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

A Phase I/II Trial of Sapanisertib in Combination With Cabozantinib in β-catenin-mutated Hepatocellular Carcinoma (SAPHIRE)

This phase I/II trial studies the side effects and best dose of sapanisertib when given together with cabozantinib, and to see how well they work in treating patients with liver cancer that has spread from where it first started to other places in the body (metastatic) and contains a mutation (change) in the β-catenin gene. Sapanisertib and cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sapanisertib and cabozantinib together may work better than giving cabozantinib alone in treating β-catenin-mutated metastatic hepatocellular carcinoma.

Study Overview

• Status: Recruiting
• Conditions: Advanced Hepatocellular Carcinoma; Stage III Hepatocellular Carcinoma AJCC v8; Stage IV Hepatocellular Carcinoma AJCC v8; Metastatic Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Cabozantinib S-malate; Procedure: Biospecimen Collection; Procedure: Imaging Procedure; Drug: Sapanisertib

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Irvine, California, United States, 92612
      • Recruiting
      • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
      • Contact: Site Public Contact; Phone Number: 877-827-8839; Email: ucstudy@uci.edu
      • Principal Investigator: April Choi
    • Orange, California, United States, 92868
      • Recruiting
      • UC Irvine Health/Chao Family Comprehensive Cancer Center
      • Contact: Site Public Contact; Phone Number: 877-827-8839; Email: ucstudy@uci.edu
      • Principal Investigator: April Choi
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health and Science University
      • Contact: Site Public Contact; Phone Number: 503-494-1080; Email: trials@ohsu.edu
      • Principal Investigator: Emerson Y. Chen
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • University of Pittsburgh Cancer Institute (UPCI)
      • Contact: Site Public Contact; Phone Number: 412-647-8073
      • Principal Investigator: Anwaar Saeed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL-184; XL184; XL 184; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Imaging Procedure; Undergo imaging scans; Other Names: Diagnostic Imaging Technique; Imaging; Imaging Procedures; Medical Imaging; imaging type; imaging_type; Type of imaging; Image Type; Imaging (procedure); IMAGING_METHOD; Imaging Technique
Experimental: 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.	Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL-184; XL184; XL 184; Procedure: Biospecimen Collection; Undergo blood collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Imaging Procedure; Undergo imaging scans; Other Names: Diagnostic Imaging Technique; Imaging; Imaging Procedures; Medical Imaging; imaging type; imaging_type; Type of imaging; Image Type; Imaging (procedure); IMAGING_METHOD; Imaging Technique; Drug: Sapanisertib; Given orally (PO); Other Names: INK-128; INK128; MLN-0128; MLN0128; TAK-228

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From registration to disease progression or death due to any cause, assessed up to 2 years
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).	From registration to disease progression or death due to any cause, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From registration to disease progression or death due to any cause, assessed up to 2 years
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.	From registration to disease progression or death due to any cause, assessed up to 2 years
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	Baseline up to 2 years
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.	At pre-treatment for phase II
Sapanisertib and cabozantinib pharmacokinetics (PK)	Sapanisertib and cabozantinib exposure will be described and compared to historical controls	From pre dose on cycle 1 day 8 to pre dose on cycle 3 day 1 for phase I and II

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor signatures in archival bulk RNAseq	For mTOR, Met and NRF2. After correction for batch effect (limma R package), gene set variation analysis scores for each gene set described will be calculated for each patient tumor sample. For sapanisertib, we propose to use 19-gene signature as well as 28-gene signature previously identified as a biomarker of Nrf2 pathway activation and used by us. For cabozantinib, we will be using signatures derived from KAPOSI_LIVER_CANCER_MET_UP" consisting of 18 genes which we have used earlier. We will evaluate any relations with peculiar response.	During phase II
Change in variant allele frequencies (VAF) of tumor mutations in circulating tumor-derived deoxyribonucleic acid (DNA) (ctDNA)	The detectable VAFs will be assessed and trended during the course of treatment. VAF change will be assessed categorically for each patient (increased or decreased at cycle 3 as compared to pre-treatment). The association of VAF change with objective response will be tested using the Fisher's test, where p<0.05 will be considered statistically significant	Pre-treatment to cycle 3
Sapanisertib and cabozantinib PK and toxicity/response	Sapanisertib and cabozantinib exposure will be exploratorily correlated with toxicity and response with non-parametric tests at a significance level of 0.05 (PK endpoints in patients with vs without presence of toxicity or response endpoints). Cabozantinib PK as single agent versus in combination with sapanisertib will be compared with a paired non-parametric test at a significance level of 0.05	From pre dose on cycle 1 day 8 to pre dose on cycle 3 day 1 for phase I and II

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anwaar Saeed, UPMC Hillman Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: February 5, 2025
• First Submitted That Met QC Criteria: February 5, 2025
• First Posted (Actual): February 6, 2025

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Physical Phenomena; Electromagnetic Phenomena; Magnetic Phenomena; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Specimen Handling; X-Rays; cabozantinib; sapanisertib
• Other Study ID Numbers: NCI-2025-00837 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186690 (U.S. NIH Grant/Contract); 10703 (Other Identifier: CTEP); 25-082

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No