Cancer, Hepatocellular Carcinoma, Liver Cancer
Conditions
Keywords
Hepatocellular Carcinoma, PI-88, Phase III, Adjuvant Therapy, Hepatoma, Liver Cancer
Brief summary
The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.
Detailed description
Primary liver cancer (hepatocellular carcinoma or HCC) is the fifth most common cancer worldwide. Surgery to remove the tumour remains the principal form of treatment for liver cancer, however recurrence of the disease after surgery is common and survival after recurrence is poor. At the moment there is no recommended standard treatment for HCC immediately after the tumour has been removed surgically. PI-88 is a new experimental drug which blocks the growth of new blood vessels in tumours to stop the tumour growing (starves it of food) and also stops tumour cells spreading. Previous experience with PI-88 has shown it has been well tolerated and has shown some benefit in delaying the time it takes for the hepatocellular carcinoma to reappear after surgery. The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.
Interventions
DRUGPI-88
Lyophilized powder reconstituted to provide 160 mg of PI-88
OTHERPlacebo
Lactose lyophilized powder
Sponsors
Medigen Biotechnology Corporation
Cellxpert Biotechnology Corp.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: 1. Histologically-proven primary hepatocellular carcinoma with curative resection performed in the 4 - 6 weeks prior to randomization. 2. Age ≥ 18 years. 3. Written, signed and dated informed consent to participate in study 4. ECOG performance status 0 to 1 5. Child Pugh score ≤ 8 6. Platelet count ≥ 80 x 109 cells/liter 7. PT-INR ≤ 1.3 8. aPTT ≤ upper limit of normal Key
Exclusion criteria
1. Pathological confirmation of single tumor \< 2 cm in diameter which obtained from the most recent hepatectomy. 2. History of immune-mediated thrombocytopenia other platelet abnormalities or other hereditary or acquired coagulopathies, or laboratory evidence of anti-heparin antibodies, or any previous history of having tested positive for anti-heparin antibodies. 3. Any evidence of tumor metastasis or co-existing malignant disease 4. Any prior recurrence of HCC or any liver resection prior to the most recent procedure 5. Clinically significant non-malignant disease including, but not limited to, surgery within 6 weeks of randomization (apart from liver resection and re-operation for complications of liver resection), active clinically significant infection within 6 weeks prior to randomization, myocardial infarction within 6 months prior to randomization, cerebrovascular event within 12 months prior to randomization or clinically-significant gastrointestinal bleeding within 12 months prior to randomization. Subjects who have experienced post-operative complications of liver resection may be enrolled providing that such complications are fully resolved at the time of screening. 6. Subjects with uncontrolled infection or serious infection within the past 4 weeks. 7. History of prior HCC therapy including chemotherapy, radiotherapy, molecular targeting agents, vaccines, transarterial embolization (TAE), transarterial chemoembolization (TACE), liver transplantation or surgical resection prior to the most recent hepatectomy, at any time prior to randomization. This includes pre-, peri- and post-operative treatments. Pre-operative portal vein embolization is permitted. Subjects should not be enrolled if, at the time of randomization, it is planned that they will subsequently undergo liver transplantation regardless of tumor recurrence. 8. Concomitant use of aspirin (\> 150 mg/day), vitamin K antagonists (other than low-dose prophylactic use), heparin within two weeks prior to randomization, or other anti-platelet drugs (e.g. abciximab, clopidogrel, dipyridamole, ticlopidine and tirofiban). Low dose aspirin (≤ 150 mg/day) and low-dose prophylactic vitamin K antagonists (e.g. warfarin ≤ 1 mg/day) are permitted as concomitant medications. 9. History of allergic, anaphylactic or other significant adverse reaction to radiographic contrast media (iodinated or non-iodinated), which cannot be managed by pre-treatment with agents such as steroids or anti-histamines, and which, in the opinion of the investigator, renders the subject unsuitable for routine CT scanning. Subjects who are contra-indicated for CT scanning for other reasons (e.g. ferromagnetic implants, profound claustrophobia), should not be enrolled. 10. Subjects with history of inflammatory bowel disease, any other abnormal bleeding tendency, or subjects at risk of bleeding due to open wounds or planned surgery. 11. Women who are pregnant or breast-feeding or women of child-bearing potential who are unable or unwilling to practice a highly effective means of contraception. 12. Active substance abuse, including alcohol, which, in the opinion of the investigator, risks impairing the ability of the subject to comply with the protocol. 13. Subjects who received other investigational or anti-neoplastic medication within the past 4 weeks. 14. Current participation in any other clinical study or research project which involves administration of a pharmaceutical product or experimental treatment, or which involves protocol-specified laboratory tests, imaging studies or other investigations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival (DFS) | End of study | To evaluate the efficacy of daily administration of PI-88 versus placebo for the adjuvant treatment of study subjects as measured by DFS during study period. As the median DFS could not be estimated, the overall 25 th percentile DFS was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence (TTR) | Time to recurrence (TTR) was defined as the time from randomization to the first time that tumor recurrence was observed or suspected during the study period (3 years). | As no subjects died without a preceding tumor recurrence , no median time to TTR could be estimated in the present study. And therefore the overall 25th percentile DFS was reported. The results of time to recurrence (TTR) were the same as that of DFS, as no subjects died without a preceding tumor recurrence. |
| Overall Survival (OS) | Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period (3 years). | Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period. |
| Tumor Recurrence Rate (TR Rate) | The cumulative tumor recurrence rate at weeks 5, 53, 101 and 149 was reported here. | TR rate was to calculate number of subjects with recurrence among the analyzed population. |
Countries
China, Hong Kong, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PI-88 Arm 1
PI-88: Lyophilized powder reconstituted to provide 160 mg of PI-88 | 258 |
| Placebo Arm 2
Placebo: Lactose lyophilized powder | 261 |
| Total | 519 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 30 | 17 |
Baseline characteristics
| Characteristic | Total | PI-88 | Placebo |
|---|---|---|---|
| AFP < 400 ng/ml | 384 Participants | 187 Participants | 197 Participants |
| AFP >= 400 ng/ml | 133 Participants | 70 Participants | 63 Participants |
| AFP Missing | 2 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 54.61 years STANDARD_DEVIATION 9.915 | 54.12 years STANDARD_DEVIATION 10.201 | 55.08 years STANDARD_DEVIATION 9.619 |
| Baseline Hepatitis Serology HBV- & HCV- | 8 Participants | 3 Participants | 5 Participants |
| Baseline Hepatitis Serology HBV+ & HCV+ | 23 Participants | 10 Participants | 13 Participants |
| Baseline Hepatitis Serology HBV+ Only | 434 Participants | 212 Participants | 222 Participants |
| Baseline Hepatitis Serology HCV+ Only | 53 Participants | 33 Participants | 20 Participants |
| Baseline Hepatitis Serology Missing | 1 Participants | 0 Participants | 1 Participants |
| BMI | 23.84 kg/m^2 STANDARD_DEVIATION 3.138 | 23.95 kg/m^2 STANDARD_DEVIATION 3.261 | 23.74 kg/m^2 STANDARD_DEVIATION 3.015 |
| Child-Pugh Stage A (5 - 6 points) | 514 units on a scale | 256 units on a scale | 258 units on a scale |
| Child-Pugh Stage B (7 - 9 points) | 3 units on a scale | 1 units on a scale | 2 units on a scale |
| Child-Pugh Stage Missing | 2 units on a scale | 1 units on a scale | 1 units on a scale |
| Differentiation of Baseline Tumor Anaplasia | 36 Participants | 15 Participants | 21 Participants |
| Differentiation of Baseline Tumor Missing | 1 Participants | 1 Participants | 0 Participants |
| Differentiation of Baseline Tumor Moderately differentiated | 260 Participants | 143 Participants | 117 Participants |
| Differentiation of Baseline Tumor Poorly differentiated | 189 Participants | 86 Participants | 103 Participants |
| Differentiation of Baseline Tumor Well differentiated | 33 Participants | 13 Participants | 20 Participants |
| ECOG Performance Score 0 | 492 Participants | 245 Participants | 247 Participants |
| ECOG Performance Score 1 | 27 Participants | 13 Participants | 14 Participants |
| Liver Cirrhosis (Pre-Operative) Mild | 239 Participants | 109 Participants | 130 Participants |
| Liver Cirrhosis (Pre-Operative) Missing | 8 Participants | 2 Participants | 6 Participants |
| Liver Cirrhosis (Pre-Operative) Moderate | 57 Participants | 35 Participants | 22 Participants |
| Liver Cirrhosis (Pre-Operative) None | 199 Participants | 105 Participants | 94 Participants |
| Liver Cirrhosis (Pre-Operative) Severe | 16 Participants | 7 Participants | 9 Participants |
| Number of Tumors 1 | 458 Participants | 223 Participants | 235 Participants |
| Number of Tumors 2 | 48 Participants | 28 Participants | 20 Participants |
| Number of Tumors >=3 | 13 Participants | 7 Participants | 6 Participants |
| Portal Vein Thrombosis Missing | 2 Participants | 1 Participants | 1 Participants |
| Portal Vein Thrombosis No | 472 Participants | 234 Participants | 238 Participants |
| Portal Vein Thrombosis Yes | 45 Participants | 23 Participants | 22 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment China | 48 participants | 24 participants | 24 participants |
| Region of Enrollment Hong Kong | 9 participants | 6 participants | 3 participants |
| Region of Enrollment South Korea | 202 participants | 106 participants | 96 participants |
| Region of Enrollment Taiwan | 260 participants | 122 participants | 138 participants |
| Sex: Female, Male Female | 96 Participants | 52 Participants | 44 Participants |
| Sex: Female, Male Male | 423 Participants | 206 Participants | 217 Participants |
| Size of the Largest Explanted Tumor >= 10 cm | 47 Participants | 24 Participants | 23 Participants |
| Size of the Largest Explanted Tumor 5 - <10 cm | 129 Participants | 63 Participants | 66 Participants |
| Size of the Largest Explanted Tumor <5 cm | 343 Participants | 171 Participants | 172 Participants |
| Stratification V-L- | 199 Participants | 101 Participants | 98 Participants |
| Stratification V-L+ | 69 Participants | 33 Participants | 36 Participants |
| Stratification V+L- | 144 Participants | 70 Participants | 74 Participants |
| Stratification V+L+ | 107 Participants | 54 Participants | 53 Participants |
| Surgical Margin of Explanted Tumor < 10 mm | 255 Participants | 118 Participants | 137 Participants |
| Surgical Margin of Explanted Tumor >= 10 mm | 263 Participants | 140 Participants | 123 Participants |
| Surgical Margin of Explanted Tumor NA | 1 Participants | 0 Participants | 1 Participants |
| Total Child-Pugh Score (categorized) 5 | 481 units on a scale | 239 units on a scale | 242 units on a scale |
| Total Child-Pugh Score (categorized) 6 | 33 units on a scale | 17 units on a scale | 16 units on a scale |
| Total Child-Pugh Score (categorized) 7 | 2 units on a scale | 1 units on a scale | 1 units on a scale |
| Total Child-Pugh Score (categorized) 8 | 1 units on a scale | 0 units on a scale | 1 units on a scale |
| Total Child-Pugh Score (categorized) Missing | 2 units on a scale | 1 units on a scale | 1 units on a scale |
| Total CLIP Score (categorized) 0 | 317 units on a scale | 146 units on a scale | 171 units on a scale |
| Total CLIP Score (categorized) 1 | 147 units on a scale | 83 units on a scale | 64 units on a scale |
| Total CLIP Score (categorized) 2 | 38 units on a scale | 19 units on a scale | 19 units on a scale |
| Total CLIP Score (categorized) 3 | 10 units on a scale | 7 units on a scale | 3 units on a scale |
| Total CLIP Score (categorized) 4 | 5 units on a scale | 2 units on a scale | 3 units on a scale |
| Total CLIP Score (categorized) Missing | 2 units on a scale | 1 units on a scale | 1 units on a scale |
| Tumor Morphology Massive or extension > 50% | 14 Participants | 10 Participants | 4 Participants |
| Tumor Morphology Missing | 2 Participants | 1 Participants | 1 Participants |
| Tumor Morphology Multinodular and extension <= 50% | 62 Participants | 34 Participants | 28 Participants |
| Tumor Morphology Uninodular and extension <= 50% | 441 Participants | 213 Participants | 228 Participants |
| Vascular Invasion Absent | 268 Participants | 134 Participants | 134 Participants |
| Vascular Invasion Macro | 40 Participants | 18 Participants | 22 Participants |
| Vascular Invasion Micro Only | 211 Participants | 106 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 233 / 258 | 201 / 260 |
| serious Total, serious adverse events | 30 / 258 | 15 / 260 |
Outcome results
Primary
Disease-Free Survival (DFS)
To evaluate the efficacy of daily administration of PI-88 versus placebo for the adjuvant treatment of study subjects as measured by DFS during study period. As the median DFS could not be estimated, the overall 25 th percentile DFS was reported.
Time frame: End of study
Population: ITT population, defined as all subjects who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PI-88 | Disease-Free Survival (DFS) | 51.0 weeks |
| Placebo | Disease-Free Survival (DFS) | 75.6 weeks |
Secondary
Overall Survival (OS)
Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period.
Time frame: Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period (3 years).
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PI-88 | Overall Survival (OS) | 71.7 weeks | Standard Error 0.37 |
| Placebo | Overall Survival (OS) | 69.2 weeks | Standard Error 0.28 |
Secondary
Time to Recurrence (TTR)
As no subjects died without a preceding tumor recurrence , no median time to TTR could be estimated in the present study. And therefore the overall 25th percentile DFS was reported. The results of time to recurrence (TTR) were the same as that of DFS, as no subjects died without a preceding tumor recurrence.
Time frame: Time to recurrence (TTR) was defined as the time from randomization to the first time that tumor recurrence was observed or suspected during the study period (3 years).
Population: ITT population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PI-88 | Time to Recurrence (TTR) | 51.0 weeks |
| Placebo | Time to Recurrence (TTR) | 75.6 weeks |
Secondary
Tumor Recurrence Rate (TR Rate)
TR rate was to calculate number of subjects with recurrence among the analyzed population.
Time frame: The cumulative tumor recurrence rate at weeks 5, 53, 101 and 149 was reported here.
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PI-88 | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 101 | 82 Participants |
| PI-88 | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 5 | 11 Participants |
| PI-88 | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 53 | 74 Participants |
| PI-88 | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 149 | 85 Participants |
| Placebo | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 149 | 74 Participants |
| Placebo | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 101 | 70 Participants |
| Placebo | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 53 | 58 Participants |
| Placebo | Tumor Recurrence Rate (TR Rate) | Cumulative Tumor Recurrence Rate at weeks 5 | 8 Participants |