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

Recruitment Status
RECRUITING
(See Contacts and Locations)Verified December 2025 by National Cancer Institute (NCI)
Sponsor
National Cancer Institute (NCI)
Information Provided by (Responsible Party)
National Cancer Institute (NCI)
Clinicaltrials.gov Identifier
NCT06811116
Other Study ID Numbers:
NCI-2025-00837
First Submitted
February 4, 2025
First Posted
February 5, 2025
Last Update Posted
May 12, 2026
Last Verified
December 2025

ClinicalTrials.gov processed this data on May 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

PRIMARY OBJECTIVES:

I. To establish the recommended phase 2 dose (RP2D) of the combination of sapanisertib and cabozantinib in advanced hepatocellular carcinoma (HCC) patients. (Safety Lead-In \[Phase I\]) II. To determine the activity by progression free survival (PFS) of the combination of sapanisertib and cabozantinib versus (vs) cabozantinib alone in advanced β-catenin mutated HCC patients. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate the activity by objective response rate (ORR) of the combination of sapanisertib and cabozantinib versus cabozantinib alone in advanced β-catenin mutated HCC patients.

II. To determine the activity by overall survival (OS) of the combination of sapanisertib and cabozantinib vs cabozantinib alone in advanced β-catenin mutated HCC patients.

III. To determine the safety and tolerability of the combination of sapanisertib and cabozantinib.

IV. To identify molecular subpopulations associated with response. V. To explore the pharmacokinetics (PK) for sapanisertib and cabozantinib.

EXPLORATORY OBJECTIVES:

I. To identify ribonucleic acid (RNA) signatures associated with response. II. To evaluate circulating tumor DNA (ctDNA) as a predictor for treatment response to therapy.

III. To explore the exposure response relationships for sapanisertib and cabozantinib.

OUTLINE: This is a phase I, dose-escalation study of sapanisertib and cabozantinib followed by a phase II randomized study. Patients in Phase I receive treatment as in Arm I. Patients in Phase II are randomized to 1 of 2 arms.

ARM I: Patients receive sapanisertib orally (PO) once daily (QD) on 3 days on and 4 days off per week, 5 days on and 2 days off per week or on days 1-28 of each cycle and cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood collection and imaging scans throughout the study.

ARM II: Patients receive cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood collection imaging scans throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Condition or DiseaseIntervention/Treatment
Advanced Hepatocellular CarcinomaMetastatic Hepatocellular CarcinomaStage III Hepatocellular Carcinoma AJCC v8Stage IV Hepatocellular Carcinoma AJCC v8
Procedure: Biospecimen CollectionProcedure: Biospecimen Collection

Study Design

Study TypeInterventional
Actual Enrollment92 participants
Design AllocationRandomized
Interventional ModelSequential Assignment
MaskingNone (Open Label)
Primary PurposeTreatment
Official TitleA Phase I/II Trial of Sapanisertib in Combination With Cabozantinib in β-catenin-mutated Hepatocellular Carcinoma (SAPHIRE)
Study Start DateNovember 16, 2025
Actual Primary Completion Date1yr 3mos from now
Actual Study Completion Date1yr 3mos from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Arm I (Sapanisertib + cabozantinib)
Patients receive sapanisertib PO QD on 3 days on and 4 days off per week, 5 days on and 2 days off per week or on days 1-28 of each cycle and cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood collection and imaging scans throughout the study.
Procedure: Biospecimen Collection
Undergo blood collection
Arm II (Cabozantinib)
Patients receive cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood collection imaging scans throughout the study.
Procedure: Biospecimen Collection
Undergo blood collection

Outcome Measures

Primary Outcome Measures
  1. Dose-limiting toxicities and incidence of adverse events
    Dose limiting toxicities and adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be tabulated for each dose level.
  2. Progression free survival (PFS)
    Treatment response will be assessed based on Response Evaluation Criteria in Solid Tumors version 1.1. PFS will be estimated by the Kaplan-Meier method, along with 95% confidence regions. Median PFS will also be calculated along with its 95% confidence intervals (CI).
Secondary Outcome Measures
  1. Objective response rate (ORR)
    Defined as the proportion of patients with complete response or partial response. ORR will be estimated along with its exact 95% CI.
  2. Overall survival (OS)
    Will be estimated by the Kaplan-Meier method, along with 95% confidence regions. Median OS will also be calculated along with its 95% CI.
  3. Incidence of adverse events
    Will be tabulated according to CTCAE version 5.0 type, grade and relation to treatment in combination and in the control arm. The worst grade of adverse event will be determined for each participant
  4. Whole exome sequencing on archival tissue
    Mutations with a focus on the MET pathway; TERT promoter mutations, NEFL2; TSC1/2; TERT; ARID1a; ARID2; CTNNB1; TP53; AXIN1-2, APOB, ALB, MLL2, and others as well as somatic mutation burden will be assessed in archival tissue and we will evaluate any relations with peculiar response.
  5. Sapanisertib and cabozantinib pharmacokinetics (PK)
    Sapanisertib and cabozantinib exposure will be described and compared to historical controls

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
Patients must have histologically or cytologically confirmed HCC, not amenable to curative treatment approach
For Phase 2, patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded 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 clinical exam
For phase 2, patients must have a β-catenin mutation, based on next generation eequencing (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 the metastatic setting, including a prior immune checkpoint inhibitor therapy unless not eligible. For the phase 2 portion, patients must have received at least one and no more than two prior lines of systemic therapy in the metastatic setting, including a prior immune checkpoint inhibitor therapy unless not eligible
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of sapanisertib in combination with cabozantinib in patients \<18 years of age, 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-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal 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
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
For the phase 2 portion, availability of archival tumor tissue at the time of patient enrollment for banking for molecular profiling studies
The effects of sapanisertib and cabozantinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and after completion of drug 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. Both men and women treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for the following duration after completion of sapanisertib and cabozantinib administration:
90 days and 120 days after last dose of sapanisertib for women of childbearing potential and men respectively,
5 months and 7 months after last dose of cabozantinib for women of childbearing potential and men respectively
Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf 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 or biologic composition to sapanisertib and cabozantinib
Use of strong CYP3A4-inhibiting agents due to drug-drug interaction with cabozantinib
Prior exposure to cabozantinib
Patients who are unable to swallow oral medications such as capsules and tablets and patients with gastrointestinal conditions that may affect the absorption of oral medications
Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
Pregnant women are excluded from this study because sapanisertib and cabozantinib have 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 sapanisertib and cabozantinib, breastfeeding should be discontinued if the mother is treated with sapanisertib and cabozantinib

Contacts and Locations

Sponsors and CollaboratorsNational Cancer Institute (NCI)
Locations
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care | Irvine California, United States, 92612UC Irvine Health/Chao Family Comprehensive Cancer Center | Orange California, United States, 92868Oregon Health and Science University | Portland Oregon, United States, 97239University of Pittsburgh Cancer Institute (UPCI) | Pittsburgh Pennsylvania, United States, 15232
Investigators
Principal Investigator: Anwaar Saeed, UPMC Hillman Cancer Center LAO