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

Phase 1Not Yet RecruitingNCT07842965

City of Hope Medical Center36 enrolled

Overview

This phase I/Ib trial tests the effect of leronlimab in combination with hepatic arterial infusion (HAI) floxuridine (FUDR)and standard of care (SOC) systemic therapy in treating patients with colorectal cancer that has spread from where it first started to the liver (metastatic). Leronlimab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets, such as CCR5 which is expressed on T cells (a type of immune cell), which may cause the body to make an immune response (antigens) and may also improve the effectiveness of treatment. HAI delivers chemotherapy, such as floxuridine, directly to the liver. Catheters are put into an artery in the groin that leads directly to the liver and drugs are given through the catheters. Floxuridine is in a class of medications called antimetabolites. It works by slowing or stopping the growth of tumor cells in your body. HAI can deliver floxuridine at up to 300 times the concentrations that can be given through the vein. Systemic therapy is treatment using substances that travel through the bloodstream, reaching and affecting cells all over the body. Giving leronlimab in combination with HAI floxuridine and SOC systemic therapy may be safe, tolerable, and/or safe in treating colorectal cancer patients with liver metastases.

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.

Interventions

Biopsy ProcedurePROCEDURE

Undergo biopsy

Biospecimen CollectionPROCEDURE

Undergo blood sample collection

Computed TomographyPROCEDURE

Undergo CT

FloxuridineDRUG

Given via HAI pump

Intrahepatic Infusion ProcedurePROCEDURE

Given floxuridine via HAI pump

LeronlimabBIOLOGICAL

Given SC

Magnetic Resonance ImagingPROCEDURE

Undergo MRI

Surgical ProcedurePROCEDURE

Undergo surgical resection with HAI pump placement

Systemic TherapyPROCEDURE

Given SOC systemic therapy

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Proportion of patients completing all four planned hepatic arterial infusion (HAI) cycles with a relative dose intensity ≥ 80% for HIA floxuridine (FUDR)

Will be calculated using the number of patients who complete all four planned HAI cycles with a relative dose intensity ≥ 80% for HAI FUDR divided by the total number of enrolled patients.

Time frame: Up to 4 cycles (cycle length = 28 days)

Secondary Outcomes

Incidence, type, and severity of adverse events (AEs) attributed to HAI

Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Events will be summarized by frequency, system organ class, preferred term, worst grade, and attribution category. Descriptive statistics will be used to summarize the safety profile.

Time frame: From first dose HAI through 30 days after the last dose of HAI

Incidence of serious AEs attributed to HAI

Will be graded according to CTCAE v 5. Events will be summarized by frequency, system organ class, preferred term, worst grade, and attribution category. Descriptive statistics will be used to summarize the safety profile.

Time frame: From first dose HAI through 30 days after the last dose of HAI

Incidence of AEs attributed to HAI leading to treatment interruption or discontinuation

Time frame: From first dose HAI through 30 days after the last dose of HAI

Incidence, type, and severity of AEs attributed to leronlimab

Time frame: From first dose leronlimab through 30 days after last dose of leronlimab

Incidence of serious AEs attributed to leronlimab

Time frame: From first dose leronlimab through 30 days after last dose of leronlimab

Incidence of AEs leading attributed to leronlimab to treatment interruption or discontinuation

Time frame: From first dose leronlimab through 30 days after last dose of leronlimab

Incidence, type, and severity of AEs attributed to systemic therapy

Time frame: From first dose systemic therapy through 30 days after last dose of systemic therapy

Incidence of serious AEs attributed to systemic therapy

Time frame: From first dose systemic therapy through 30 days after last dose of systemic therapy

Incidence of AEs attributed to systemic therapy leading to treatment interruption or discontuation

Time frame: From first dose systemic therapy through 30 days after last dose of systemic therapy

Incidence and extent of liver toxicity attributed to HAI/FUDR requiring dose reductions based on standard of care nomogram

Data will be summarized by incidence, indication, dose delays, dose interruptions, additional intraarterial corticosteroid doses administered, duration of additional intraarterial corticosteroid therapy, and association with treatment hold, dose reduction, or permanent discontinuation of HAI/FUDR. Descriptive statistics will be used to summarize the safety profile.

Time frame: From the first HAI infusion through 30 days after the final dose of HAI therapy

Incidence and characteristics of dose reductions and treatment interruption of HAI/FUDR therapy

Dose reductions will be summarized by incidence, number of dose reductions per patient, time to first dose reduction, primary reason for dose reduction, and lowest dose level reached and whether treatment was subsequently discontinued. Descriptive statistics will be used to summarize the safety profile.

Time frame: From first administration of HAI therapy and up through 30 days after the final administration of HAI therapy

Radiographic progression free survival (PFS)

Will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Will be summarized as the proportion of patients who meet definition. Will be graphically represented using Kaplan-Meier methods.

Time frame: From enrollment to first objective occurrence of tumor progression or death due to any cause, whichever occurs first, assessed up to 1 year

Radiographic PFS

Will be assessed using RECIST v 1.1. Will be summarized as the proportion of patients who meet the definition. Will be graphically represented using Kaplan-Meier methods.

Time frame: From enrollment to first objective occurrence of tumor progression or death due to any cause, whichever occurs first, assessed up to 2 years

Median PFS

Will be graphically represented using Kaplan-Meier methods.

Time frame: Up to 24 months

Median liver-PFS

Will be graphically represented using Kaplan-Meier methods.

Time frame: Up to 24 months

Liver-PFS

Will be graphically represented using Kaplan-Meier methods.

Time frame: From enrollment to the first occurrence of radiographic progression within the liver or death due to any cause, assessed up to 1 year

Liver-PFS

Will be graphically represented using Kaplan-Meier methods.

Time frame: From enrollment to the first occurrence of radiographic progression within the liver or death due to any cause, assessed up to 2 years

Change in circulating tumor deoxyribonucleic acid (ctDNA)

Change in ctDNA will be quantified as the difference between the baseline value and each subsequent measurement. Proportion achieving clearance defined as 100% reduction in the ctDNA will also be reported. Will be quantitatively assessed to determine their correlation with clinical outcomes/findings.

Time frame: At baseline (weeks 0, 2, 4, and 6) and post operatively (weeks 2, 4, 6, 8, 10, 12, 14 and 16)

ctDNA clearance

Will be quantitatively assessed to determine their correlation with clinical outcomes/findings

Time frame: Up to 24 months

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

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes