Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma

Abstract

Background: Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II.

Methods: This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria.

Results: Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m² I.V. and 20 mg/m² I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions.

Discussion: TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.

Keywords: hepatocellular carcinoma; hypoxia activated agent; image guided locoregional therapies; phase I trial; transarterial chemoembolization.

Figure 1

Flow chart of patients.

Figure 2

(A) Waterfall plot of best target lesion response. (B) Waterfall plot for best target lesion response for tumors greater than 5 cm. The results are shown per mRECIST criteria and color-coded by dose cohort.

Figure 3

73-year-old female with new large liver lesion. The patient had an AFP of 6,000, history of lymphoma in remission for over 5 years, diabetes, and obesity. Since the lesion did not show avid arterial enhancement and the patient lacked HCC risk factors as well as the history of lymphoma, a biopsy was performed and demonstrated grade ¾ hepatocellular carcinoma. (A) Post-contrast coronal magnetic resonance imaging demonstrating washout of the large lesion in hepatic segments 5 and 8. (B) The embolization with navigation. The tumor feeding vessels are determined by software with input of the operator. The tumor is segmented as seen with meshed and teal outlines. (C) Coronal post-contrast magnetic resonance imaging at first follow-up post-procedure demonstrating no enhancement and significant reduction in size. (D) 20 months follow-up post-initial procedure showing a continued decrease in size of the treated lesion and no new lesions.

Figure 4

Details the best percentage change from baseline in the target lesion size as a function of the baseline target lesion volume by cm³.

Figure 5

(A) Kaplan–Meier curve of progression free survival by mRECIST. (B) Kaplan–Meier curve of progression free survival by RECIST. Median PFS and 95% CI are provided in each case.

Figure 6

Kaplan–Meier with the overall survival with median and 95% CI.

Figure 7

69-year-old male with history of hepatitis C and newly discovered biopsy proven HCC, AFP was 2.1. Two lesions were present, one in the right lobe and one in the left lobe (not shown). (A) Axial arterial phase MRI demonstrated arterially enhancing lesion measuring 5.1 cm. (B) Delayed coronal phase MRI demonstrates capsular enhancement. (C) Axial MRI obtained 6 months after the procedure demonstrating no enhancement and decrease in lesion size. (D) Axial venous phase MRI 18 months post-treatment demonstrates continued lesion size decrease, and no enhancement was seen on arterial (now shown) or delayed phases.

Figure 8

65-year-old male with history of alcohol and non-steatohepatitis with biopsy proven HCC and AFP 6.9. (A) An axial delayed phase MRI which demonstrates a large lesion with capsule (biopsy proven) measuring 51 mm in segment 4B at the portal bifurcation. The patient also had a second lesion in segment 5 measuring 17 mm (not shown). (B) Axial subtraction arterial phase MRI demonstrating the lesion with mild enhancement. (C) The arterial phase MRI without subtraction. The lesion is hypo-enhancing. (D) Fluoroscopy imaging during the embolization showing the lesion segmented (blue), the second lesion is seen in teal. (E) An axial image of a subtraction arterial phase MRI obtained 9 months after the embolization with TPZ showing a significant decrease in size in the segment 4B lesion at the portal bifurcation. There is no enhancement. The second lesion also showed complete response. (F) is an axial image of the same arterial phase MRI without subtraction depicting the decreased size of the lesion without any enhancement.