CLOVER - CCR5-targeting Leronlimab With Oral Chemotherapy and VEGF-inhibitor Enriched Regimen

Inclusion Criteria (Main Study): 1. Male or female subjects age ≥ 18 years with a history of treated colorectal cancer with unresectable metastases of the primary colorectal cancer to other organs. 2. If HIV-1 positive, (known or documented), viral load must be \< 50 copies/ml and the participant must be on stable ART for at least 3 months. HIV testing is not required for eligibility determination unless clinically indicated. 3. Adult patients with metastatic colorectal cancer (mCRC) received and progressed, or are intolerant, of at least two prior standard of care treatment regimes, which may have included fluoropyrimidine-, oxaliplatin-, or irinotecan chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. 4. Histologically confirmed for microsatellite stable MSS colorectal cancer by PCR, Immunohistochemistry (IHC) or Next-generation sequencing (NGS). 5. Have measurable disease per RECIST v1.1 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Expected survival of at least three months. 8. No anti-cancer treatment within the last two weeks or at least 5 half-lives prior to treatment (whichever is shorter), except for palliative radiation therapy from which the patient has recovered from all adverse events. 9. Patients must have adequate organ and bone marrow function within 28 days prior to the first dosing visit, defined as: i. Acceptable liver function: 1. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 × ULN (participants with known Gilbert's disease may enroll with Total bilirubin ≤ 2.5 × ULN AND direct bilirubin is ≤1.5 × ULN) (if liver metastases are present, Total bilirubin ≤2.0 × ULN). 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases). ii. Acceptable renal function: a) GFR ≥ 30 mL/min iii. Acceptable hematologic status: 1. Hemoglobin ≥ 9 g/dL Note: Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months). 2. White blood cells \> 2500/µL 3. Absolute neutrophil count \> 1500/µL 4. Platelet count \> 100 000/µL. 10. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator. a) No QTC interval exceeding 460 milliseconds (ms) for females, no QTC interval exceeding 450 ms for males. 11. Both male and female patients and their partners of childbearing potential must agree to use two medically accepted methods of contraception (e.g., barrier contraceptives \[male condom, female condom, or diaphragm with a spermicidal gel\], hormonal contraceptives \[implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings\], or one of the following methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or must practice complete abstinence from intercourse of reproductive potential from study entry to 6 months after the last day of treatment (excluding women who are not of childbearing potential and men who have been sterilized). 12. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at Screening Visit and negative urine pregnancy test prior to receiving the first dose of study. 13. Male participants must agree to use contraception and refrain from donating sperm for at least 6 months after the last dose of study intervention. 14. Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study. Exclusion Criteria (Main Study): 1. Known severe hypersensitivity towards monoclonal antibodies. 2. Clinically significant, active coronary heart disease and cardiovascular insufficiency with compromised hemodynamics per PI discretion. 3. Had a known additional malignancy that was progressing or had required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, incidentally diagnosed prostate cancer (i.e., during a TURP), carcinoma in situ (breast or cervical), excluding carcinoma in situ of bladder, that had undergone potentially curative therapy are not excluded. 4. Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test) or active hepatitis C infection (defined as detectable hepatitis C virus \[HCV\] RNA), or other known or suspected viral infections. Routine HBsAg/HCV screening is not mandated; however, participants with known or suspected infection are excluded. 5. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention. 6. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 7. Stroke and/or transient ischemic attack within 6 months prior to screening. 8. Placement of a cardiac stent or bypass surgery within 6 months of screening. 9. Tumor invasion of a large vascular structure (e.g., pulmonary artery, superior or inferior vena cava). 10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 11. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. 12. Inability to follow protocol. 13. Patients who received Trifluridine + Tipiracil (TAS-102) prior to receiving first study drug dose. 14. Serious non-malignant or malignant disease (e.g. hepatic compromise, obstructive hydronephrosis, or other conditions which may worsen) that could compromise study objectives in the opinion of the investigator, including recurrent ascites or pleural effusion requiring more than one paracentesis or thoracentesis or a single paracentesis or thoracentesis removing more than 3.0 liters of ascites within 30 days prior to screening. Inclusion Criteria (Extension Cohort): All inclusion criteria applicable to the two main study treatment arms (leronlimab 350 mg and leronlimab 700 mg, each in combination with Trifluridine + Tipiracil \[TAS-102\] and bevacizumab) apply, except Inclusion Criterion #8. Continued treatment with Trifluridine + Tipiracil (TAS-102), with or without bevacizumab, from the main study is allowed. Exclusion Criteria (Extension Cohort): All exclusion criteria applicable to the two main study treatment arms (leronlimab 350 mg and leronlimab 700 mg, each in combination with Trifluridine + Tipiracil \[TAS-102\] and bevacizumab) apply, except Exclusion Criteria #10 and #13. Prior participation in the main study is allowed and continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed. Inclusion Criteria (Leronlimab plus Pembrolizumab Cohort): 1. Meet all applicable inclusion criteria from the main study, except Item #8: No anti-cancer treatment within the last two weeks or at least 5 half-lives prior to treatment (whichever is shorter), except for palliative radiation therapy from which the patient has recovered from all adverse events. Continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed. 2. Have adequately recovered from prior therapy, defined as resolution of all clinically significant treatment-related toxicities from prior trifluridine and tipiracil + bevacizumab to Grade ≤1 (or baseline). 3. Have received their last dose of trifluridine and tipiracil at least 3 weeks prior to the first dose of the leronlimab-pembrolizumab combination. 4. Have documented disease progression. 5. Provide written informed consent to participate in the pembrolizumab cohort. Exclusion Criteria (Leronlimab plus Pembrolizumab Cohort): 1. Meet all applicable exclusion criteria from the main study, except Items #10 and #13. Prior participation in the main study is allowed and continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed. 2. Evidence of rapidly deteriorating clinical status or disease-related complications that would limit safe participation (e.g., organ dysfunction or failure, hematologic complications), in the opinion of the investigator. 3. Prior or current evidence of clinically significant immune-mediated or inflammatory conditions (including pneumonitis) that, in the opinion of the investigator, would increase the risk of treatment with pembrolizumab. 4. Subjects who have entered or are participating in the optional treatment extension phase.