Ignite Creation Date:
2024-05-05 @ 11:50 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00149565
Status:
COMPLETED
Last Update Posted:
2005-12-16
First Post:
2005-09-07
Brief Title:
Phase Ⅲ Randomized Trial in Postoperative Hepatocellular Carcinoma
Sponsor:
National Health Research Institutes Taiwan
Organization:
National Health Research Institutes Taiwan
Study Overview
Official Title:
Hepatocellular Carcinoma Postoperative Adjuvant Therapy Disease Committee of Taiwan Cooperative Oncology Group
Status:
COMPLETED
Status Verified Date:
2004-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
OBJECTIVES
1 To investigate whether adjuvant IFN-α therapy can delay or reduce the 2-5 years recurrence rate in curatively resected HCC
2 To examine whether adjuvant IFN-α therapy can prolong the disease-free survival in curatively resected HCC
3 To determine the safety and tolerance of adjuvant IFN-α therapy in postoperative HCC with or without cirrhosis
4 To investigate the change of activity of HBV and HCV in postoperative HCC patients with adjuvant IFN-α therapy
5 To correlate the changes of viral status with the clinical outcome in post-operative HCC patients with adjuvant IFN-α therapy
1 To investigate whether adjuvant IFN-α therapy can delay or reduce the 2-5 years recurrence rate in curatively resected HCC
2 To examine whether adjuvant IFN-α therapy can prolong the disease-free survival in curatively resected HCC
3 To determine the safety and tolerance of adjuvant IFN-α therapy in postoperative HCC with or without cirrhosis
4 To investigate the change of activity of HBV and HCV in postoperative HCC patients with adjuvant IFN-α therapy
5 To correlate the changes of viral status with the clinical outcome in post-operative HCC patients with adjuvant IFN-α therapy
Detailed Description:
1 TREATMENT PLAN
11 Eligible patients are randomized to receive adjuvant IFN-α for 53 wks or 12 Administration of IFN-α 121 IFN-α will be started after randomization 122 IFN-α will be administered by subcutaneous injection at the bed time 123 Escalation of IFN-α dosage 1231 During the first 2 days 1 x 106 uday will be given 1232 If tolerable the dose of IFN-α will be escalated to 3 x 106 uday in days 3 and 4 and to 5 x 106 uday at day 5
124 After dose escalation IFN-α 5 x 106 uday will be given in the following ways 1241 induction therapy 5 times per week for the first 4 weeks followed by 1242 maintenance therapy 3 times per weeks for additional 48 weeks 125 Modification of IFN-α dosage 1251 In the presence of any moderate adverse events as listing in Appendix II it required a dose reduction to 3 x 106 uday
12511 If any moderate adverse events occur at the 3 x 106 uday level the patients will be withdraw from the study 1252 In the presence of any severe adverse events as listing in Appendix II it requires immediate discontinuation of therapy 12521 IFN-α will be discontinued until a return to baseline or moderate toxicity Then IFN-α will be reinstituted at the dose level of 3 x 106 uday 12522 If moderate or severe adverse events occur at the 3 x 106 uday level the patients will be withdraw from the study
1253 Flare-up of hepatitis activity as manifested by increment of serum transaminase per se is not an indication for dose modification 1254 If symptomssigns SS of hepatic decompensation occur after the presence of ALT flare-up during IFN-α therapy the drug will be held
12541 The presence of two of following five criteria is considered as evidence of hepatic decompensation 125411 Presence of ascites 125412 Presence of hepatic encephalopathy 125413 hypoalbuminemia with serum albumin 3 gdl 125414 hyperbilirubinemia with serum bilirubin 3 mgdl 125415 Prolongation of prothrombin time with PT 2 sec above base-line 12542 Serial workup have to be taken to rule out the presence of other predisposing factor such as spontaneous bacterial peritonitis constipation electrolyte imbalanceect to cause the SS of hepatic decompensation If any start specific treatment
12543 If SS of hepatic decompensation recovered with a return of serum ALT to 15 times upper limit of normal range IFN-α will be restarted at the level of 3 x 106 uday and escalated to 5 x 106 uday within 1 week
12544 If SS of hepatic decompensation recovered with persistent elevation of serum ALT 15 times upper limit of normal range IFN-α will be given and maintained at the level 3 x 106 uday 3 times per week
12545 After excluding other specific etiologies and SS of hepatic decompensation persist longer than 4 weeks patients will be withdrawn from the study
12546 Recurrent episodes of hepatic decompensation will be considered as severe adverse events and managed as listing in section 5252
1255 If symptomssigns SS of hepatic decompensation occur in the absence of ALT flare-up the patients will be managed as listing in section 5252
1256 In the presence of severe bacterial infection such as bacterial peritonitis bacterial pneumonia and etc IFN-a will be held until resolution of infection after adequate antibiotics therapy Then the patients will be managed as listing in section 5252
126 Before IFN-α if necessary patients will be pretreated with acetaminophen 500 - 1000 mg q 6 hours for 4 doses started 12 hours before IFN-α administration to alleviate the associated flu-like symptoms
13 Adverse Drug Reaction ADR Reports 131 Any life threatening andor unexpected and serious grade 3 or 4 toxicity will be reported within 48 hours to the principal investigator Li-Tzong Chen MD Cancer Clinical Research Center National Health Research Institutes A191 Ward Veteran General Hospital Taipei 201 Shih-Pai Road Sec 2 Taipei 112 Taiwan Tel886-2-8712121-2737 Fax 886-2-8716467 andor Per-Jei Chen MD PhD Department of Internal Medicine National Taiwan University Liver Disease Research Center National Taiwan University Hospital Tel 886-2-3970800-7072 Fax 886-2-3317624 The initial contact should be made by calling the Coordinate Center of TCOGat 886-2-7852459 A written report will follow within 7 working days
132 A written report will be submitted within 7 working days describing any life-threatening or lethal grade 4 or 5 known reactions except for grade 4 myelosuppression and any grade 2 or 3 unknown reactions The address for submitting ADR reports is Coordinate Center of TCOG National Health Research Institutes in Biomedical Science Academia Sinica Taipei Taiwan
133 Above toxicity grading is according to the ECOG toxicity criteria Appendix III
20 Evaluation
The following tests should be performed within 2 weeks before the initiation of therapy as the baseline data and then repeated as request following the initiation of therapy
21 Physical examination and comprehensive history are recorded bi-weekly during induction period first month and monthly during maintenance therapy for one year After first year patients will be followed bi-monthly After 6 years patients will be followed 3 monthly
22 Complete blood count and liver functional tests bilirubin directindirect ASTALT and alkaline phosphatasegGT albumin AC sugar will be checked bi-weekly during induction period first month and monthly during maintenance therapy for one year After first year patients will be followed bi-monthly After 6 years patients will be followed 3 monthly
23 Chest PA every 4 months for one year and then every 6 months 24 ECG for those with history of cardiac disease at time of symptom recurrence
25 a-fetoprotein will be checked monthly for one year and then bi-monthly After 6 years patients will be followed 3 monthly
26 Abdominal sonography every 2 months After 6 years patients will be followed 3 monthly
27 Abdominal computed tomography performed every 12 months or whenever abdominal sonography shows suspicious recurrent lesions
28 Any suspicious lesion found on abdominal sonography andor computed tomography should undergo angiography and sono-guided biopsy for histological examination
29 UGI endoscopy at the time of UGI bleeding or dyspepsia CANCEAL 291 Preoperative endoscopy is acceptable as the base-line data CANCEAL 210 Bone scan at the time of symptoms suggest the occurrence of bony metastases
211 Serum for HBV and HCV status study collected bi-monthly 212 HBeAg and anti-HBe will be checked every 4 months in those with HBeAg After 6 years patients will be followed 6 monthly
213 HBsAg will be checked every 6 months in those with HBsAg
30 Off-study Criteria 31 Development of a serious medical condition which makes administration of IFN-α life threatening
311 Patients present with SS of hepatic decompensation should be managed as list in sections 52544 and 52545
312 as those listed in 52511 and 52522 32 Occurrence of tumor recurrence 33 Non-compliance by a patient with protocol requirement 34 Patient refusal further therapy 35 Patient death 36 Interruption of IFN-α therapy 4 weeks
40 Statistical Consideration 41 Sample size Review of literatures showed that the 2-year survival rate of post-operative HCC was 25 to 60 7-14 We estimate that adjuvant IFN-α can improve the 2-year survival rate from 50 to 70 According to the methods of Casagrande et al129 to give a 90 power for detecting the increase of 20 for a two-sided statistical significance test 134 patients for each of the two treatment arms are needed 42 Randomization Patients are stratified into two strata one with HBsAganother with HBsAg- but with anti-HCV Randomization of patients into control or treatment group is taken within each stratum Balanced block sizes of two strata for randomization are different 43 Analysis 431 The primary objectives are as follows 4311 To determine if adjuvant IFN-α can reduce or delay the occurrence in curatively resected HCC 4312 To determine if adjuvant IFN-α prolong disease-free survival DFS andor overall survival OS in curatively resected HCC 4313 To determine the safety and tolerance of IFN-αin post-operative HCC patients 4314 To evaluate the anti-viral activity of IFN-α in post-operative HCC patients 432 DFS and OS are computed from the date of randomization 4321 In analysis of DFS patients died without disease recurrence will be censored for recurrence at the date of death 4322 In analysis of OS an event is defined as death from any cause 4323 The survival distributions of DFS and OS will be estimated by the Kaplan and Meier method 130 4 4324 Statistical comparisons of DFS and OS between the two treatment arms will be performed with the log-rank statistic 131 4325 Cox proportional hazards model 132 will be used to assess the importance of potential prognostic factors as well as to test the significance of treatment when adjusting for factors 433 Tumor size Liver inflammation viral status such as HBsAg anti- HCVand
Patients Specific Factor
Performance status Age Sex Family history of HCC and liver diseases Esophageal varices Prior Hx of esophageal varices bleeding Serum ALT SGPT level Serum albumin level Pre-operative serum α-FP level
Underlying Liver Diseases Specific Factors
HBsAg by RIA HBeAg by RIA anti-HBc anti-δ antibody anti-HCV antibody Severity of underlying liver disease in nontumor portion Concurrent management of esophageal varices
Tumors Specific Factors
Presence of capsule Tumor type Venous invasion Tumor size the largest in multiple lesions Histological grading will be treated as potential prognostic factors
44 Interim Analysis The interim analyses will be conducted according to the alpha spending function approach proposed by DeMets and Lan 1994 which provides flexibility about the time for interim analysis The a1 spending function which generates the approximate OBrien-Fleming boundaries OBrien and Fleming 1979 will be used for a conservation termination at the early stage of the study In addition the method of B-value developed by Lan and Wittes 1988 Li 1998 will be used to monitor the data and to compute the conditional probability of detecting either a positive or negative treatment effect at the scheduled end of the study given the present status The primary efficacy endpoint for the interim analyses is the time to occurrence of second primary tumors The toxicity will be monitored constantly throughout the study The conduct of interim analyses and dissemination of the results of the interim analysis will follow the TCOG Data and Safety Monitoring guidelines for confidentiality The TCOG Data and Safety Monitoring Committee will review the results of interim analyses for a possible early termination of the trial
11 Eligible patients are randomized to receive adjuvant IFN-α for 53 wks or 12 Administration of IFN-α 121 IFN-α will be started after randomization 122 IFN-α will be administered by subcutaneous injection at the bed time 123 Escalation of IFN-α dosage 1231 During the first 2 days 1 x 106 uday will be given 1232 If tolerable the dose of IFN-α will be escalated to 3 x 106 uday in days 3 and 4 and to 5 x 106 uday at day 5
124 After dose escalation IFN-α 5 x 106 uday will be given in the following ways 1241 induction therapy 5 times per week for the first 4 weeks followed by 1242 maintenance therapy 3 times per weeks for additional 48 weeks 125 Modification of IFN-α dosage 1251 In the presence of any moderate adverse events as listing in Appendix II it required a dose reduction to 3 x 106 uday
12511 If any moderate adverse events occur at the 3 x 106 uday level the patients will be withdraw from the study 1252 In the presence of any severe adverse events as listing in Appendix II it requires immediate discontinuation of therapy 12521 IFN-α will be discontinued until a return to baseline or moderate toxicity Then IFN-α will be reinstituted at the dose level of 3 x 106 uday 12522 If moderate or severe adverse events occur at the 3 x 106 uday level the patients will be withdraw from the study
1253 Flare-up of hepatitis activity as manifested by increment of serum transaminase per se is not an indication for dose modification 1254 If symptomssigns SS of hepatic decompensation occur after the presence of ALT flare-up during IFN-α therapy the drug will be held
12541 The presence of two of following five criteria is considered as evidence of hepatic decompensation 125411 Presence of ascites 125412 Presence of hepatic encephalopathy 125413 hypoalbuminemia with serum albumin 3 gdl 125414 hyperbilirubinemia with serum bilirubin 3 mgdl 125415 Prolongation of prothrombin time with PT 2 sec above base-line 12542 Serial workup have to be taken to rule out the presence of other predisposing factor such as spontaneous bacterial peritonitis constipation electrolyte imbalanceect to cause the SS of hepatic decompensation If any start specific treatment
12543 If SS of hepatic decompensation recovered with a return of serum ALT to 15 times upper limit of normal range IFN-α will be restarted at the level of 3 x 106 uday and escalated to 5 x 106 uday within 1 week
12544 If SS of hepatic decompensation recovered with persistent elevation of serum ALT 15 times upper limit of normal range IFN-α will be given and maintained at the level 3 x 106 uday 3 times per week
12545 After excluding other specific etiologies and SS of hepatic decompensation persist longer than 4 weeks patients will be withdrawn from the study
12546 Recurrent episodes of hepatic decompensation will be considered as severe adverse events and managed as listing in section 5252
1255 If symptomssigns SS of hepatic decompensation occur in the absence of ALT flare-up the patients will be managed as listing in section 5252
1256 In the presence of severe bacterial infection such as bacterial peritonitis bacterial pneumonia and etc IFN-a will be held until resolution of infection after adequate antibiotics therapy Then the patients will be managed as listing in section 5252
126 Before IFN-α if necessary patients will be pretreated with acetaminophen 500 - 1000 mg q 6 hours for 4 doses started 12 hours before IFN-α administration to alleviate the associated flu-like symptoms
13 Adverse Drug Reaction ADR Reports 131 Any life threatening andor unexpected and serious grade 3 or 4 toxicity will be reported within 48 hours to the principal investigator Li-Tzong Chen MD Cancer Clinical Research Center National Health Research Institutes A191 Ward Veteran General Hospital Taipei 201 Shih-Pai Road Sec 2 Taipei 112 Taiwan Tel886-2-8712121-2737 Fax 886-2-8716467 andor Per-Jei Chen MD PhD Department of Internal Medicine National Taiwan University Liver Disease Research Center National Taiwan University Hospital Tel 886-2-3970800-7072 Fax 886-2-3317624 The initial contact should be made by calling the Coordinate Center of TCOGat 886-2-7852459 A written report will follow within 7 working days
132 A written report will be submitted within 7 working days describing any life-threatening or lethal grade 4 or 5 known reactions except for grade 4 myelosuppression and any grade 2 or 3 unknown reactions The address for submitting ADR reports is Coordinate Center of TCOG National Health Research Institutes in Biomedical Science Academia Sinica Taipei Taiwan
133 Above toxicity grading is according to the ECOG toxicity criteria Appendix III
20 Evaluation
The following tests should be performed within 2 weeks before the initiation of therapy as the baseline data and then repeated as request following the initiation of therapy
21 Physical examination and comprehensive history are recorded bi-weekly during induction period first month and monthly during maintenance therapy for one year After first year patients will be followed bi-monthly After 6 years patients will be followed 3 monthly
22 Complete blood count and liver functional tests bilirubin directindirect ASTALT and alkaline phosphatasegGT albumin AC sugar will be checked bi-weekly during induction period first month and monthly during maintenance therapy for one year After first year patients will be followed bi-monthly After 6 years patients will be followed 3 monthly
23 Chest PA every 4 months for one year and then every 6 months 24 ECG for those with history of cardiac disease at time of symptom recurrence
25 a-fetoprotein will be checked monthly for one year and then bi-monthly After 6 years patients will be followed 3 monthly
26 Abdominal sonography every 2 months After 6 years patients will be followed 3 monthly
27 Abdominal computed tomography performed every 12 months or whenever abdominal sonography shows suspicious recurrent lesions
28 Any suspicious lesion found on abdominal sonography andor computed tomography should undergo angiography and sono-guided biopsy for histological examination
29 UGI endoscopy at the time of UGI bleeding or dyspepsia CANCEAL 291 Preoperative endoscopy is acceptable as the base-line data CANCEAL 210 Bone scan at the time of symptoms suggest the occurrence of bony metastases
211 Serum for HBV and HCV status study collected bi-monthly 212 HBeAg and anti-HBe will be checked every 4 months in those with HBeAg After 6 years patients will be followed 6 monthly
213 HBsAg will be checked every 6 months in those with HBsAg
30 Off-study Criteria 31 Development of a serious medical condition which makes administration of IFN-α life threatening
311 Patients present with SS of hepatic decompensation should be managed as list in sections 52544 and 52545
312 as those listed in 52511 and 52522 32 Occurrence of tumor recurrence 33 Non-compliance by a patient with protocol requirement 34 Patient refusal further therapy 35 Patient death 36 Interruption of IFN-α therapy 4 weeks
40 Statistical Consideration 41 Sample size Review of literatures showed that the 2-year survival rate of post-operative HCC was 25 to 60 7-14 We estimate that adjuvant IFN-α can improve the 2-year survival rate from 50 to 70 According to the methods of Casagrande et al129 to give a 90 power for detecting the increase of 20 for a two-sided statistical significance test 134 patients for each of the two treatment arms are needed 42 Randomization Patients are stratified into two strata one with HBsAganother with HBsAg- but with anti-HCV Randomization of patients into control or treatment group is taken within each stratum Balanced block sizes of two strata for randomization are different 43 Analysis 431 The primary objectives are as follows 4311 To determine if adjuvant IFN-α can reduce or delay the occurrence in curatively resected HCC 4312 To determine if adjuvant IFN-α prolong disease-free survival DFS andor overall survival OS in curatively resected HCC 4313 To determine the safety and tolerance of IFN-αin post-operative HCC patients 4314 To evaluate the anti-viral activity of IFN-α in post-operative HCC patients 432 DFS and OS are computed from the date of randomization 4321 In analysis of DFS patients died without disease recurrence will be censored for recurrence at the date of death 4322 In analysis of OS an event is defined as death from any cause 4323 The survival distributions of DFS and OS will be estimated by the Kaplan and Meier method 130 4 4324 Statistical comparisons of DFS and OS between the two treatment arms will be performed with the log-rank statistic 131 4325 Cox proportional hazards model 132 will be used to assess the importance of potential prognostic factors as well as to test the significance of treatment when adjusting for factors 433 Tumor size Liver inflammation viral status such as HBsAg anti- HCVand
Patients Specific Factor
Performance status Age Sex Family history of HCC and liver diseases Esophageal varices Prior Hx of esophageal varices bleeding Serum ALT SGPT level Serum albumin level Pre-operative serum α-FP level
Underlying Liver Diseases Specific Factors
HBsAg by RIA HBeAg by RIA anti-HBc anti-δ antibody anti-HCV antibody Severity of underlying liver disease in nontumor portion Concurrent management of esophageal varices
Tumors Specific Factors
Presence of capsule Tumor type Venous invasion Tumor size the largest in multiple lesions Histological grading will be treated as potential prognostic factors
44 Interim Analysis The interim analyses will be conducted according to the alpha spending function approach proposed by DeMets and Lan 1994 which provides flexibility about the time for interim analysis The a1 spending function which generates the approximate OBrien-Fleming boundaries OBrien and Fleming 1979 will be used for a conservation termination at the early stage of the study In addition the method of B-value developed by Lan and Wittes 1988 Li 1998 will be used to monitor the data and to compute the conditional probability of detecting either a positive or negative treatment effect at the scheduled end of the study given the present status The primary efficacy endpoint for the interim analyses is the time to occurrence of second primary tumors The toxicity will be monitored constantly throughout the study The conduct of interim analyses and dissemination of the results of the interim analysis will follow the TCOG Data and Safety Monitoring guidelines for confidentiality The TCOG Data and Safety Monitoring Committee will review the results of interim analyses for a possible early termination of the trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None