The study will assess the safety, PK, PD, and preliminary efficacy of ABBV-CLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI).

The trial aims to establish a safe, tolerable, and efficacious dose of ABBV-CLS-484 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation and Part 3 Dose Expansion (Monotherapy and Combination therapy).

Part 1, ABBV-CLS-484 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors.

Part 2, ABBV-CLS-484 will be administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects who have advanced solid tumors.

Part 3, ABBV-CLS-484 will be administered alone as a monotherapy at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). ABBV-CLS-484 will also be administered at the determined recommended dose in combination with a PD-1 targeting or with a VEGFR TKI agent in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.

Inclusion Criteria:

• Must weigh at least 35 kilograms (kg).
• An Eastern Cooperative Oncology Group (ECOG) performance status <= 2.
• Life expectancy of >= 12 weeks.
• Laboratory values meeting protocol criteria.
• QT interval corrected for heart rate < 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.
• Measurable disease defined by RECIST 1.1 criteria.

For Monotherapy and Combination Dose Escalation:

• Participants with histologically or cytologically proven metastatic or locally advanced tumors, for which no effective standard therapy exists, or where standard therapy has failed. Participants must have received at least 1 prior systemic anticancer therapy for the indication being considered.

For Monotherapy Dose Expansion only:

• Participants must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with a best response by RECIST v1.1 of CR/PR/stable (any duration) or stable disease (for greater than 6 months); AND

• Must have been previously treated with 1 or more prior lines of therapy in the locally advanced or metastatic setting with the following tumor types:

  • Relapsed/refractory HNSCC
  • Relapsed/refractory NSCLC
  • Advanced ccRCC

For PD-1 Targeting Agent Combination Dose Expansion only:

• For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with response by RECIST v1.1 of CR/PR (any duration) or stable disease (for greater than 6 months):

  • Relapsed HNSCC
  • Relapsed NSCLC
  • Relapsed Advanced ccRCC

• For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy and have had disease progression with PD-1/PD-L1 targeted therapy:

  • Locally Advanced or metastatic MSI-H tumors

For VEGFR TKI Combination Dose Expansion only:

• Relapsed advance ccRCC with no more than 1 prior VEGFR TKI
• Participants no recent history of hemorrhage, including hemoptysis, hematemesis, or melena
• Participants with poorly controlled hypertension are excluded.

Exclusion Criteria:

• Untreated brain or meningeal metastases (i.e., subjects with history of metastases are eligible provided they do not require ongoing steroid treatment and have shown clinical and radiographic stability for at least 28 days after definitive therapy)

• Unresolved Grade 2 or higher toxicities related to previous anticancer therapy except alopecia.

• Unresolved Grade 2 or higher peripheral neuropathy.

• History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

• Recent history (within 6 months) of congestive heart failure (defined as New York Heart Association, Class 2 or higher), ischemic cardiovascular event, pericarditis, or clinically significant pericardial effusion or arrythmia.

• Recent history (within 6 months) of Childs-Pugh B or C classification of liver disease.

• History of clinically significant medical and/or psychiatric conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.

• History of uncontrolled, clinically significant endocrinopathy.

• Known gastrointestinal disorders making absorption of oral medications problematic; subject must be able to swallow capsules.

• If treated with a PD-1/aPD-L1 targeting or other immune-oncology agents in the past, excluded if had prior pneumonitis, prior Grade 3 or higher immune mediated toxicity, hypersensitivity to administered drug or drug related toxicity requiring discontinuation.

• Active autoimmune disease requiring systemic treatment in past 2-years (exceptions for endocrinopathies, vitiligo or atopic conditions).

• History of solid organ transplant or allogeneic stem cell transplant.

• History of other malignancy, with the following exceptions:

  • No known active disease present within >= 3 years before first dose of study treatment and felt to be at low recurrence by investigator.
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease.

• History of interstitial lung disease or pneumonitis.

• Major surgery <= 28 days prior to first dose of study drug

• Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing practices.