The Safety and Maximum Tolerated Dose of Axitinib in Combination With Radiotherapy for HCC

A Phase I Clinical Trial Evaluating the Safety and Maximum Tolerated Dose of Axitinib in Combination With Radiotherapy for Advanced Hepatocellular Carcinoma (HCC)

To determine the maximal tolerated dose (MTD) of axitinib in combination with RT for advanced HCC.

Study Overview

• Status: Completed
• Conditions: Advanced Hepatocellular Carcinoma (HCC)
• Intervention / Treatment: Drug: Axitinib; Radiation: Radiation

Detailed Description

The goal of this study is to conduct a phase I clinical trial evaluating the safety and MTD of axitinib in combination with RT for advanced HCC. There are some rationales of conducting this clinical trial. Firstly, there is evidence of benefit from the combination of a variety of anti-angiogenic agents with RT at the pre-clinical level. Numerous pre-clinical models have documented improved outcome with the combination of RT (e.g. bevacizumab ... etc). Potential increasing the oxygenation of tumors with anti-angiogenesis is also expected to improve the therapeutic ratio of radiation therapy to hypervascular caner like HCC. Secondly, spatial cooperation may exist between local treatment (e.g. RT) and systemic therapy (e.g. axitinib). From the experience of sorafenib, the majority of patients eventually progress within the liver and die of liver failure, providing rationale to use local therapies like RT. On the other hand, from the experience of RT, the most common site of first recurrence was in the liver outside the irradiated volume, providing rationale for studies combining regional or systemic therapies with RT. Thirdly, clinical experiences with RT and anti-angiogenic agent are few but still exist with encouraging results. For example, one retrospective review from Taiwan with advanced HCC treated with RT and sunitinib (a TKI with similar mechanisms as sorafenib) reported objective response rate of 74% and a median survival of 16 months, and concluded hypofractionated RT and sunitinib can be delivered safely in HCC patients, which was compatible with the result of several phase I or II studies using sorafenib plus. Fourthly, the safety and MTD of axitinib combined with RT is needed to be established before launch of a phase II study

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 11101
    • Shin Kong Wu Ho-Su Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age of 20-85 years, with ECOG performance 0-2.
• Advanced hepatocellular carcinoma (HCC), histologically or clinically diagnosed. (Multiple tumors, portal vein thrombosis, nodal metastasis or distant metastasis is allowed.)
• Unsuitable for resection, liver transplantation, radiofrequency ablation (RFA) or transarterial chemoembolization (TACE), or recurrent / refractory after prior local-regional treatment.
• ≥ One measurable tumor.
• Child-Pugh score A or B.

• Patients who fulfill all of the following criteria:

  1. Serum total bilirubin ≤ 3 mg/dL
  2. Serum alanine transaminase (ALT) ≤ 5 times ULN
  3. INR ≤ 2.20
  4. Platelet count ≥ 50,000 /mm3
  5. WBC count ≥ 3,000 /mm3 or ANC ≥ 1,500 /mm3
  6. Serum creatinine ≤ 2.0 mg/dL
• Normal thyroid function confirmed.
• Absence of grant for sorafenib.
• Sorafenib failure or intolerability (if ever used).

Exclusion Criteria:

• Considered to have high risk of bleeding (e.g. active peptic ulcer, unstable esophageal/gastric varices, history of aneurysm, and requirement of anticoagulant therapy).
• Pre-existing uncontrolled hypertension (systolic >140 mmHg, diastolic >90 mmHg) or proteinuria ≧500 mg/24 hours.
• Prior history of coronary artery disease.
• The patient is participating in other clinical trials.
• Pregnant women.
• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
• Patients with non-healing wound.
• Requiring the use of potent CYP3A4/5 inhibitors or inducers (see Appendix).
• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation and in the judgment of the investigator would make the patient inappropriate for entry into this study.

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: Axitinib; Combined axitinib and radiotherapy (fixed strength)

Drug: Axitinib; Axitinib (dose escalation): for total 8 weeks during and after RT, with starting dose of 1mg BID. According to the rule of traditional 3 + 3 design, 3-level axitinib dose escalation will be conducted: 1mg BID (level - I), 2mg BID (level - II) and 3mg BID (level - III).; Other Names: Inlyta; Radiation: Radiation; Radiotherapy (RT) dose (fixed strength for normal liver): 37.5 to 67.5 Gy in 15 fractions (2.5 to 4.5 Gy per fraction) to liver tumor(s) (e.g. portal vein thrombosis, tumors with size ≥3 cm, or recurrent/refractory tumors). The final prescribed dose is based on an upper limit of mean liver dose of 18 Gy for all plans. (Daily Entecavir 0.5-1mg or Telbivudine 600mg is recommended for patients with positive hepatitis B during and 3 months after RT.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The maximal tolerated dose (MTD)	To determine the maximal tolerated dose (MTD) of axitinib in combination with RT for advanced HCC.	Within 12 weeks

Collaborators and Investigators

• Sponsor: Shin Kong Wu Ho-Su Memorial Hospital

Publications and helpful links

General Publications

• Yang KL, Chi MS, Ko HL, Huang YY, Huang SC, Lin YM, Chi KH. Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial. Radiat Oncol. 2021 Jan 20;16(1):18. doi: 10.1186/s13014-020-01742-w.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): November 1, 2018

Study Registration Dates

• First Submitted: June 23, 2016
• First Submitted That Met QC Criteria: June 24, 2016
• First Posted (Estimate): June 27, 2016

Study Record Updates

• Last Update Posted (Actual): September 23, 2019
• Last Update Submitted That Met QC Criteria: September 19, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• 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; Protein Kinase Inhibitors; Axitinib
• Other Study ID Numbers: 20150704M

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED