A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors
A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors
Researchers are looking for a better way to treat people with solid tumors. Before a
 treatment can be approved for people to take, researchers do clinical trials to better
 understand its safety and how it works.

 In this trial, the researchers want to learn about regorafenib taken together with nivolumab
 in a small number of participants with different types of tumors. These include tumors in the
 head and neck, the esophagus, the pancreas, the brain, and the biliary tract. The biliary
 tract includes gall bladder and bile ducts.

 The trial will include about 200 participants who are at least 18 years old. All of the
 participants will take 90 mg of regorafenib as a tablet by mouth. The dose of regorafenib can
 be adjusted up to 120 mg or down to 60 mg by the doctor based on how well a participant
 tolerates treatment. All of the participants will receive 480 milligrams (mg) of nivolumab
 through a needle put into a vein (IV infusion).

 The participants will take treatments in 4-week periods called cycles. They will take
 regorafenib once a day for 3 weeks, then stop for 1 week. In each cycle, the participants
 will receive nivolumab one time. These 4-week cycles will be repeated throughout the trial.
 The participants can take nivolumab and regorafenib until their cancer gets worse, until they
 have medical problems, or until they leave the trial. The longest nivolumab can be given is
 up to 2 years.

 During the trial, the doctors will take pictures of the participants' tumors using CT or MRI
 and will take blood and urine samples. The doctors will also do physical examinations and
 check the participants' heart health using an electrocardiogram (ECG). They will ask
 questions about how the participants are feeling and if they have any medical problems.
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.