A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors

Inclusion Criteria:

* Histologically confirmed selected recurrent or metastatic solid tumor types that have progressed after treatment with standard therapies and for which there are no curative intent surgery or chemoradiation.
* Cohort 1: subjects with HNSCC (Head and neck squamous-cell carcinoma) who have not received prior PD-1/PD-L1 inhibitor therapy.
* Cohort 2: subjects with HNSCC who have progressed on or after prior systemic therapy, at least one of which included a PD-1/PD-L1 inhibitor alone or in combination with chemotherapy.
* Cohort 3: subjects with ESCC (Esophageal Squamous Cell Carcinoma) who progressed on or after platinum and/or fluoropyrimidine based regimen.
* Cohort 4: subjects with PDAC (Pancreatic ductal adenocarcinoma) who have progressed on or after gemcitabine or fluoropyrimidine based regimens.
* Cohort 5: subjects with BTC (Biliary tract carcinoma) (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder cancer) who have progressed on gemcitabine or fluoropyrimidine or platinum therapy or a combination of these agents.
* Cohort 6: subjects with Grade IV GBM (Glioblastoma multiforme) or Grade III AA (Anaplastic astrocytoma) (World Health Organization \[WHO\] criteria) with unequivocal first progression after surgery followed by radiotherapy and temozolomide.
* Documented HPV (Human papilloma virus) / p16 status for oropharyngeal cancer.
* Capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
* Adult participants of legal maturity (18 years or older).
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1.
* Adequate hematologic and organ function as assessed by the following laboratory tests performed within 7 d before start of study treatment including:

  * Total bilirubin ≤1.5 x the upper limit of normal (ULN). Total bilirubin (≤3 x ULN) is allowed if Gilbert's syndrome is documented
  * Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN (≤5 x ULN for participants with liver involvement of their cancer)
* Measurable disease by baseline CT or MRI per RECIST 1.1 or RANO.
* Participants must consent to provide recent biopsy/tumor tissue of a primary tumor lesion or from metastases (e.g. liver, lung) for HNSCC (IO treated) for Stage 1 and 2 and in HNSCC (IO naïve) cohort for Stage 2.
* Anticipated life expectancy greater than 3 months.
* Be able to swallow and absorb oral tablets.

Exclusion Criteria:

* Presence of symptomatic central nervous system (CNS) metastases, leptomeningeal metastases or spinal cord compression. Previously-treated lesions should be stable for at least 6 weeks prior to study entry.
* Participants with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment.
* Prior therapy with PD-1/PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy to treat cancer (except cohort 2).
* Cohort 2: More than one prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any other form of immunotherapy to treat cancer.
* ESCC:

  * patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., the aorta or respiratory tract).
  * patients who have previously received taxane agents for recurrent/metastatic cancer.
* GBM/AA

  * Primary tumors localized to the brainstem or spinal cord.
  * Presence of diffuse leptomeningeal disease or extracranial disease.
  * Participants requiring \> 4 mg of dexamethasone or biologic equivalent per day to control symptoms related to brain tumor and cerebral edema within 21 days of starting study treatment.
* Participants who have known dMMR/MSI-H cancers or NTRK (tropomyosin receptor kinase) fusions.
* Prior therapy with regorafenib.
* Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment.
* Participants who have permanent discontinuation of PD-1/PD-L1 therapy due to toxicity.
* Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study treatment. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen as per investigator's judgement.
* History of cardiac disorders as defined by:

  * Congestive heart failure ≥ New York Heart Association (NYHA) class 2:
  * Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug.
  * Uncontrolled cardiac arrhythmias.
* Poorly controlled hypertension, defined as a blood pressure consistently above 140/90 mmHg despite optimal medical management.
* Participants with an active, known or suspected autoimmune disease.
* History of (non-infectious) pneumonitis that required steroids, current pneumonitis or interstitial lung disease.
* Active infection \> NCI-CTCAE Grade 2.
* Positive test (from historical data or tested during screening) for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive (except for participants on anti-viral therapy for HBV with a viral load \< 100 IU/mL), or Hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid \[RNA\] negative).
* Pregnancy or breast feeding.
* Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with the participation for the full duration of the trial.
* Participants with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings.