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

• ClinicalTrials.gov Identifier: NCT02174549
• Recruitment Status: Active, not recruiting
• First Posted: June 25, 2014
• Last Update Posted: May 2, 2022
• Sponsor: Teclison Ltd.
• Information provided by (Responsible Party): Teclison Ltd.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma; Gastrointestinal Cancer Metastatic; Neuroendocrine Tumors	Drug: Tirapazamine; Procedure: Transarterial embolization (TAE)	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open label, dose escalation 3+3 design; 3 expansion cohorts: hepatocellular carcinoma, advanced solid tumors and neuroendocrine tumor.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Dose-Escalating Study of Combining Intravenous Tirapazamine and Transarterial Embolization (TAE) in Liver Cancer
• Study Start Date: September 2014
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tirapazamine; Administration with dose escalated tirapazamine before embolization until maximally tolerated dose achieved.	Drug: Tirapazamine; Intra-arterial injection into the tumor feeding artery; Procedure: Transarterial embolization (TAE); Lipiodol and Gelfoam used to embolize tumor vessels and induce tumor hypoxia; Other Name: Lipiodol and Gelfoam as the standard embolizing agents.

Outcome Measures

Primary Outcome Measures :

1. determine the recommended phase 2 dose [ Time Frame: 2 years ]
   future dose used for randomzied trials

Secondary Outcome Measures :

1. Complete Response (CR) rate [ Time Frame: 2 years ]
   mRECIST based on mRECIST
2. Duration of response [ Time Frame: 2 years ]
   From randomization to progression

Other Outcome Measures:

1. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 2 years ]
   PK parameter

Eligibility Criteria

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

Criteria

• Confirmed diagnosis of HCC > 10 mm with a characteristic 4-phase CT or dynamic contrast enhanced MRI finding showing intense arterial uptake followed by "washout" of contrast in the venous-delayed phases per American Association for the Study of Liver Disease (AASLD) criteria.
• Patients between ages 20 and 80
• Patients with single or multiple (2-4 nodules) HCC who are unsuitable or unwilling for surgical resection or RFA. The largest tumor nodule should be less than 10 cm in the largest diameter. The total volume of tumor cannot exceed 50% of liver; or patients with liver metastatic gastrointestinal cancer, including neuroendocrine tumor
• Patients are candidates for TAE or Transarterial ChemoEmbolization (TACE). No tumor invasion to portal vein or thrombosis in portal vein.
• ECOG score 0-1 with no known cardiac, pulmonary or renal dysfunction
• Child-Pugh score group A or B7 liver functional score
• Prior local therapies such as surgical resection, radiofrequency ablation, or alcohol injection are allowed as long as tumor progresses from the prior treatment and the patients are still candidates for TAE. All prior therapy must be at least 4 weeks prior to enrollment and free from treatment-related toxicity.
• No TAE/TACE in the past
• Patients have normal organ function: ANC ≥ 1000 /µL, Hemoglobin ≥ 9 gm/dL, Platelets ≥ 50,000 /µL, Creatinine ≤ 2 mg/dL, AST and ALT < 5 X upper normal limit of the current institution; bilirubin ≤ 3.0 mg/dL, PT prolongation no more than 4 sec above upper limit of normal.

For the expansion cohort of neuroendocrine tumor or metastatic solid tumor with liver involvement

• Unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), neuroendocrine tumors (NET).
• Metastatic solid tumor with liver involvement.

Contacts and Locations

Locations

United States, California

University of California Irvine Medical Center

Orange, California, United States, 92868

Univ. of California, San Francisco

San Francisco, California, United States, 94143

Sponsors and Collaborators

Teclison Ltd.

Investigators

• Principal Investigator: Nadine Abi-Jaoudeh, MD; Univ. of California, Irvine

More Information

• Responsible Party: Teclison Ltd.
• ClinicalTrials.gov Identifier: NCT02174549
• Other Study ID Numbers: LT001
• First Posted: June 25, 2014
• Last Update Posted: May 2, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Teclison Ltd.:

Hypoxia; Embolization; Tirapazamine

Additional relevant MeSH terms:

Liver Neoplasms; Neuroendocrine Tumors; Gastrointestinal Neoplasms; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Gastrointestinal Diseases; Tirapazamine; Antineoplastic Agents