A Phase III PI-88 in the Adjuvant Treatment of Subjects With Hepatitis Virus Related HCC After Surgical Resection

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Prospective, Randomized, Double-blind, Placebo Controlled, Parallel-group, International Multicenter Phase III Trial of PI-88 in the Adjuvant Treatment of Subjects With Hepatitis Virus Related HCC After Surgical Resection

Conditions
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Cancer, Liver Cancer, Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: PI-88
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Histologically-proven primary hepatocellular carcinoma with curative resection performed in the 4 - 6 weeks prior to randomization. Age ≥ 18 years. Written, signed and dated informed consent to participate in study ECOG performance status 0 to 1 Child Pugh score ≤ 8 Platelet count ≥ 80 x 109 cells/liter PT-INR ≤ 1.3 aPTT ≤ upper limit of normal Key exclusion criteria: Pathological confirmation of single tumor < 2 cm in diameter which obtained from the most recent hepatectomy. 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. Any evidence of tumor metastasis or co-existing malignant disease Any prior recurrence of HCC or any liver resection prior to the most recent procedure 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. Subjects with uncontrolled infection or serious infection within the past 4 weeks. 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. 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. 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. 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. 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. Active substance abuse, including alcohol, which, in the opinion of the investigator, risks impairing the ability of the subject to comply with the protocol. Subjects who received other investigational or anti-neoplastic medication within the past 4 weeks. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PI-88<br>Arm 1 | Drug: PI-88<br>* Lyophilized powder reconstituted to provide 160 mg of PI-88<br>* Other names: Muparfostat;|
| Placebo Comparator: Placebo<br>Arm 2 | Other: Placebo<br>* Lactose lyophilized powder<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | End of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Recurrence Rate (TR Rate) | TR rate was to calculate number of subjects with recurrence among the analyzed population. | The cumulative tumor recurrence rate at weeks 5, 53, 101 and 149 was reported here. | 
| 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 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). | 
| Overall Survival (OS) | Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period. | Overall survival was defined as the time, in weeks, from randomization to death from any cause during the study period (3 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PI-88, Hepatocellular Carcinoma, Phase III, Adjuvant Therapy, Hepatoma, Liver Cancer