for 5 days
• REGISTRATION: Inability to discontinue cytochrome P450 (CYP)2D6 inhibitor concomitant medication from start of trial treatment to day 28
• REGISTRATION: Inoperability due to underlying chronic diseases and co-morbidities as assessed by the hepatobiliary surgeon during screening visit
• REGISTRATION: Anticipated need to start adjuvant chemotherapy prior to completion of 28 day treatment period
• REGISTRATION: Positive test at screening for active hepatitis B virus (HBV)/hepatitis C virus (HCV), defined as history of seropositivity for hepatitis B virus (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy), i.e., positive test for anti-hepatitis B core antigen and negative test for anti-hepatitis B surface antibody. Ongoing, non-cured hepatitis C virus (HCV) infection. Likewise, autoimmune hepatitis will be excluded based on serological [antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and biochemical parameters AST and ALT], patients with serological and/or biochemical findings suggestive of probable autoimmune hepatitis will be excluded
• REGISTRATION: Legal incapacity (persons in custody or under guardianship)
• REGISTRATION: Deprived of liberty subject (by judicial or administrative decision)
• REGISTRATION: Impossibility to sign the informed consent document or to adhere to the medical follow-up of the trial for geographical, social, or psychological reasons

• REGISTRATION: Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential who are unwilling to employ adequate contraception. Participants of childbearing potential must use highly effective contraception (hormonal methods, intrauterine device (IUD)/intrauterine system (IUS), bilateral tubal occlusion, or vasectomized partner) during treatment and for a defined post-treatment period of 30 days. True abstinence is acceptable if consistent with lifestyle. Barrier methods alone are insufficient unless combined. Male participants with partners of childbearing potential must use condoms and avoid sperm donation during and after treatment

• REGISTRATION: Any of the following prior therapies:

  • Major surgical procedures ≤ 3 weeks prior to registration
  • Bevacizumab as part of systemic cancer treatment ≤ 2 weeks prior to registration

• REGISTRATION: Failure to recover from any adverse events related to any of the following therapies received prior to registration:

  • Chemotherapy
  • Immunotherapy
  • Targeted therapies
  • Other investigational agents
  • Radiation therapy
  • Major surgical procedures
• REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • Psychiatric illness/social situations that would limit compliance with study requirements

• REGISTRATION: Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy

  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
• REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm in the neoadjuvant setting or during active treatment phase of this study (adjuvant treatment after active treatment phase is completed does not apply)
• REGISTRATION: Another active malignancy requiring therapy such as radiation, chemotherapy, or immunotherapy at time of study inclusion or within the past five years with the exception of basal cell carcinoma or carcinoma in situ of the cervix. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria
• REGISTRATION: History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (HRX215, PVE, hepatectomy); Patients undergo scheduled PVE on day 0. Starting 2 hours before undergoing PVE, patients receive HRX215 PO BID (orally twice daily) on days 0-27 in the absence of disease progression or unacceptable toxicity. Starting on or after day 32, patients may undergo scheduled hepatectomy. Patients also undergo blood sample collection, CT, MRI, and CT-PET throughout the study. Additionally, patients may undergo tissue biopsy during scheduled hepatectomy on study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Biopsy Procedure; Undergo tissue biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Procedure: Computed Tomography; Undergo CT and CT-PET; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Darizmetinib; Given PO; Other Names: HRX 215; HRX-215; HRX215; LN 3348; LN-3348; LN3348; Drug: Embolization Therapy; Undergo PVE; Other Names: Embolization; therapy, embolization; Procedure: Hepatectomy; Undergo hepatectomy; Other Names: Liver Resection; Procedure: Positron Emission Tomography; Undergo CT-PET; Other Names: Medical Imaging, Positron Emission Tomography; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); PET (positron emission tomography)
Placebo Comparator: Arm II (placebo, PVE, hepatectomy); Patients undergo scheduled PVE on day 0. Starting 2 hours before undergoing PVE, patients receive placebo PO BID (orally twice daily) on days 0-27 in the absence of disease progression or unacceptable toxicity. Starting on or after day 32, patients may undergo scheduled hepatectomy. Patients also undergo blood sample collection, CT, MRI, and CT-PET throughout the study. Additionally, patients may undergo tissue biopsy during scheduled hepatectomy on study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Placebo Administration; Given PO; Procedure: Biopsy Procedure; Undergo tissue biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Procedure: Computed Tomography; Undergo CT and CT-PET; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Embolization Therapy; Undergo PVE; Other Names: Embolization; therapy, embolization; Procedure: Hepatectomy; Undergo hepatectomy; Other Names: Liver Resection; Procedure: Positron Emission Tomography; Undergo CT-PET; Other Names: Medical Imaging, Positron Emission Tomography; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); PET (positron emission tomography)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Future liver remnant size (FLR)	Will be defined as the percentage of the liver expected to remain after a planned hepatectomy. Will be compared between the two treatment groups [HRX215 versus (vs) placebo] utilizing an analysis of covariance (ANCOVA) F-test controlling for age, gender, and FLR at baseline.	At day 28 post-baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FLR size	Will be defined as the percentage of the liver expected to remain after a planned hepatectomy. Will be compared between the two treatment groups (HRX215 vs placebo) utilizing an ANCOVA F-Test controlling for age, gender, and FLR at baseline.	At day 7 post-baseline
Incidence of adverse events (AEs)	AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Each type of AE and grade will be recorded for each patient. The distribution of serious AEs as well as AEs of special interest will be compared between treatment arms descriptively to look for trends.	Up to 28 days after last dose of study treatment
Resectability after PVE	The proportion of patients will be compared between treatment arms utilizing a Chi-Square test.	At or after 28 days post-baseline
Post-hepatectomy liver failure (PHLF)	Will be defined according to the criteria issued by the International Study Group for Liver Surgery (ISGLS). Grading of PHLF into grades A to C will be performed, and grades B-C will be defined as severe PHLF. The proportion of patients will be compared between treatment arms utilizing a Chi-Square test.	Between postoperative days 5 and 7
Post-operative mortality	Defined as patient death within the first 90 days after liver resection. The proportion of patients will be compared between treatment arms utilizing a Chi-Square test.	Up to the first 90 days after liver resection
Recurrence-free survival (RFS)	Defined as the time from major liver resection to disease recurrence. Will be analyzed using the Kaplan-Meier Method. The distribution of RFS will be compared between treatment arms utilizing a two-sided log-rank test.	From major liver resection to disease recurrence, assessed up to 360 days
Overall survival (OS)	Defined as the time from randomization to death from any cause. Will be analyzed using the Kaplan-Meier Method. The distribution of OS will be compared between treatment arms utilizing a two-sided log-rank test.	From randomization to death from any cause, assessed up to 360 days
Post-operative morbidity	Will be defined according to the system issued in "Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey," a standardized, therapy-oriented system for grading postoperative surgical complications according to the treatment required to manage them rather than subjective severity. Complications range from Grade I, defined as any deviation from the normal postoperative course not requiring specific therapy, to Grade V, defined as death. Intermediate grades reflect increasing therapeutic intensity, from pharmacological treatment (Grade II), to interventions with or without general anesthesia (Grade III), and life-threatening complications requiring intensive care (Grade IV).. The proportion of patients will be compared between treatment arms utilizing a Chi-square test.	Up to 360 days post-PVE

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Scott L. Nyberg, MD, PhD, Mayo Clinic in Rochester

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: May 21, 2026
• First Submitted That Met QC Criteria: May 21, 2026
• First Posted (Actual): May 28, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Chemistry Techniques, Analytical; Spectrum Analysis; Hemostatic Techniques; Therapeutic Occlusion; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; Hepatectomy; Embolization, Therapeutic
• Other Study ID Numbers: MC250412; 25-010359 (Other Identifier: Mayo Clinic Institutional Review Board); R01DK140085 (U.S. NIH Grant/Contract)

Drug and device information, study documents

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