A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or TransCon TLR7/8 Agonist or Other Anticancer Therapies in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies

TransCon IL-2 β/γ is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This is a first-in-human, open-label, Phase 1/2, dose escalation and dose expansion study of TransCon IL-2 β/γ as monotherapy or in combination therapy in adult participants with advanced or metastatic solid tumors. Given the unique PK profile enabled by the TransCon technology, TransCon IL-2 β/γ presents the opportunity to enhance the therapeutic index of current IL-2 therapy.

IL-2 is a key cytokine that directs the immune system through pleiotropic effects mediated by promoting expansion of both cytotoxic effector cells and Tregs. TransCon IL-2 β/γ is designed as a long-acting delivery prodrug of IL-2 β/γ, a potent cytokine signaling molecule, with the potential to improve the safety and efficacy of IL-2.

Key Inclusion Criteria: * At least 18 years of age, or country defined local legal age * Demonstrated adequate organ function at screening * Life expectancy \>12 weeks as determined by the Investigator * Female and male participants of childbearing potential who are sexually active must agree to use highly effective methods of contraception * Participants must have histologically confirmed locally advanced, recurrent, or metastatic solid tumor malignancies that cannot be treated with curative intent (surgery or radiotherapy), with the exception of the neoadjuvant cohorts * Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * Part 3 and Part 4: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Participants who have undergone treatment with anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated protein (CTLA-4) antibody must have a washout of at least 4 weeks from the last dose and evidence of disease progression per investigator assessment before Cycle 1 Day 1 (C1D1) with the exception of the neoadjuvant cohorts * Participants who have previously received an immunotherapy prior to C1D1 must have any immune-related toxicities resolved to ≤Grade 1 or baseline (prior to the immunotherapy) to be eligible, with the exception of participants on well controlled physiologic endocrine replacement * Part 3: Neoadjuvant cohorts: participants must have completely resectable disease Key Exclusion Criteria: * Symptomatic central nervous system metastases and/or carcinomatous meningitis * Active autoimmune diseases, regardless of need for immunosuppressive treatment, with the exception of participants well controlled on physiologic endocrine replacement * Any uncontrolled bacterial, fungal, viral, or other infection * Significant cardiac disease * A marked clinically significant baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>480 ms) \[CTCAE Grade 1\]) using Fridericia's QT correction formula * Positive for human immunodeficiency virus (HIV) or has known active hepatitis B or C infection * Known hypersensitivity to any study treatment(s) used in the specific study part/cohort * Participants who have been previously treated with IL-2 or IL-2 variants (all participants) * Systemic immunosuppressive treatment with the exception for patients on corticosteroid taper (for example, for chronic obstructive pulmonary disease exacerbation). * Vaccination with live, attenuated vaccines within 4 weeks of C1D1 * Treatment with any other anti-cancer systemic treatment (approved or investigational) or radiation therapy within 4 weeks of C1D1 * Part 3: Other active malignancies within the last 2 years * Women who are breastfeeding or have a positive serum pregnancy test during screening