Key Inclusion Criteria:

1. Age ≥ 18 years at time of signing ICF
2. ECOG Performance Status of 0 or 1
3. Histologic documentation of incurable, locally advanced or metastatic tumor of the type being evaluated in individual cohorts.
4. Adequate hepatic and renal function and adequate bone marrow reserve function.
5. For combination cohorts, participants must be eligible to receive the chemotherapy or targeted agent.
6. Ph1a only: No more than three prior therapeutic regimens.
7. Ph1b only: Must be FOLFIRI naïve participants and must have received only 1 prior therapeutic regimen administered for the treatment of cancer in the advanced/metastatic setting - OR - FOLFIRI naïve participants that only received adjuvant therapy who progressed within six months after completing adjuvant therapy, and are confirmed to have locally advanced/metastatic disease

Key Exclusion Criteria:

1. Inability to comply with study and follow-up procedures.
2. Prior DR5 agonist therapy.
3. Concomitant use of agents well-known to cause liver toxicity.
4. Concomitant use of anti-cancer agents
5. Palliative radiation to bone metastases within 2 weeks prior to Day 1.
6. Major surgical procedure within 4 weeks prior to Day 1.
7. Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). Participants with a history of treated CNS metastases are eligible.
8. Prior use of any chemotherapeutic agent or small molecule inhibitors (SMI) within 2 weeks or 5 half-lives, prior to the first dose of study treatment
9. Treatment with a monoclonal antibody, or any other anticancer agent (including biologic, experimental, or hormonal therapy) investigational or otherwise, that is not chemotherapy or a SMI, within 4 weeks or five half-lives prior to first dose of study treatment.
10. Ph1b: Participants who have previously received FOLFIRI treatment in the adjuvant, advanced, or metastatic disease setting