CCR5-blockade in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The surface molecule CCR5 is found on tumor cells within liver metastases of colorectal cancer. Inhibition of this molecule leads to a reduction in growth signals for tumor cells and subsequent slowed or halted tumor growth. The agent for the inhibition of CCR5 has already received FDA approval for treatment of HIV and has shown little side effects and toxicities even on long term treatment. Therefore CCR5-inhibition has the potential of providing non-toxic tumor growth inhibition.

Official Title
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Treatment of Advanced Colorectal Cancer Patients With Hepatic Liver Metastases Using the CCR5-Antagonist Maraviroc (Phase I Maracon Trial)

Conditions
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Colorectal Cancer, Neoplasm Metastasis, Liver Metastases

Intervention / Treatment
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* Drug: Maraviroc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: written informed consent (must be available before enrollment in the trial) age ≥ 18 years male or female patient with a history of treated metastatic stage IV colorectal cancer with liver metastases of the primary colorectal cancer histologically confirmed liver metastasis of colorectal cancer with histologically confirmed CCR5 (C-C chemokine receptor type 5) expression in the tumor cells expected survival of at least three months Karnofsky performance status > 70 % patients that have received current standard treatment options (progression or intolerance to oxaliplatin, irinotecan and 5-Fluorouracil with or without treatment combinations of cetuximab and/or bevacizumab or panitumumab) no chemotherapy treatment within the last three weeks within the last 2 weeks prior to study day 1 the following laboratory parameters, which should be within the ranges specified (or as deemed acceptable by trial investigator): absolute neutrophil count (ANC) ≥ 1000/mm3 (≥ 1.0 x 109/L), platelets ≥ 80.000/mm3 (≥ 80 x 109/L), creatinine Clearance limit as assessed by glomerular filtration rate > 60 mL/min/1.73m², ALT (alanine transaminase), AST (aspartate transaminase), and total bilirubin all ≤ 5.0 x ULN (upper limit normal) able and willing to give valid written informed consent and to understand character and individual consequences of the clinical trial if the patient is female, she must be of non-childbearing potential, or practice adequate contraception. Exclusion Criteria: Patients with severe kidney disorders (GFR of <30 mL/min/1.73m² and diagnosed kidney disease) or who are on hemodialysis. The patient requires concomitant chronic treatment with systemic corticosteroids or any other immunosuppressive agents. Topical or inhalational steroids are permitted. Patients taking immunomodulatory medication (Type 1 interferons). Use of any investigational or non-registered product (drug or vaccine) other than the study treatment Patients with single metastatic lesions (intent to resect the metastasis) Patients with metastatic colorectal cancer that have a drastic clinical progression (e.g. from Karnofsky performance 100% to 60%) within the last six weeks before screening cannot participate The patient has a history of autoimmune disease. The patient has a family history of congenital or hereditary immunodeficiency. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV).or has another confirmed or suspected immunosuppressive or immunodeficient condition. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures. The patient has concurrent chronic severe medical problems (heart failure, uncontrolled diabetes, bleeding disorder etc.), unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. The patient has previous or concomitant malignancies at other sites, except effectively treated carcinoma in situ of the cervix or effectively treated malignancy that has been in remission for over 5 years and is highly likely to have been cured. For female patients: the patient is pregnant or lactating. Women of childbearing potential: Refusal or inability to use effective means of contraception History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product Participation in other clinical trials or observation period of competing trials, respectively No subject will be allowed to enroll in this trial more than once.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CCR5-inhibitor at 300 mg/bid<br>colorectal cancer patients with liver metastases (twelve patients treated with 300 mg/bid) | Drug: Maraviroc<br>* Twelve patients with 300 mg/bid<br>* Other names: Celsentri;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety as occurence of adverse events ≥ Grade 3 according to CTCAE, Version 4.0 criteria, that are definitely, probably, or possible related to the administration of the investigational agent | safety, tolerability and feasibility will be assessed after eight weeks of continuous intake of the CCR5-inhibitor. Safety measures include blood analyses (hematologic, liver function, renal function etc.) and the overall performance status of the patient. Especially infections and infection-related events are investigated. | after eight weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Patients will be evaluated for one year afterwards to assess progression free survival. | one year after eight weeks of treatment | 
| Tumor response according to the Response Evaluation Criteria in Solid Tumors (RECIST) | Tumor response will be evaluated after eight weeks of continuous treatment with the CCR5-inhibitor, using the RECIST criteria on MRI images (comparing pre- and post-treatment) | after eight weeks of treatment | 
| Tissue level responses of growth inhibition via the CCR5 axis | The evaluation of tissue alterations within the tumor microenvironment induced by CCR5-inhibition will be performed during the first four weeks of treatment, comparing the pre-treatment tissue situation with the post-treatment situation. | during the first four weeks of treatment | 
| Overall survival | Patients will be evaluated for one year afterwards to assess overall survival. | one year after eight weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, liver metastases, chemotherapy, chemokine, CCR5 inhibition