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

NCT06811116 | Recruiting Phase 1 FDA Drug

• 4 other identifiers: NCI-2025-0083725-08210703UM1CA186690
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Advanced Hepatocellular Carcinoma; Metastatic Hepatocellular Carcinoma; Stage III Hepatocellular Carcinoma AJCC v8; Stage IV Hepatocellular Carcinoma AJCC v8

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Objective response rate (ORR)

  From registration to disease progression or death due to any cause, assessed up to 2 years

• Overall survival (OS)

  From registration to disease progression or death due to any cause, assessed up to 2 years

• Incidence of adverse events

  Baseline up to 2 years

• Whole exome sequencing on archival tissue

  At pre-treatment for phase II

• Sapanisertib and cabozantinib pharmacokinetics (PK)

  From pre dose on cycle 1 day 8 to pre dose on cycle 3 day 1 for phase I and II

Other Outcomes (3)

• Tumor signatures in archival bulk RNAseq

  During phase II

• Change in variant allele frequencies (VAF) of tumor mutations in circulating tumor-derived deoxyribonucleic acid (DNA) (ctDNA)

  Pre-treatment to cycle 3

• Sapanisertib and cabozantinib PK and toxicity/response

  From pre dose on cycle 1 day 8 to pre dose on cycle 3 day 1 for phase I and II

Study Arms (2)

Arm I (Sapanisertib + cabozantinib)

EXPERIMENTAL

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; Drug: Cabozantinib S-malate; Procedure: Imaging Procedure; Drug: Sapanisertib

Arm II (Cabozantinib)

ACTIVE COMPARATOR

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; Drug: Cabozantinib S-malate; Procedure: Imaging Procedure

Interventions

Imaging Procedure PROCEDURE

Undergo imaging scans

Also known as: Diagnostic Imaging Technique, Image Type, Imaging, Imaging (procedure), Imaging Procedures, Imaging Technique, imaging type, IMAGING_METHOD, imaging_type, Medical Imaging, Type of imaging

Arm I (Sapanisertib + cabozantinib); Arm II (Cabozantinib)

Biospecimen Collection PROCEDURE

Undergo blood collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm I (Sapanisertib + cabozantinib); Arm II (Cabozantinib)

Cabozantinib S-malate DRUG

Given PO

Also known as: BMS-907351, Cabometyx, Cometriq, XL 184, XL-184, XL184

Arm I (Sapanisertib + cabozantinib); Arm II (Cabozantinib)

Sapanisertib DRUG

Given orally (PO)

Also known as: INK-128, INK128, MLN-0128, MLN0128, TAK-228

Arm I (Sapanisertib + cabozantinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California, 92612, United States

RECRUITING

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

RECRUITING

Oregon Health and Science University

Portland, Oregon, 97239, United States

RECRUITING

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Specimen Handling; cabozantinib; X-Rays; sapanisertib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing

Study Officials

• Anwaar Saeed

  UPMC Hillman Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2025
• First Posted: February 6, 2025
• Study Start: November 17, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: April 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (4)