A Phase III Study in Post-operative HBV-related Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

A Randomization Trial of Adjuvant Lamivudine/ Adefovir Dipivoxil Against Recurrence in Post-operative HBV-related Hepatocellular Carcinoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00455091
• Other study ID #: T1206
• Status: Terminated
• Phase: N/A
• First received: April 2, 2007
• Last updated: April 26, 2017
• Start date: May 2007
• Est. completion date: April 2018

Study information

• Verified date: June 2009
• Source: National Health Research Institutes, Taiwan
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Research Objective and Study End Points To evaluate the anti-HBV as well as HCC recurrence reducing effects of standard (18 months) lamivudine treatment at time of HBV reactivation with hepatitis flare up (HBV DNA > 105 copies/mL and ALT level > 2.0 x UNL) or prophylactic, prolong (36 months) adefovir dipivoxil therapy in post-operative HBsAg(+),< 5 cm HCC patients, and to compare the results of who group with historical controls (T1297, HBsAg+,< 5 cm HCC cohort),in terms of the following endpoints.

1. Primary endpoint:

the 3-years recurrence rate (excluding those recur within first year).

2. Secondary endpoints:

the first 2 year tumor recurrence rates the recurrence-free survival the overall survival. anti-viral efficacy, i.e. biochemical response and viral response rate. to correlate the changes of viral titer with the clinical outcome in post- operative HCC patients with adjuvant lamivudine or adefovir therapy.

Description:

Treatment plan and Randomization scheme:

HBsAg+, HCC< 5 cm with curative resection Stratified with HBV DNA < 105 OR ≥ 105 copies/mL Genotype B or C RANDOMIZATION Prophylactic group Therapeutic control group Adefovir Dipivoxil 10mg/day x 36 months Lamivudine 100 mg/day x 18 months#, when HBV DNA =/> 105 copies/mL and ALT > 2.0 x UNL

• When YMDD mutant present, switch to Adefovir dipivoxil 10mg/day x 24 months. Selection of patients

1. Eligibility Criteria (1)Histologically proven hepatocellular carcinoma. (2)HCC underwent curative resection within 6 weeks before registration. (3)Grossly, the resection margin should be > 1 cm. (4)Tumors, either single, < 5 cm in size or no more than 3 for size < 3 cm. (5)Patients must have a performance status of ECOG score < 2. (6)Patients must have adequate liver reservation and adequate hemogram. (i)Pugh-Child's Score < 7. (ii)The serum total bilirubin level are < 2 mg/dl. (iii)The prothrombin times are < 3 sec above normal control. (iv)The platelet are > 7.5 x 104 / mm3. (v)The WBC are > 3,000 / mm3. (7)Patient must have serum creatinine < 1.5 mg/dl (8)Cardiac function with NYHA classification < Grade II (9)HBsAg (+) . (10)Signed informed consent.

2. Ineligibility Criteria

1. Patients who have non-curative resection are not eligible.

2. Resected HCCs with histologically positive margins are not eligible.

3. HCCs with radiological evidence of portal vein thrombus are not eligible.

4. Patients with other systemic diseases which required concurrent usage of glucoticosteroid or immunosuppressant agent(s) are not eligible.

5. Patients with advanced second primary malignancy are not eligible.

6. Patients with pregnancy or breast-feeding are not eligible.

7. Patients with severe cardiopulmonary diseases are not eligible.

8. Patients with clinically significant psychiatric disorder are not eligible.

9. Patients who had antineoplastic chemotherapeutic or immuno-therapeutic drugs or corticosteroids within 6 weeks of commencing the protocol are not eligible.

10. Patients who had prior lamividine and/or adefovir dipivoxil therapy are not eligible.

11. Anti-HCV positive patients are not eligible. Statistical Consideration

Sample size:

With a phase III superior study design, to give an 80% power with a two-sided 5% significance level, 139 patients per each treatment arm should be included in the study. If a 10% drop-out rate is included, totally, 309 patients (155 per study arm) will be required.

Analysis

The objectives are as follows:

1.Primary endpoint: the 3-year recurrence rate (excluding those recur within 1st year)

1. Second endpoints the recurrence-free survival.

2. Second endpoints: the overall survival.

3. Second endpoints: anti-viral efficacy, in terms of sustained biochemical response rate and viral response rate. To correlate the changes of viral titer with the clinical outcome 2 RFS and OS are computed from the date of randomization.

(1) In analysis of RFS, patients died without disease recurrence will be censored for recurrence at the date of death (2) In analysis of OS, an event is defined as death from any cause. (3) The survival distributions of RFS and OS will be estimated by the Kaplan and Meier method.

(4) Statistical comparisons of RFS and OS between the two treatment arms will be performed with the log-rank test.

(5) Cox proportional hazards model will be used to assess the importance of potential prognostic factors, as well as to test the significance of treatment when adjusting for factors [39].

3.Tumor size, Liver inflammation, viral status, i.e. HBV genotype and DNA titer

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 117
• Est. completion date: April 2018
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Histologically proven hepatocellular carcinoma.

2. HCC underwent curative resection within 6 weeks before registration.

3. Grossly, the resection margin should be > 1 cm.

4. Tumors, either single, < 5 cm in size or no more than 3 for size < 3 cm.

5. Patients must have a performance status of ECOG score < 2.

6. Patients must have adequate liver reservation and adequate hemogram.

• Pugh-Child's Score < 7.

• The serum total bilirubin level are < 2 mg/dl.

• The prothrombin times are < 3 sec above normal control.

• The platelet are > 7.5 x 104 / mm3.

• The WBC are > 3,000 / mm3.

7. Patient must have serum creatinine < 1.5 mg/dl

8. Cardiac function with NYHA classification < Grade II

9. HBsAg (+) .

10. Signed informed consent.

Exclusion Criteria:

1. Patients who have non-curative resection are not eligible.

2. Resected HCCs with histologically positive margins are not eligible.

3. HCCs with radiological evidence of portal vein thrombus are not eligible.

4. Patients with other systemic diseases which required concurrent usage of glucoticosteroid or immunosuppressant agent(s) are not eligible.

5. Patients with advanced second primary malignancy are not eligible.

6. Patients with pregnancy or breast-feeding are not eligible.

7. Patients with severe cardiopulmonary diseases are not eligible.

8. Patients with clinically significant psychiatric disorder are not eligible.

9. Patients who had antineoplastic chemotherapeutic or immuno-therapeutic drugs or corticosteroids within 6 weeks of commencing the protocol are not eligible.

10. Patients who had prior lamividine and/or adefovir dipivoxil therapy are not eligible.

11. Anti-HCV positive patients are not eligible.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Adefovir Dipivoxil and Lamivudine
Adefovir Dipivoxil 10mg/day x 36 months,Lamivudine 100 mg/day x 18 months#, when HBV DNA =/> 105 copies/mL and ALT > 2.0 x UNL

Locations

Country	Name	City	State
Taiwan	Chang-Gung Memorial Hospital	Kaohsiung
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Veterans General Hospital-Kaohsiung	Kaohsiung
Taiwan	Chang-Gung Memorial Hospital (Lin-Kou)	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Veterans General Hospital-Taipei	Taipei

Sponsors (10)

Lead Sponsor	Collaborator
National Health Research Institutes, Taiwan	Chang Gung Memorial Hospital, Changhua Christian Hospital, Kaohsiung Medical University, Kaohsiung Veterans General Hospital., Mackay Memorial Hospital, National Cheng-Kung University Hospital, National Taiwan University Hospital, Taichung Veterans General Hospital, Taipei Veterans General Hospital, Taiwan

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary endpoint: Primary endpoint: the 3-years recurrence rate (excluding those recur within first year).		6 years
Secondary	Secondary endpoints: the first 2 year tumor recurrence rates,the recurrence-free survival,the overall survival.anti-viral efficacy.		7 years