Clinical trial NCT02174549: Dose-defining Study of Tirapazamine Combined With Embolization in Liver Cancer
Official title: Phase I Dose-Escalating Study of Combining Intravenous Tirapazamine and Transarterial Embolization (TAE) in Liver Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Gastrointestinal Cancer Metastatic
Neuroendocrine Tumors
Keywords: Hypoxia
Embolization
Tirapazamine
Lead sponsor: Teclison Ltd.
Sponsor class: INDUSTRY
First posted: 2014-06-25
Enrollment: 25
Sex: ALL
Minimum age (years): 20
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label, dose escalation 3+3 design completed; now only for expansion cohort in neuroendocrine tumor.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response rate (ORR) by RECIST
timeFrame: 2 years
Secondary outcomes:
measure: Overall Response Rate
timeFrame: 2 years
measure: Duration of Response
timeFrame: 2 years
Other outcomes:
measure: Response Rate in TATE-treated target lesions
timeFrame: 2 years
measure: Progressive Free Survival
timeFrame: 2 years
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Univ. of Pennsylvania
name: Michael Soulen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.