Inclusion Criteria:

1. Male or female patients, age ≥18 years 2. Patients with a histological/cytological or radiological diagnosis of HCC (mixed HCC cholangiocarcinoma may be included; patients who are candidates for surgical and non-surgical treatment, as well as those being followed without specific HCC therapy may be included)

Exclusion Criteria:

1. Inability to provide written informed consent

Inclusion Criteria (all subjects):

1. At least 18 years of age 2. Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 3. Recovered from toxicities of prior therapy to Grade 0 or 1 4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 6. Acceptable liver function: 1. Bilirubin ≤1.5 × institutional ULN 2. AST and ALT ≤3.0 × ULN, or ≤5.0 × ULN for subjects with liver involvement 7. Acceptable renal function: a. Creatinine clearance >30 mL/min according to the Cockcroft-Gault formula 8. Acceptable hematologic status (without hematologic support, other than red blood cell transfusion): 1. ANC ≥1500 cells/μL 2. Platelet count ≥100,000/μL 3. Hemoglobin ≥9.0 g/dL (prior packed red blood cell transfusion or erythropoietin support is allowed). 9. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation.

Dose Escalation Phase Subjects Only (Inclusion Criteria):

10. Histologically or cytologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective 11. Tumor progression after most recent therapy

Expansion Phase Subjects Only (Inclusion Criteria):

12. Available tumor tissue, either archival or fresh (fresh preferred). 13. For treatment, an AKR1C3 IHC H-score of ≥ 100 using a validated IHC assay in one of the following tumor types to be enrolled in the respective cohort: 1. Cohort A: Pancreatic Adenocarcinoma 2. Cohort B: Basket (any solid tumor type other than pancreatic adenocarcinoma)

Exclusion Criteria:

1. Prior radiotherapy to more than 25% of the bone marrow 2. Symptomatic brain metastases, unless previously treated and well controlled for at least 4 weeks after central nervous system (CNS)-directed treatment as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the Screening Period. Patients with known leptomeningeal disease are excluded. 3. Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancers whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the current study 4. Patients with hepatocellular carcinoma (applies to Expansion Phase only) 5. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery 6. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy 7. Treatment with radiation therapy, surgery, chemotherapy, targeted therapies or hormones within 3 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C) 8. Concomitant use of strong CYP3A4 inhibitors/inducers 9. Concomitant use of naproxen within a 48-hour window before and after OBI-3424 dosing 10. Females who are pregnant or breast-feeding 11. Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study 12. Unwillingness or inability to comply with the study protocol for any reason

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:
• Written informed consent and HIPAA authorization for release of personal health information must be obtained either from the subject or their representative. See protocol. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-1.
• Locally advanced, metastatic, or unresectable hepatocellular carcinoma that has not received prior systemic therapy. Note: if no prior histologic diagnosis exists, prefer fresh biopsy if it is both safe and feasible. If fresh biopsy is not safe and feasible, imaging criteria may be used for diagnosis as per AASLD criteria in cirrhotic patients (please see www.aasld.org for up to date guidelines).
• Child Pugh Class B7 or B8 liver dysfunction or cirrhosis with the following limitations:
• Bilirubin ≤ 3 mg/dL
• Albumin ≥ 2.8 g/dL
• INR ≤ 1.7
• Absent to slight [CP=1 to 2] (no moderate [CP=3]) ascites (Also see exclusion criteria).
• No clinically significant encephalopathy (Also see exclusion criteria).
• At least 1 untreated measurable lesion according to RECIST 1.1.
• Willingness to undergo fresh tumor biopsy at baseline if safe and feasible. Note: archival tissue may be used at baseline provided histologic diagnosis was made and sufficient tissue is available for NGS analysis.
• NGS analysis must be requested from archival tissue or fresh biopsy (if applicable) as per standard of care. Foundation One CDX is the preferred platform. Prior NGS sequencing results (including from another platform) will be accepted if NGS sequencing was previously obtained (please see protocol).
• Demonstrate adequate bone marrow and organ function as defined below:
• Hematologic
• Absolute neutrophil count (ANC) ≥ 1,000/mcL
• Lymphocyte count ≥ 0.5 x 10^9/L (500uL)
• Hemoglobin ≥ 90 g/L (9 g/dL)
• Platelet count ≥ 70,000/mcL
• Renal
• Serum creatinine OR calculated* serum creatinine clearance (GFR can be used in place of creatinine or creatinine clearance) ≤ 1.5 x ULN OR ≥ 30 mL/min for participants with creatinine levels > 1.5 x institutional ULN *calculate serum creatinine clearance using the standard Coccroft-Gault formula
• Urine protein: Urine dipstick for proteinuria < 2+ within 7 days prior to start of study treatment *Patients with with ≥ 2+ proteinuria on dipstick analysis at baseline should undergo a 24-hour urine collection which must demonstrate < 1g of protein in 24 hours.
• Hepatic
• AST (SGOT) and ALT (SGPT) ≤ 8 x ULN
• Alkaline phosphastase (ALP) ≤ 8 x ULN
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab, or 6 months after the last dose of bevacizumab. See also the protocol for definition of childbearing potential.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use effective contraceptive measures. Men with female partners of childbearing potential must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of bevacizumab. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of bevacizumab to avoid exposing the embryo. See also the protocol for additional information.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand a written informed consent document, and ability and willingness to comply with study procedures for the entire length of the study. Patients with impaired decision-making capacity (IDMC) who have a close caregiver or legally authorized representative (LAR) and/or family member available are also eligible.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:
• Histologic diagnosis of fibrolamellar or sarcomatoid HCC or mixed cholangiocarcinoma-HCC.
• Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 21 days of first planned dose of study therapy (within 14 days for palliative radiation). Patients who have had major surgery within 4 weeks of start of study therapy or anticipation of need for a major surgical procedure during the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > CTCAE Grade 1) with the exception of alopecia or neuropathy.
• Patients who have received prior systemic therapy for HCC.
• Patients who have received prior immunotherapy.
• Patients with clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control within 3 months prior to the first dose of study treatment. Note: Patients with ascites meeting eligibility criteria who require pharmacologic intervention (e.g. diuretics) to maintain symptomatic control and who have been on stable doses of diuretics for 2 months prior to the first dose of study treatment are eligible.
• Patients with clinically meaningful encephalopathy, defined as a history of hepatic encephalopathy within 6 months prior to first dose of study treatment or requirement for medications to prevent or control encephalopathy (e.g. lactulose, rifaximin).
• Any of the following additional high-risk features:
• Patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding. Note: Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD with appropriate management of varices (if applicable) within 6 months of prior to initiation of study treatment do not need to repeat the procedure.
• History of esophageal and/or gastric hemorrhage within 3 months prior to study treatment.
• History of hemoptysis (< 2.5 mL of bright red blood per episode) within 1 month prior to study treatment.
• History of intracranial hemorrhage within 1 month prior to study treatment.
• History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure.
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture within 30 days prior to start of study treatment.
• Metastatic disease that involves major airways or blood vessels. Patients with vascular invasion of the portal or hepatic veins may be enrolled.
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair) or vasculitis within 6 months prior to initiation of study treatment.
• History of arterial thrombotic event (e.g. myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months prior to initiation of study treatment.
• Chronic or recent (within 10 days of first dose of study treatment) use of aspirin > 325 mg/day, dipyramidaole, ticlopidine, clopidogrel, or dilostazol. Note: Use of aspirin < 325 mg/day is allowed.
• History of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary embolism, portal vein thrombosis, or any other significant thromboembolism) must be on a stable dose of anticoagulation for 1 month prior to initiation of study treatment and must have completely treated varices.
• Use of Coumadin-like products or full dose oral or parenteral anticoagulants. Use of prophylactic low dose anticoagulation, unfractionated heparin or LMWH is allowed.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Core biopsy or other minor surgical procedure within 3 days prior to the first dose of bevacizumab.
• History of intestinal obstruction. Note: Patients with previous intestinal obstruction may be enrolled if they have received definitive treatment for symptom resolution.
• History of inflammatory process within 6 months prior to start of study treatment including but not limited to active peptic ulcer disease, diverticulitis or colitis.
• Significant traumatic injury within 4 weeks prior to start of study treatment.
• Uncontrolled pleural effusion or pericardial effusion requiring frequent drainage procedures (> once monthly). Patients with indwelling catheters (e.g. PleurX®) are allowed.
• History of nephrotic or nephritic syndrome.
• Uncontrolled hypertension defined as systolic pressure ≥ 150/90 in spite of maximum anti-hypertensive therapy.
• Patients with untreated/uncontrolled CNS/leptomeningeal disease. Note: Patients with asymptomatic, treated CNS disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy and the following criteria are met:
• No evidence of interim progression between the completion of CNS-directed therapy and the start of study enrollment.
• No stereotactic radiation or whole-brain radiation within 28 days prior to randomization.
• No evidence of intracranial hemorrhage or spinal cord hemorrhage.
• Patients with active autoimmune disease requiring systemic corticosteroids greater than the equivalent of prednisone 10 mg daily or other systemic immunosuppressive medications including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the following exceptions:
• Patients with a history of autoimmune hypothyroidism on thyroid replacement hormone are eligible.
• Patients with Type 1 diabetes mellitus on an insulin regimen are eligible.
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only are eligible provided: 1) rash covers < 10% of body surface area (BSA), 2) disease is well controlled at baseline and requires only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%).
• See protocol for a more comprehensive list of autoimmune diseases and immune deficiencies.
• Patients receiving treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 6 weeks must discontinue these medications prior to starting protocol therapy, with the exception of:
• Patients with active autoimmune disease managed with systemic corticosteroids less than the equivalent of prednisone 10 mg daily.
• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea).
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension and adrenocortical insufficiency.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Patients who have undergone prior solid organ or bone marrow transplant with the exception of patients with prior renal transplant for whom dialysis may be employed in the event of graft rejection.
• Patients with serious active infection within 2 weeks prior to enrollment (e.g. requiring hospitalization and/or intravenous [IV] antibiotics) infection within 2 weeks prior to enrollment, or currently receiving oral or IV antibiotics for the treatment of infection. Patients receiving prophylactic antibiotics are eligible.
• Patients must have documented hepatitis virology status.
• Patients with active hepatitis B virus (HBV) infection must have a viral load < 500 IU/mL within 28 days prior to start of study treatment and be on suppressive therapy (per local standard of care) for a minimum of 14 days prior to start of study treatment and for the length of the study.
• Patients with co-infection with HBV and hepatitis C virus (HCV) are excluded. Patients with a history of HCV infection but with negative HCV RNA by PCR are considered non-infected with HCV.
• Patients with known human immunodeficiency virus (HIV) are allowed on study provided they have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent concurrent antibiotics or antifungal agents for the prevention of opportunistic infection
• A CD4 count above 250 cells/mcL
• An undetectable HIV viral load on standard PCR-based testing
• Patients with uncontrolled intercurrent illness (e.g., including but not limited to uncontrolled HTN [systolic BP ≥ 150, diastolic BP ≥ 100 despite optimal medical management or history of hypertensive crisis or hypertensive encephalopathy], symptomatic congestive heart failure [CHF], uncontrolled cardiac arrhythmia, or other within 3 months prior to start of study treatment or psychiatric illness/social situations or other conditions that would limit compliance with study requirements or substantially increase risk of incurring AEs in the opinion of the treating investigator.
• Patients with known concurrent malignancy that is expected to require active treatment within two years or may interfere with the interpretation of the efficacy and safety outcomes of this study in the opinion of the treating investigator. Note: Superficial bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring cytotoxic therapy should not exclude participation in this trial. Patients with CLL may be enrolled if they do not require active chemotherapy and their hematologic, renal and hepatic function meets criteria previously mentioned.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator.
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins or know hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab infusion.
• Uncontrolled tumor-related pain. NOTE: Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• Active tuberculosis
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

Inclusion Criteria:

• Age >= 18 years.
• HCC diagnosis confirmed by histology/cytology or clinically by American Association for Study of Liver Diseases (AASLD) criteria in cirrhotic patients.
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Locally advanced, metastatic, or unresectable disease.
• Child Pugh class A.
• Barcelona clinic liver cancer (BCLC) stage B (not amenable to liver directed therapy) or stage C.
• Prior treatment with atezolizumab and bevacizumab combination with radiographic progression that necessitates change in treatment per treating physician. Patients with rapid progression on atezolizumab and bevacizumab (defined as patients who progressed radiographically in the first restaging scan that necessitates change in treatment) are excluded.
• Washout period >= 4 weeks prior to registration is required since last atezolizumab and bevacizumab dose.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. (Form is available on the Academic and Community Cancer Research United [ACCRU] website).
• Absolute neutrophil count (ANC) >= 1000/mm ^ 3 (obtained =< 28 days prior to registration).
• Platelet count >= 60,000/mm^3 (obtained =< 28 days prior to registration).
• Hemoglobin >= 8.5 g/dL (obtained =< 28 days prior to registration).
• Total bilirubin =< 3 x upper limit of normal (ULN) (obtained =< 28 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 5 x ULN (obtained =< 28 days prior to registration).
• International normalized ratio (INR) =< 2.3 or Prothrombin time (PT) =< 6 seconds above control OR if patient is receiving anticoagulant therapy and INR is within target range of therapy creatinine =< 1.5x ULN (obtained =< 28 days prior to registration).
• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only.
• Note: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Provide informed written consent =< 28 days prior to registration.
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
• Note: During the active monitoring phase of a study (i.e., active treatment), participants must be willing to return to the consenting institution for follow-up.
• Willing to provide mandatory tissue specimens and blood specimens for correlative research purposes.

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
• Pregnant persons
• Nursing persons
• Persons of childbearing potential who are unwilling to employ adequate contraception.
• Major surgery =< 4 weeks prior to registration.
• Liver directed therapy (transarterial chemoembolization [TACE], Y-90, liver directed radiation) =< 28 days prior to registration. Prior liver directed therapy > 28 days prior to registration is allowed as long as patient has at least one measurable untreated lesion by RECIST v1.1.
• Patients with rapid progression on atezolizumab and bevacizumab (who progressed radiographically in the first restaging scan that necessitates change in treatment) are excluded.
• Prior treatment =< 4 weeks prior to registration with anti-CTLA-4 antibody for HCC.
• Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.
• Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection excluding hepatitis C virus (HCV)
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Unstable cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients with chronic HBV infection as evidenced by detectable HBV surface antigen or HBV deoxyribonucleic acid (DNA) are eligible if on antiviral therapy and have HBV DNA < 100 IU/mL. Patients with active or resolved hepatitis C (HCV) infection as evidenced by detectable HCV ribonucleic acid (RNA) or antibody are eligible.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 4 weeks prior to registration.
• Other active malignancy =< 2 years prior to registration. Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone
• History of leptomeningeal carcinomatosis.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Current or prior use of immunosuppressive medication =< 14 days prior to registration. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
• Receipt of live attenuated vaccine =< 30 days prior to registration; Note: Patients, if enrolled, should not receive live vaccine whilst on study treatment and up to 30 days after the last dose of study treatment.
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• History of grade 3 or 4 immunotherapy related toxicity NCI CTCAE v5.0 due to prior regimen attributed to atezolizumab.

Inclusion Criteria:

• Have provided signed informed consent for the trial
• Aged ≥18 years at the time of informed consent
• Histologic proof of malignancy
• Radiologic or histologic evidence of bone metastases or non-bone metastases
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≥3
• Pain Score ≥ 3
• Life expectancy of six months or more
• Willing and able to comply with all aspects of the protocol
• A female participant is eligible to participate if she is not pregnant and not breastfeeding
• Woman of childbearing potential who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
• A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment

Exclusion Criteria:

• Metastasis from a highly radiosensitive tumor (eg, lymphoma, myeloma, germ cell tumor)
• Spinal metastasis
• Active compression of spinal cord/cauda equina
• Previous RT or SBRT to the same site
• > 3 sites requiring radiation treatment

Inclusion Criteria:

• Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining
• For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2
• For Groups B, C and D, rapid review is required if patients are either >= 8 years of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
• For all Groups E and F patients, rapid central pathology review is required
• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy
• Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
• Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
• Uncorrectable coagulopathy
• For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
• The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
• Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
• Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• Age: maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 06 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 10 x upper limit of normal (ULN) for age
• Shortening fraction of >= 28% by echocardiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment) or
• Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment)
• Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males and =< 470 milliseconds for females (assessed within 8 weeks prior to study enrollment)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy [Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
• Group D:
• Patients with chronic inflammatory bowel disease and/or bowel obstruction
• Patients with concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment
• Group F:
• Patients with peripheral sensitive neuropathy with functional impairment
• Patients with a personal or family history of congenital long QT syndrome
• These criteria apply ONLY to patients who may receive chemotherapy (all groups other than Group E1):
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment

Inclusion Criteria:

• PHASE 1: Patients must have a histologically confirmed metastatic or locally advanced unresectable solid tumor that has progressed on or after available standard of care therapy or for which no acceptable standard of care therapy exists, or in which the patient declines standard of care therapy (each patient that declines standard of care therapy will be documented in the case report form)
• PHASE 2: Patients must have a histologically confirmed metastatic or locally advanced unresectable cholangiocarcinoma/gallbladder carcinoma that has progressed on at least 1 prior standard of care therapy or for which no acceptable standard of care therapy exists, or in which the patient declines standard of care therapy (each patient that declines standard of care therapy will be documented in the case report form)
• Age >= 18 years
• Because no dosing or adverse event data are currently available on the use of M3814 in combination with avelumab in patients < 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Patients with at least 1 index lesion to irradiate for whom palliative radiation treatment is indicated (including but not limited to pain and/or symptom control, prevention of disease -related complications, and preservation of organ function). Lung and liver lesions are preferred, though alternate lesions may be considered after discussion with trial principal investigator (PI). Up to 2 lesions may be considered for irradiation provided at least 1 lesion will receive the study treatment of total of 60 Gy
• Patients with at least 1 Response Evaluation Criteria in Solid Tumors (RECIST) measurable lesion (to be unirradiated) (defined as those accurately measured in at least one dimension, with the longest diameter to be recorded for non-nodal lesions and the shortest diameter for nodal lesions). Measurable is defined as at least 10 mm in longest diameter for solid tumors, at least 15 mm in shortest diameter for lymph nodes
• Patients must be willing to undergo fresh biopsies at baseline (as opposed to using archival tissue), in the event their baseline tissue was obtained > 12 months prior to study enrollment and/or they are randomized to the gamma H2AX pNBS1 multiplex IFA assay
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelet count >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated serum creatinine clearance (glomerular filtration rate [GFR] can be used in place of creatinine or creatinine clearance) >= 60 mL/min for participants with creatinine levels > 1.5 x institutional ULN
• Calculate serum creatinine clearance using the standard Cockcroft-Gault formula
• Serum total bilirubin =< 1.5 x ULN or direct bilirubin =< ULN for participants with total bilirubin > 1.5 x ULN
• Patients with known Gilbert disease with serum bilirubin level =< 3 x ULN are eligible
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN or =< 5.0 x ULN for patients with hepatobiliary tumors/liver metastases
• Albumin >= 2.8 g/L
• International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• This applies only to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
• Participants must have the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption
• Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The effects of M3814 and avelumab on the developing human fetus are unknown and there is the potential for teratogenic or abortifacient effects. For this reason, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 6 months after completion of M3814 and avelumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and avelumab
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a close caregiver or legally authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

• Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 21 days of first planned dose of study therapy (within 14 days for palliative radiation). Previously irradiated lesions may be re-irradiated provided there is disease progression in the irradiated lesion and the prescribed radiation dosage can safely be re- administered
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Common Terminology Criteria for Adverse Events [CTCAE] grade 1) with the exception of alopecia
• Patients who received prior immunotherapy
• Patients with untreated/uncontrolled central nervous system (CNS)/leptomeningeal disease. Patients with asymptomatic, treated CNS disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy and the following criteria are met:
• Radiographic demonstration of clinical stability upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study done >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
• No stereotactic radiation or whole-brain radiation within 28 days prior to randomization
• Patients with active autoimmune disease requiring systemic corticosteroids greater than the equivalent of prednisone 10 mg daily including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the following exceptions:
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only who require only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) are eligible
• Patients receiving treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 6 weeks must discontinue these medications prior to starting M3814 and avelumab on day 7, with the exception of:
• Patients with active autoimmune disease managed with systemic corticosteroids less than the equivalent of prednisone 10 mg daily
• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea)
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension and adrenocortical insufficiency
• Patients who have undergone prior solid organ or bone marrow transplant with the exception of patients with prior renal transplant for whom dialysis may be employed in the event of graft rejection
• Patients with uncontrolled intercurrent illness (e.g., including but not limited to uncontrolled hypertension [HTN] [systolic blood pressure (BP) > 150, diastolic BP > 100], symptomatic congestive heart failure [CHF], unstable angina pectoris, ischemic myocardial infarction [MI] within 6 months, cardiac arrhythmia, recent transient ischemic attack [TIA or cerebrovascular accident (CVA)]) within 6 months
• Patients with serious active infection within 4 weeks prior to enrollment (e.g. requiring hospitalization and/or intravenous [IV] antibiotics), signs/symptoms of infection within 2 weeks prior to enrollment, or currently receiving oral or IV antibiotics for the treatment of infection. Patients receiving prophylactic antibiotics are eligible
• Patients with known chronic hepatitis B virus (HBV) infection must have an undetectable viral load on suppressive therapy if indicated. Patients with known chronic hepatitis C (HCV) infection must have been treated and cured. Patients who are currently on curative treatment are eligible if they have an undetectable HCV viral load
• Patients with known human immunodeficiency virus (HIV) are allowed on study provided they have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infection
• A CD4 count above 250 cells/mcL
• An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based testing
• Patients with history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (e.g., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Patients with known concurrent malignancy that is expected to require active treatment within two years, or may interfere with the interpretation of the efficacy and safety outcomes of this study in the opinion of the treating investigator. Superficial bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring cytotoxic therapy should not exclude participation in this trial. Patients with chronic lymphocytic leukemia (CLL) may be enrolled if they do not require active chemotherapy and their hematologic, renal and hepatic function meets criteria previously mentioned
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M3814 or avelumab
• Patients unable to discontinue medications or substances that are potent inhibitors, inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to starting M3814 and avelumab on day 7 are ineligible. Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must be discontinued at least 1 week prior to first M3814 dose. Strong inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first dose. Drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the investigator must stop at least 1 day prior to first M3814 dose. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. The primary elimination mechanism of avelumab is proteolytic degradation, thus there are no contraindicated medications with respect to avelumab
• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs) prior to starting M3814 and avelumab. These must be discontinued >= 5 days prior to study treatment. Patients do not need to discontinue calcium carbonate. H2 blockers are allowed provided they are taken at least 2 hours after M3814 dose
• Patients receiving sorivudine or any chemically related analogues (such as brivudine) and not able to discontinue prior to starting M3814 and avelumab are excluded
• Pregnant and lactating women are excluded from this study because M3814 and avelumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and avelumab
• Patients who have received live vaccination within 30 days before the study