Antibody DS-8273a Administered in Combination With Nivolumab in Subjects With Advanced Colorectal Cancer

Inclusion Criteria: 1. A pathologically documented colorectal cancer that: 2. Is unresectable or metastatic 3. Has undergone ≥ 2 prior standard therapies 4. Is MMR-proficient \[selected by the site based on microsatellite instability assay (MSI) and/or immunohistochemistry (IHC) for MMR proteins\] 5. At least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 7. Peripheral blood MDSC level ≥ 10% of mononuclear cell fraction (assayed at a central laboratory) 8. Adequate bone marrow, renal, hepatic, and blood clotting function 9. Able to comply with protocol visits and procedures 10. Agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study (women for 23 weeks and men for 31 weeks after the last dose of study drug) 11. Are fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Institutional Review Board (IRB)-approved informed consent form (ICF), including Health Insurance Portability and Accountability Act authorization, if applicable, before performance of any study-specific procedures or tests 12. Are willing to provide available pre-existing diagnostic or resected tumor samples. Providing fresh tumor biopsies are optional for all subjects in Dose Escalation cohorts. In the Dose Expansion cohort, up to 6 subjects may be requested to provide pre- and post-treatment tumor biopsies based on eligibility for the procedure. For those subjects who do not have an MMR status, inclusion in the Dose Escalation and Dose Expansion can be achieved by providing a fresh tumor biopsy for MMR testing. 13. Subjects with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. Inhaled steroids and intra-articular steroid injections are permitted in this study. Exclusion Criteria: 1. Active infection or chronic comorbidity that would interfere with therapy 2. History of other malignancy(ies), except adequately treated non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥ 3 years. 3. History of severe hypersensitivity reactions to other monoclonal antibodies. 4. Any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that requires concomitant use of chronic systemic corticosteroids or other immunosuppressive medications, except for subjects with vitiligo, treated thyroiditis or resolved asthma/atopy. 5. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody (or any other antibody targeting T-cell co-stimulation pathways). 6. Tested positive for hepatitis B or C serological markers (hepatitis B surface antigen or antibodies to hepatitis C virus) or human immunodeficiency virus. 7. Recipient of vaccines within 1 month of or during study drug treatment. 8. Requires daily supplemental oxygen. 9. Recipient of a stem cell or bone marrow transplant. 10. A concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor. 11. Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy). 12. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy). 13. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small-molecule targeted agents within 2 weeks, or 5 half-lives before study drug treatment, whichever is longer. 14. Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment. 15. Participation in a therapeutic clinical study within 3 weeks before study drug treatment (for small-molecule targeted agents, this non-participation period is 2 weeks or 5 half-lives, whichever is longer), or current participation in other investigational procedures. 16. Pregnant or breastfeeding, or planning to become pregnant. 17. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results. 18. Life expectancy \< 3 months, in the opinion of the Investigator.