Testing the Addition of an Anti-cancer Drug, Sapanisertib, to the Usual Chemotherapy Treatment (Cabozantinib) in Metastatic Liver Cell Cancer With a Change in Genes for the Protein β-Catenin, The SAPHIRE Trial

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed HCC, not amenable tocurative treatment approach

• For Phase 2, patients must have measurable disease, defined as at least one lesionthat can be accurately measured in at least one dimension (longest diameter to berecorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm)by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers by clinicalexam

• For phase 2, patients must have a β-catenin mutation, based on next generationeequencing (NGS) testing through Clinical Laboratory Improvement Amendments (CLIA)-certified commercially available standard of care assay

• Patients must have received at least one prior line of systemic therapy in themetastatic setting, including a prior immune checkpoint inhibitor therapy unless noteligible. For the phase 2 portion, patients must have received at least one and nomore than two prior lines of systemic therapy in the metastatic setting, including aprior immune checkpoint inhibitor therapy unless not eligible

• Age ≥ 18 years. Because no dosing or adverse event data are currently available onthe use of sapanisertib in combination with cabozantinib in patients <18 years ofage, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 50%)

• Child Pugh score of A

• Absolute neutrophil count ≥ 1,000/mcL

• Platelets ≥ 30,000/mcL

• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 5 × institutional ULN

• Glomerular filtration rate (eGFR) ≥ 40 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class II or better

• For the phase 2 portion, availability of archival tumor tissue at the time ofpatient enrollment for banking for molecular profiling studies

• The effects of sapanisertib and cabozantinib on the developing human fetus areunknown. For this reason, women of child-bearing potential and men must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry, for the duration of study participation, and after completionof drug administration. Should a woman become pregnant or suspect she is pregnantwhile she or her partner is participating in this study, she should inform hertreating physician immediately. Both men and women treated or enrolled on thisprotocol must agree to use adequate contraception prior to the study, for theduration of study participation, and for the following duration after completion ofsapanisertib and cabozantinib administration:

• 90 days and 120 days after last dose of sapanisertib for women of childbearingpotential and men respectively,

• 5 months and 7 months after last dose of cabozantinib for women of childbearingpotential and men respectively

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to sapanisertib and cabozantinib

• Use of strong CYP3A4-inhibiting agents due to drug-drug interaction withcabozantinib

• Prior exposure to cabozantinib

• Patients who are unable to swallow oral medications such as capsules and tablets andpatients with gastrointestinal conditions that may affect the absorption of oralmedications

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous

• Pregnant women are excluded from this study because sapanisertib and cabozantinibhave the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with sapanisertib and cabozantinib, breastfeeding should bediscontinued if the mother is treated with sapanisertib and cabozantinib