Inclusion Criteria:
1. Age ≥18 years.
2. Participants must have documented advanced (metastatic or unresectable) colorectal cancer that has progressed on or after prior standard-of-care treatment and must have received, or been unable to receive, applicable standard therapies as defined in the protocol.
3. Life expectancy ≥12 weeks.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
5. Have at least 1 measurable lesion at baseline suitable for repeat imaging evaluation by RECIST v1.1.
6. Adequate bone marrow, liver, kidney, and coagulation function per protocol requirements.
7. Agree to provide adequate tumor tissue for protocol-required biomarker assessment. Participants in designated cohorts must be willing to provide fresh tumor biopsies, unless medically contraindicated.
8. Female participants must not be pregnant or breastfeeding. Male and female participants must comply with protocol-defined reproductive and contraception requirements.
9. Have suitable venous access for study treatment and required blood sampling.
10. Be willing and able to comply with study assessments, schedule, and restrictions.
11. Written informed consent must be obtained before any study-related procedures are performed.
Exclusion Criteria:
1. Prior treatment with certain antibody-drug conjugates, as defined in the protocol. Protocol-defined exceptions may apply.
2. Recent anticancer therapy, investigational treatment, major surgery, or radiation therapy within the protocol-defined washout periods.
3. Ongoing clinically significant toxicity from prior therapy that has not recovered to the protocol-required level.
4. Active central nervous system (CNS) metastases or suspected or confirmed leptomeningeal disease. Participants with treated and stable brain metastases may be eligible.
5. Recent thromboembolic event or clinically significant cardiovascular disease.
6. Active or uncontrolled infection, including active viral hepatitis, unless protocol-defined eligibility criteria are met.
7. Known HIV infection or AIDS-related illness unless protocol-defined eligibility criteria are met.
8. History of or current drug-induced interstitial lung disease/pneumonitis, suspected interstitial lung disease (ILD)/pneumonitis, or other severe or uncontrolled chronic pulmonary disease.
9. Another malignancy within the previous 3 years, except certain malignancies with a low risk of recurrence.
10. Recent systemic corticosteroid therapy or live attenuated vaccination, except as permitted by the protocol.
11. Known hypersensitivity to DEM301 or its ingredients, or any serious medical, psychiatric, or other condition that, in the Investigator's opinion, could affect participant safety, study participation, or interpretation of study results.
