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

Official title

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)

Overview

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.

Interventions

• Procedure Biopsy Procedure
  Undergo tissue biopsy
• Procedure Biospecimen Collection
  Undergo blood sample collection
• Procedure Computed Tomography
  Undergo CT and CT-PET
• Drug Darizmetinib
  Given PO
• Drug Embolization Therapy
  Undergo PVE
• Procedure Hepatectomy
  Undergo hepatectomy
• Procedure Magnetic Resonance Imaging
  Undergo MRI
• Drug Placebo Administration
  Given PO
• Procedure Positron Emission Tomography
  Undergo CT-PET

Primary outcome measures

• Future liver remnant size (FLR) [Time frame: At day 28 post-baseline]

Secondary outcome measures (8)

• FLR size [Time frame: At day 7 post-baseline]
• Incidence of adverse events (AEs) [Time frame: Up to 28 days after last dose of study treatment]
• Resectability after PVE [Time frame: At or after 28 days post-baseline]
• Post-hepatectomy liver failure (PHLF) [Time frame: Between postoperative days 5 and 7]
• Post-operative morbidity [Time frame: Up to 360 days post-PVE]
• Post-operative mortality [Time frame: Up to the first 90 days after liver resection]
• Recurrence-free survival (RFS) [Time frame: From major liver resection to disease recurrence, assessed up to 360 days]
• Overall survival (OS) [Time frame: From randomization to death from any cause, assessed up to 360 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Mayo Clinic in Rochester — Rochester

Identifiers

NCT: NCT07612007 · MC250412 · 25-010359 · R01DK140085

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗