PI-88 in Hepatocellular Carcinoma After Hepatectomy

• Sponsor: Cellxpert Biotechnology Corp. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00247728
• Collaborator: Medigen Biotechnology Corporation (Industry)
• Enrollment: 172
• Locations: 6
• Arms: 3
• Duration (Months): 48
• Patients Per Site: 28.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of PI-88 to inhibit or reduce tumor recurrence in patients with hepatocellular carcinoma following hepatectomy.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: PI-88	Phase 2

Detailed Description

Although early diagnosis and treatment improve survival, hepatocellular carcinoma (HCC) is rarely cured and recurs frequently after regional therapy or transplantation. Hepatic resection can improve 5-year recurrence-free survival by up to 25%. Micrometastases of HCC have been detected by molecular techniques in 88% of patients at the time of surgery, and probably cause postoperative recurrence. Efforts to reduce the risk of recurrence after a curative resection have been tried, including various regimens of adjuvant and neoadjuvant therapy.

In this study , an anti-angiogenic agent, PI-88, is being used as an adjuvant therapy for HCC patients after curative hepatic resection. The efficacy endpoints, including tumour non-recurrence rate, time to first recurrence and 1-year survival rate are being evaluated. Several risk factors associated with tumour recurrence are also being analysed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multi-centre, Efficacy Evaluation of PI-88 in Patients With Hepatocellular Carcinoma After Hepatectomy - A Phase II Study
• Study Start Date: Jun 1, 2004
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Untreated Control Untreated control arm
Experimental: 160 mg PI-88/Day PI-88 160 mg/day SC injection	Drug: PI-88; Once-daily SC injection for four consecutive days per week, for 3 weeks out of every 4 weeks
Experimental: 250 mg PI-88/Day PI-88 250 mg/day SC injection	Drug: PI-88; Once-daily SC injection for four consecutive days per week, for 3 weeks out of every 4 weeks

Outcome Measures

Primary Outcome Measures

1. Tumour Non-recurrence Rate [Week 48]

   The tumor non-recurrence rate at the end of the 48-week study period

Secondary Outcome Measures

1. Time to Recurrence [until confirmed tumour recurrence, or for a maximum of 48 weeks]

   Time to recurrence during the 48-week study period

2. Survival Rate [Week 48]

   Survival rate at the end of the 48-week study period

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients have voluntarily given written informed consent

• Age ≥ 18 years but ≤ 75 years

• Males or females

• Histological diagnosis of hepatocellular carcinoma

• Curative hepatectomy within the past 4-6 weeks

• ECOG performance status of 0 to 2

• Cardiac functional capacity ≤ to class II (New York Heart Association)

• Patients with adequate renal, hepatic, and haematopoietic function as defined by:

• Serum creatinine ≤ 2.0 mg/dL

• Total bilirubin < 2.5 mg/dL

• Neutrophil count > 1.5 x 10^9/L

• ALT < 5 x upper limit of normal (ULN)

• White blood cell (WBC) count ≥ 3 x 10^9/L

• Platelet count ≥ 80 x 10^9/L

• Prothrombin time international normalized ratio (PT-INR) ≤ 1.3 (or PT-INR ≤ 1.4 but PT within normal range)

• Activated partial thromboplastin time (APTT) < ULN

Exclusion Criteria:

• Patients with history of allergy and/or hypersensitivity to anticoagulants/thrombolytic agents, especially heparin.

• Patients with history of immune mediated thrombocytopenia, thrombotic thrombocytopenic purpura, or other platelet disease

• Patients with previous positive result in a heparin-induced thrombocytopenia (HIT) antibody test.

• Patients with any tumour metastasis.

• Patients with uncontrolled infection or serious infection within the past 4 weeks.

• Patients with myocardial infarction, stroke, or congestive heart failure within the past 3 months.

• Patients with history of inflammatory bowel disease, any other abnormal bleeding tendency, or patients at risk of bleeding due to open wounds or planned surgery.

• Patients with acute or chronic gastrointestinal bleeding within the past 1 year.

• Patients with a history of drug abuse or psychiatric disorder.

• Patients with known HIV infection or AIDS-related illness.

• Patients who received other investigational or anti-neoplastic medication within the past 4 weeks.

• Use of aspirin, aspirin-containing medications, non-steroidal anti-inflammatory drugs (except for COX-2 inhibitors), heparin, low molecular weight heparin, warfarin, anti-platelet drugs, or any other anticoagulant medications 2 weeks prior to or during the study period.

• Women who are pregnant or breast-feeding.

• Women of child-bearing potential who are not using an adequate method of contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaohsiung Veterans General Hospital	Kaohsiung		Taiwan	813-46
2	China Medical University Hospital	Taichung		Taiwan	404
3	Taichung Veterans General Hospital	Taichung		Taiwan	407
4	National Cheng Kung University Hospital	Tainan		Taiwan	704
5	National Taiwan University Hospital	Taipei		Taiwan	100
6	Chang Gung Memorial Hospital-Linkou Medical Centre	Taoyuan		Taiwan	333

Sponsors and Collaborators

• Cellxpert Biotechnology Corp.
• Medigen Biotechnology Corporation

Investigators

• Principal Investigator: Pei-Jer Chen, MD, PhD, National Taiwan University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cellxpert Biotechnology Corp.
• ClinicalTrials.gov Identifier: NCT00247728
• Other Study ID Numbers: MG 002; PR88204
• First Posted: Nov 2, 2005
• Last Update Posted: Jun 23, 2022
• Last Verified: Jun 1, 2022

• Keywords provided by Cellxpert Biotechnology Corp.: PI-88; post resection hepatoma; adjuvant therapy; hepatectomy; hepatoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Recruitment Details	215 patients were screened between June 2004 and December 2006. Patients were randomized in balanced blocks per center.

Arm/Group Title	Group A - Untreated Control	Group B - 160 mg PI-88/Day	Group C - 250 mg PI-88/Day
Arm/Group Description	untreated control with standard of care	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week	250 mg PI-88 via subcutaneous injection for four consecutive days per week, every week
Period Title: Overall Study
STARTED	58	57	57
COMPLETED	55	51	43
NOT COMPLETED	3	6	14

Baseline Characteristics

Arm/Group Title	Group A - Untreated Control	Group B - 160 mg PI-88/Day	Group C - 250 mg PI-88/Day	Total
Arm/Group Description	untreated control with standard of care, ITT population	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week, ITT population	250 mg PI-88 via subcutaneous injection for four consecutive days per week, every week, ITT population	Total of all reporting groups
Overall Participants	58	56	54	168
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.96 (12.54)	51.47 (12.57)	52.41 (12.03)	52.39 (12.38)
Sex: Female, Male (Count of Participants)
Female	15 25.9%	10 17.9%	10 18.5%	35 20.8%
Male	43 74.1%	46 82.1%	44 81.5%	133 79.2%
Region of Enrollment (participants) [Number]
Taiwan	58 100%	56 100%	54 100%	168 100%

Outcome Measures

1. Primary Outcome

Title	Tumour Non-recurrence Rate
Description	The tumor non-recurrence rate at the end of the 48-week study period
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT population, defined as all randomized subjects who had received at least one dose of study medication (if in a treatment arm) and who had undergone at least one study visit following randomization, including an abdominal CT scan.

Arm/Group Title	Group A - Untreated Control	Group B - 160 mg PI-88/Day	Group C - 250 mg PI-88/Day
Arm/Group Description	untreated control with standard of care	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week	250 mg PI-88 via subcutaneous injection for four consecutive days per week, every week
Measure Participants	58	56	54
Number [Participants]	32 55.2%	40 71.4%	35 64.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Untreated Control, Group B - 160 mg PI-88/Day
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Sample size is based on the paper 'Two-stage selection and testing design for comparative clinical trials', Thall, PF, Simon, R and Ellenberg, SS. Biometrika (1988),75,(2),303-310.
Statistical Test of Hypothesis	p-Value	0.072
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group A - Untreated Control, Group C - 250 mg PI-88/Day
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Sample size is based on the paper 'Two-stage selection and testing design for comparative clinical trials', Thall, PF, Simon, R and Ellenberg, SS. Biometrika (1988),75,(2),303-310.
Statistical Test of Hypothesis	p-Value	0.298
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Time to Recurrence
Description	Time to recurrence during the 48-week study period
Time Frame	until confirmed tumour recurrence, or for a maximum of 48 weeks

Outcome Measure Data

Analysis Population Description

ITT population, defined as all randomized subjects who had received at least one dose of study medication (if in a treatment arm) and who had undergone at least one study visit following randomization, including an abdominal CT scan.

Arm/Group Title	Group A - Untreated Control	Group B - 160 mg PI-88/Day	Group C - 250 mg PI-88/Day
Arm/Group Description	Untreated control with standard of care	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week
Measure Participants	58	56	54
Median (95% Confidence Interval) [Weeks]	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A - Untreated Control, Group B - 160 mg PI-88/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.087
	Comments
	Method	Mantel Haenszel
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group A - Untreated Control, Group C - 250 mg PI-88/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.653
	Comments
	Method	Mantel Haenszel
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Survival Rate
Description	Survival rate at the end of the 48-week study period
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT population, defined as all randomized subjects who had received at least one dose of study medication (if in a treatment arm) and who had undergone at least one study visit following randomization, including an abdominal CT scan.

Arm/Group Title	Group A - Untreated Control	Group B - 160 mg PI-88/Day	Group C - 250 mg PI-88/Day
Arm/Group Description	untreated control with standard of care	160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week	250 mg PI-88 via subcutaneous injection for four consecutive days per week, every week
Measure Participants	58	56	54
Number [Participants]	54 93.1%	51 91.1%	51 94.4%

Adverse Events

Time Frame	During the course of the study (maximum 48 weeks)
Arm/Group Title	Group A - Untreated Control		Group B - 160 mg PI-88/Day		Group C - 250 mg PI-88/Day
Arm/Group Description	untreated control with standard of care in safety population defined as all randomized subjects, who had at least one assessment following randomization.		160 mg PI-88 via subcutaneous injection for four consecutive days per week, every week, safety population (defined as all randomized subjects, who had at least one assessment following randomization)		250 mg PI-88 via subcutaneous injection for four consecutive days per week, every week, safety population defined as all randomized subjects, who had at least one assessment following randomization
All Cause Mortality
	Group A - Untreated Control		Group B - 160 mg PI-88/Day		Group C - 250 mg PI-88/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A - Untreated Control		Group B - 160 mg PI-88/Day		Group C - 250 mg PI-88/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/58 (1.7%)		7/57 (12.3%)		8/57 (14%)
Cardiac disorders
Myocardial infarction	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Tachyarrhythmia	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Gastrointestinal disorders
Ascites	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Gastric ulcer hemorrhage	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Gastrointestinal hemorrhage	1/58 (1.7%)	1	1/57 (1.8%)	1	0/57 (0%)	0
Pancreatitis acute	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
General disorders
Edema peripheral	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Gingival bleeding	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Ileus	0/58 (0%)	0	1/57 (1.8%)	1	1/57 (1.8%)	1
Hepatobiliary disorders
Liver disorder	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Infections and infestations
Carbuncle	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Injury, poisoning and procedural complications
Foot fracture	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Pelvic fracture	1/58 (1.7%)	1	0/57 (0%)	0	0/57 (0%)	0
Radius fracture	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Metabolism and nutrition disorders
Hyperkalemia	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Hypocalcemia	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Hypoglycemia	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Nervous system disorders
Cerebral infarction	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	2
Dizziness	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Hemorrhage intracranial	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Hepatic encephalopathy	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Respiratory Failure	0/58 (0%)	0	1/57 (1.8%)	1	0/57 (0%)	0
Vascular disorders
Hemorrhage	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Hypovalemic shock	0/58 (0%)	0	0/57 (0%)	0	1/57 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Group A - Untreated Control		Group B - 160 mg PI-88/Day		Group C - 250 mg PI-88/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/58 (75.9%)		55/57 (96.5%)		54/57 (94.7%)
Blood and lymphatic system disorders
Neutropenia	0/58 (0%)	0	6/57 (10.5%)	20	4/57 (7%)	24
Splenomegaly	3/58 (5.2%)	3	7/57 (12.3%)	7	3/57 (5.3%)	3
Thrombocytopenia	1/58 (1.7%)	1	6/57 (10.5%)	14	7/57 (12.3%)	18
Gastrointestinal disorders
Abdominal discomfort	1/58 (1.7%)	1	8/57 (14%)	8	1/57 (1.8%)	1
Abdominal distension	5/58 (8.6%)	5	6/57 (10.5%)	6	5/57 (8.8%)	5
Abdominal pain	4/58 (6.9%)	5	6/57 (10.5%)	6	5/57 (8.8%)	6
Abdominal pain upper	1/58 (1.7%)	1	5/57 (8.8%)	7	8/57 (14%)	8
Ascites	1/58 (1.7%)	1	6/57 (10.5%)	9	4/57 (7%)	8
Diarrhoea	1/58 (1.7%)	1	7/57 (12.3%)	9	3/57 (5.3%)	3
Nausea	1/58 (1.7%)	1	0/57 (0%)	0	5/57 (8.8%)	5
Periodontits	0/58 (0%)	0	3/57 (5.3%)	3	0/57 (0%)	0
General disorders
Fatigue	1/58 (1.7%)	1	3/57 (5.3%)	3	3/57 (5.3%)	6
Injection site haemorrhage	0/58 (0%)	0	7/57 (12.3%)	8	9/57 (15.8%)	9
Injection site pain	0/58 (0%)	0	6/57 (10.5%)	6	4/57 (7%)	4
Injection site reaction	0/58 (0%)	0	4/57 (7%)	6	4/57 (7%)	4
Malaise	3/58 (5.2%)	3	4/57 (7%)	5	5/57 (8.8%)	6
Oedema peripheral	1/58 (1.7%)	1	4/57 (7%)	4	4/57 (7%)	7
Infections and infestations
Nasopharyngitis	1/58 (1.7%)	2	1/57 (1.8%)	3	3/57 (5.3%)	3
Upper respiratory tract infection	14/58 (24.1%)	15	8/57 (14%)	8	10/57 (17.5%)	12
Injury, poisoning and procedural complications
Wound complication	2/58 (3.4%)	3	5/57 (8.8%)	5	2/57 (3.5%)	2
Investigations
ALT increased	4/58 (6.9%)	6	14/57 (24.6%)	21	19/57 (33.3%)	33
APPT prolonged	0/58 (0%)	0	20/57 (35.1%)	20	18/57 (31.6%)	22
AST increased	3/58 (5.2%)	3	10/57 (17.5%)	18	13/57 (22.8%)	24
Hepatic enzyme increased	0/58 (0%)	0	0/57 (0%)	0	3/57 (5.3%)	4
PT prolongation	0/58 (0%)	0	0/57 (0%)	0	3/57 (5.3%)	3
Metabolism and nutrition disorders
Hyperalbuminaemia	1/58 (1.7%)	1	3/57 (5.3%)	5	1/57 (1.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/58 (5.2%)	3	3/57 (5.3%)	3	1/57 (1.8%)	2
Back pain	2/58 (3.4%)	2	2/57 (3.5%)	2	5/57 (8.8%)	6
Muscle spasms	0/58 (0%)	0	2/57 (3.5%)	2	3/57 (5.3%)	4
Musculoskeletal pain	0/58 (0%)	0	4/57 (7%)	4	1/57 (1.8%)	1
Nervous system disorders
Dizziness	5/58 (8.6%)	6	1/57 (1.8%)	2	6/57 (10.5%)	6
Headache	2/58 (3.4%)	3	3/57 (5.3%)	3	4/57 (7%)	4
Psychiatric disorders
Insomnia	10/58 (17.2%)	10	11/57 (19.3%)	13	11/57 (19.3%)	16
Sleep disorders	1/58 (1.7%)	1	1/57 (1.8%)	1	3/57 (5.3%)	3
Renal and urinary disorders
Nephrolithiasis	2/58 (3.4%)	2	3/57 (5.3%)	3	0/57 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	7/58 (12.1%)	7	5/57 (8.8%)	8	5/57 (8.8%)	6
Dyspnoea	2/58 (3.4%)	2	3/57 (5.3%)	3	1/57 (1.8%)	1
Pharyngolaryngeal pain	0/58 (0%)	0	3/57 (5.3%)	4	1/57 (1.8%)	1
Pleural effusion	0/58 (0%)	0	5/57 (8.8%)	5	1/57 (1.8%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/58 (0%)	0	6/57 (10.5%)	7	13/57 (22.8%)	13
Puritus	1/58 (1.7%)	1	2/57 (3.5%)	2	7/57 (12.3%)	7
Rash	1/58 (1.7%)	1	1/57 (1.8%)	1	3/57 (5.3%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.