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
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.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
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 sequencing (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
Disqualifiers
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
Trial design
Design model
Sequential
Treatments tested in this trial
Biospecimen Collection
Procedure/Surgery
Undergo blood collection
Cabozantinib S-malate
Drug
Given PO
Imaging Procedure
Procedure/Surgery
Undergo imaging scans
Sapanisertib
Drug
Given orally (PO)
Treatment groups
92 Participants
are divided into 2 treatment groups
Group A: Arm I (Sapanisertib + cabozantinib)Experimental treatment 4 interventions
Group B: Arm II (Cabozantinib)Active comparator 3 interventions
Trial outcomes
Primary outcomes
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.
Time frame
From registration to disease progression or death due to any cause, assessed up to 2 years
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).
Time frame
From registration to disease progression or death due to any cause, assessed up to 2 years
Secondary outcomes
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.
Time frame
From registration to disease progression or death due to any cause, assessed up to 2 years
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.
Time frame
From registration to disease progression or death due to any cause, assessed up to 2 years
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
Time frame
Baseline up to 2 years
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 will evaluate any relations with peculiar response.
Time frame
At pre-treatment for phase II
Other outcomes
1
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, will propose to use 19-gene signature as well as 28-gene signature previously identified as a biomarker of Nrf2 pathway activation and used. For cabozantinib, will be using signatures derived from KAPOSI\_LIVER\_CANCER\_MET\_UP" consisting of 18 genes which have used earlier. Will evaluate any relations with peculiar response.
Time frame
During phase II
2
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
Time frame
Pre-treatment to cycle 3
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
Time frame
From pre dose on cycle 1 day 8 to pre dose on cycle 3 day 1 for phase I and II
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