Dose-defining Study of Tirapazamine Combined With Embolization in Liver Cancer

Phase I Dose-Escalating Study of Combining Intravenous Tirapazamine and Transarterial Embolization (TAE) in Liver Cancer

This phase 1 study is to determine the optimal dose and tolerability of a hypoxia-activating agent, tirapazamine, when it is combined with embolization in liver cancer. Liver cancer patients who are Child-Pugh score A, suitable for embolization with tumor no more than 4 nodules are eligible. Tirapazamine will be given by intra-arterial injection before embolization. Treatment effect is evaluated by MRI based on mRECIST criteria. Repeat treatment is necessary only if disease progression. Dose escalation cohort has been completed. Expansion cohort is open for metastatic liver dominant neuroendocrine tumor.

Study Overview

• Status: Active, not recruiting
• Conditions: Hepatocellular Carcinoma; Neuroendocrine Tumors; Gastrointestinal Cancer Metastatic
• Intervention / Treatment: Drug: Tirapazamine; Procedure: Conventional Transarterial Embolization (TAE)

Detailed Description

The study is a 3+3 design for dose escalation. Each cohort will have 3-6 patients based on tolerability. Patients will receive escalated doses of tirapazamine until maximally tolerated dose. Embolization is performed per standard practice using Lipiodol and Gelfoam under X-ray guidance. Once a suitable dose is determined, an expansion cohort of 15 patients will be treated with the recommended phase 2 dose to determine preliminary efficacy. Expansion cohorts include (1) hepatocellular carcinoma, (2) metastatic solid tumors with liver metastasis, and (3) neuroendocrine tumor. Adverse events are evaluated by CTCAE vs. 5.0 and efficacy is evaluated by MRI using modified RECIST criteria and RECIST criteria.

The dose escalation part has been completed. Only the third cohort or neuroendocrine tumor remains active for future patient enrollment.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with well-differentiated NET and liver-dominant metastatic disease with intrahepatic disease progression, regardless of primary tumor origin or tumor functional status. Patients may have extrahepatic lesions as long as the majority of the disease burden is intrahepatic.
2. No limitation in hepatic lesion tumor size or number but the total volume of liver tumors cannot exceed 50% of the liver volume.
3. Patients are allowed to have prior US Food and Drug Administration (FDA)-approved treatments, including systemic therapies, surgery, ablation, or transarterial therapies for the metastatic NET.
4. Age 20 or higher, ECOG functional status 0-1, and with no known major cardiac, pulmonary, or renal dysfunction.
5. Are candidates for TAE or TACE and without portal vein occlusion per treating interventional radiologists.
6. ANC no less than 1000 /μL. Hemoglobin ≥ 9 gm/dL. Platelets no less than 50,000 /μL. Creatinine no more than 2.0 mg/dL. AST, ALT no more than 5X upper limit of normal. Bilirubin no more than 2.5 mg/dl. PT prolongation ≤ 4 sec above upper limit of normal.
7. Woman of child-bearing potential (WOCBP) should use highly effective contraception during trial participation and for 6 months after the last dose of tirapazamine and men who are partners with WOCBP should use highly effective contraception, including barrier contraception, during trial participation and for 3 months after the last dose of tirapazamine.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirapazamine; Intra-arterial administration with tirapazamine before embolization to evaluate the response in metastatic liver lesions of NET	Drug: Tirapazamine; Intra-arterial injection into the tumor feeding artery; Procedure: Conventional Transarterial Embolization (TAE); Lipiodol and Gelfoam used to embolize tumor vessels and induce tumor hypoxia; Other Names: TAE conducted with Lipiodol and Surgifoam as the embolizing agents.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response rate (ORR) by RECIST	Overall Response Rate by RECIST criteria	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall Response Rate by mRECIST criteria	2 years
Duration of Response	Duration of Response by RECIST and mRECIST	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate in TATE-treated target lesions	by mRECIST and RECIST	2 years
Progressive Free Survival	by RECIST and mRECIST	2 years

Collaborators and Investigators

• Sponsor: Teclison Ltd.
• Investigators: Principal Investigator: Michael Soulen, MD, Univ. of Pennsylvania

Publications and helpful links

General Publications

• Abi-Jaoudeh N, Dayyani F, Chen PJ, Fernando D, Fidelman N, Javan H, Liang PC, Hwang JI, Imagawa DK. Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma. J Hepatocell Carcinoma. 2021 May 17;8:421-434. doi: 10.2147/JHC.S304275. eCollection 2021.

Helpful Links

• Phase 1 dose escalation result in Hepatocellular carcinoma

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 10, 2014
• First Submitted That Met QC Criteria: June 23, 2014
• First Posted (Estimated): June 25, 2014

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 19, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Hypoxia; Embolization; Tirapazamine
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Gastrointestinal Neoplasms; Liver Neoplasms; Neuroendocrine Tumors; Antineoplastic Agents; Tirapazamine
• Other Study ID Numbers: LT001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO