AD HOC Trial: Artificial Intelligence-Based Drug Dosing In Hepatocellular Carcinoma

This study will test the hypothesis that a novel combination of three drugs (sorafenib, sonidegib, and irinotecan), in conjunction with individually optimized doses, can be safely administered and lead to improved clinical outcomes in patients with hepatocellular carcinoma compared to standard of care. The main objective of this study is to establish safe dose ranges for the coadministration of sorafenib, sonidegib, and irinotecan in patients with hepatocellular carcinoma. Furthermore, we will collect data to inform the application of an artificial intelligence/computational approach to individual dosing of combination chemotherapy. Individualization of dosing will be achieved by using Phenotypic Personalized Medicine (PPM) to maximize treatment efficacy in patients with hepatocellular carcinoma, while minimizing toxicity. Drug efficacy will be assessed by measuring plasma circulating tumor DNA (ctDNA). Toxicity will be assessed by quantitating organ injury and patient tolerability. Recommended dosing for future studies will be based on the totality of the data.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Irinotecan; Drug: Sonidegib; Drug: Sorafenib

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Teresa Ware, MPH; Phone Number: 352-273-5739; Email: PMO@cancer.ufl.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
      • Contact: Allison Springer; Phone Number: 352-265-0702; Email: sheehanallison@ufl.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults ≥ eighteen years of age
• Biopsy proven advanced-stage hepatocellular carcinoma (HCC), as confirmed by pathological analysis.
• Not eligible for, or had disease progression after, surgical or locoregional therapies.
• Subjects must not have more than one active malignancy at the time of enrollment (Subjects 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 [as determined by the treating physician and approved by the PI] may be included).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less.
• Child-Pugh liver function class A or B7
• Life expectancy of 12 weeks or more
• At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (mRECIST).

• Must have lab values consistent with the following:

  1. Platelet count ≥ 60,000
  2. Hemoglobin, ≥8.0 g/dL
  3. INR ≤2.5
  4. Albumin ≥2.5 g/dL
  5. Total bilirubin, ≤5 mg/dL
  6. ALT & AST ≤5 times the upper limit of normal
  7. Creatinine ≤ 2 times the upper limit of normal
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
• Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 20 months after the last dose of study drug to minimize the risk of pregnancy.
• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 8 months following the last dose of study drug.

Exclusion Criteria:

• Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 20 months after the last dose of study drug.
• Subjects who are pregnant or breastfeeding.
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications or protocol noncompliance, in the opinion of the treating physician.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
• Inability to follow up with treatment center for up to 12 weeks after enrollment
• Anticipated major surgery during the time of planned study
• Homozygosity for UGT1A1*28 via genotyping
• History of liver transplant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Irinotecan, Sonidegib, and Sorafenib; Subjects will be assigned to a dose of each drug following a 3 + 3 design

Drug: Irinotecan; All subjects will be given either 25 mg/m2 (dose level -1), 50 mg/m2 (dose level 0), or 75 mg/m2 (dose level +1) irinotecan intravenously every 7 days.; Drug: Sonidegib; All subjects will take 200 mg sonidegib orally either every 96 hours (dose level -1), every 48 hours (dose level 0), or every 24 hours (dose level +1).; Drug: Sorafenib; All subjects will take 200 mg sorafenib orally either every 48 hours (dose level -1), every 24 hours (dose level 0), or every 12 hours (dose level +1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximally tolerated dose	Determine the maximum tolerated dose of irinotecan, sonidegib, and sorafenib	32 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Determine the objective response rate, as measured by mRECIST 1.1 criteria	32 days
Change in the biomarker AFP	Measure the change in the blood level of the biomarker AFP	32 days
Change in the biomarker AFP-L3	Measure the change in the blood level of the biomarker AFP-L3	32 days
Change in the biomarker DGC	Measure the change in the blood level of the biomarker DGC	32 days
Change in the biomarker TGF-B	Measure the change in the blood level of the biomarker TGF-B	32 days

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Sun Pharmaceutical Industries Ltd
• Investigators: Principal Investigator: Ali Zarrinpar, MD, PhD, University of Florida

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: December 20, 2022
• First Submitted That Met QC Criteria: December 20, 2022
• First Posted (Actual): December 30, 2022

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: hepatocellular carcinoma; Phenotypic Personalized Medicine
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Topoisomerase I Inhibitors; Sorafenib; Irinotecan
• Other Study ID Numbers: UF-GI-015; OCR43006 (Other Identifier: University of Florida)

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