UK Center for Clinical and Translational Science

Monotherapy - Dose Escalation and Dose Expansion Parts - Participants with non-CNS solid tumors that is metastatic or unresectable and for whom there is no available standard therapy. - Participants with a confirmed diagnosis of relapsed or refractory, advanced and/or metastatic melanoma, NSCLC, or CRC and for whom there is no available standard therapy Combination Therapy - Dose Expansion Part - Participants with unresectable Stage III or Stage IV melanoma with no prior systemic anticancer therapy for unresectable or metastatic disease. Primary ocular or mucosal melanoma is excluded. - Participants with Stage IV metastatic or recurrent NSCLC with no prior systemic anticancer therapy, no actionable mutation. - Participants with recurrent or metastatic HNSCC with no prior systemic therapy administered in the recurrent or metastatic setting. - Participants with confirmed metastatic PDAC with no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease. General (all phases): - Must be age ≥ 18 years of age on the day of signing informed consent, or the legal age of consent in the jurisdiction in which the trial is taking place. - Measurable disease according to RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) 0-1 - Normal or adequate liver, renal, cardiac and bone marrow function

Monotherapy - Dose Escalation and Dose Expansion Parts - Treatment with an anti-cancer agent (within 21 days or after at least 5 half-lives of the drug, whichever is shorter), prior to GEN1042 administration - Radiotherapy within 14 days prior to first GEN1042 administration - Toxicities from previous anti-cancer therapies that have not resolved Combination Therapy - Dose Expansion Part - Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major surgery within 3 weeks or at least 5 half-lives of the drug (whichever is shorter) of the first dose of trial treatment. - Radiotherapy within 14 days of start of trial treatment or received lung radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment. General (all phases) - Participants has an active, known, or suspected autoimmune disease. - History of non-infectious pneumonitis that required steroids or currently has pneumonitis. - History of ≥ grade 3 allergic reactions to monoclonal antibody (mAb) therapy - Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.