CCR5 Targeting Leronlimab in Combination With Hepatic Arterial Infusion Floxuridine and Systemic Therapy for the Treatment of Colorectal Cancer Liver Metastases, CHAMP Trial

PRIMARY OBJECTIVE:

I. To evaluate the feasibility of administering four planned cycles of combined standard-of-care systemic therapy, hepatic arterial infusion (HAI) floxuridine (FUDR), and leronlimab as reflected by relative dose intensity in the study population.

SECONDARY OBJECTIVES:

I. To characterize the safety profile of the combined regimen. II. To evaluate the anti-tumor activity of leronlimab administered subcutaneously alongside HAI pump and systemic therapy in patients with colorectal cancer with liver metastases, as assessed by 1 year and 2 year progression-free survival (PFS) and median progression free-survival.

III. To evaluate liver-specific disease control with leronlimab plus HAI pump and systemic therapy.

IV. To evaluate the anti-tumor activity of Leronlimab administered subcutaneously alongside HAI pump and systemic therapy in patients with colorectal cancer with liver metastases, as assessed by changes in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and ctDNA clearance.

EXPLORATORY OBJECTIVES:

I. To characterize baseline and on-treatment tissue and circulatory biomarkers of immune evasion and metastatic potential, including PD-L1 expression, immune genomic and phenotypic biomarkers, and circulating tumor cells.

II. To assess liver damage and healing associated with leronlimab plus HAI pump and systemic therapy.

III. To evaluate standard-of-care imaging findings and liver parenchyma for evidence of liver damage and disease progression.

OUTLINE:

Patients receive leronlimab subcutaneously (SC) weekly with SOC systemic therapy for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection with HAI pump placement. Starting 4 weeks after surgery, patients receive floxuridine continuously via HAI pump every 14 days of each cycle and resume leronlimab SC weekly in combination with SOC systemic therapy of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study. Additionally, patients may optionally undergo biopsy on study.

After completion of study treatment, patients are followed up at 30 days and then for up to 24 months.

Inclusion criteria

• Documented informed consent of the participant and/or legally authorized representative
• Agreement to allow the use of archival tissue from diagnostic tumor and/or surgical biopsies

• If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Age: ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Confirmed metastatic colorectal cancer with liver dominant metastases amenable and a candidate for adjuvant HAI floxuridine (FUDR) pump therapy as determined by the clinical team.

• Note: patients should be candidates for an R0/R1 complete resection of the liver metastases with the goal of ideally achievement of no evidence of disease (NED) or treated disease
• Note: peri/intra-operative interventional ablation therapy, radiation therapy, as well as liver-directed therapy to achieve NED/treated disease is allowed. Patients who are getting a liver pump only and no surgery due to unresectable liver metastases are not eligible for this study
• Hemoglobin ≥ 8 g/dL (within 14 days prior to day 1 of protocol therapy)

• NOTE: Iron replacement and/or red blood cell transfusions are permitted as long as the patient is not actively bleeding
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's syndrome) (within 14 days prior to day 1 of protocol therapy)

• NOTE: If the patient has Gilbert's disease, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be ≤ 3.0 x ULN
• AST ≤ 5.0 x ULN (within 14 days prior to day 1 of protocol therapy)
• ALT ≤ 5.0 x ULN (within 14 days prior to day 1 of protocol therapy)
• Creatinine ≤ 1.5 x institutional ULN (within 14 days prior to day 1 of protocol therapy) OR

• Creatinine clearance ≥ 50 mL/min calculated by the Cockcroft-Gault method
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 14 days prior to day 1 of protocol therapy)

• If the urine test is positive or cannot be confirmed as negative, a qualitative or quantitative serum pregnancy test will be required
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least three months after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion criteria

• Concurrent participation in another interventional study. Participation in observational clinical studies is permitted
• Chemotherapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy

• Note: Radiation therapy and/or other peri/intra-operative other liver directed therapy is allowed; patients need to have sufficiently recovered from it as assessed by the treating physician or site PI
• Patients using herbal medications or supplements. These also need to be stopped 14 days prior to day 1 of protocol therapy. Exceptions are over-the-counter medications or supplements taken for supportive care (e.g., vitamins, ginseng or electrolytes for fatigue) are permitted. Participants will be advised to discuss with the study team prior to initiating any new medication or supplement during the study
• Significant comorbidities or conditions that would impede candidacy for surgery or trial participation
• Known hypersensitivity to leronlimab or components of the formulation
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)