UMIN-CTR Clinical Trial

Public title

Phase I clinical trial of preoperative arterial immuno-embolization with OK-432 / fibrinogen / lipiodol for resectable primary hepatocellular carcinoma

Acronym

Phase I clinical trial of preoperative immuno-embolization for resectable primary hepatocellular carcinoma

Scientific Title

Phase I clinical trial of preoperative arterial immuno-embolization with OK-432 / fibrinogen / lipiodol for resectable primary hepatocellular carcinoma

Scientific Title:Acronym

Phase I clinical trial of preoperative immuno-embolization for resectable primary hepatocellular carcinoma

Region

Japan

Condition

Primary hepatocellular carcinoma

Classification by specialty

Hepato-biliary-pancreatic medicine	Hepato-biliary-pancreatic surgery	Radiology

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

Hepatectomy is the most effective treatment for resectable primary hepatocellular carcinoma. However, postoperative recurrence is a major problem.
To prevent postoperative recurrence, Clinical trial of preoperative transarteial immune-embolization (TIE) with OK-432 / fibrinogen / thrombin / lipiodol was carried out in our department. The safety of TIE has been confirmed and the significant inhibitory effect of tumor recurrence was suggested through immune response.
In previous clinical trial, it is difficult to create a uniform formulation because thrombin is included in the embolic material.
To be widely applied preoperative TIE for primary hepatocellular carcinoma, it is necessary to improve the uniformity of the embolization procedure without thrombin and to confirm the safety of this procedure.

Basic objectives2

Safety

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Phase I

Primary outcomes

Safety

Key secondary outcomes

Systemic immune response
Histological immune responses with resected specimen

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

TIE with embolic material containing OK-432 (2.5KE/ml), fibrinogen (60mg/ml) with lipiodol (0.5ml). Injection volume is determined depending on the tumor size (2.5-10ml). Hepatectomy will be performed within one month after TIE.

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

75

years-old

>

Gender

Male and Female

Key inclusion criteria

1. Patients with primary hepatocellular carcinoma.
2. Patients who have resectable hepatocellular carcinoma without any previous treatment.
3. age 20-75 years old
4. ECOG performance status 0-2
5.Meets the following criteria within 14 days before enrollment.
white blood count: >3,500/mm3
absolute neutrophill: >2,000/mm3
hemoglobin: >9 g/dL
platelet count: >80,000/mm3
total bilirubin: < 2.0mg/dL
AST and ALT: <100 U/L
Creatinine =< 1.2 mg/dL
CCr: =< 60mL/min

6.Patients who can take oral ingestion.
7.Patients who have no abnormal electrocardiogram within 28 days before enrollment.
8.Patients who provide a personally signed and dated informed consent document.

Key exclusion criteria

1. Patients who do not meet inclusion criteria.
2. Patients whohave a history of shock against OK-432, fibrinogen or r active peptic ulcer etc)
3. with active infection.
4. Serious complications (organ failure, o or pleural effusion.
5. confirm the presence of moderate ascitesbenzylpenicillin.
6. Active double cancer
7. Patients who can not discontinue anticoagulant drugs.
8.Pregnancy
9.Severe mental disorder, or central nervous system disorders
10.Serious drug allergy
11.Patients having trauma unhealed
12.Patients with allergic to iodine-based contrast agent
13.Inappropriate for this study judged by the investigator.

Target sample size

9

Name of lead principal investigator

1st name	Shigeru
Middle name
Last name	Marubashi

Organization

Fukushima Medical University

Division name

Department of Hepato-Biliary-Pancreatic and Transplant Surgery

Zip code

960-1295

Address

1 Hikarigaoka, Fukushima

TEL

024-547-1254

Email

mgotoh@fmu.ac.jp

Name of contact person

1st name	Akira
Middle name
Last name	Kenjo

Organization

Fukushima Medical University

Division name

Department of Hepato-Biliary-Pancreatic and Transplant Surgery

Zip code

960-1295

Address

1 Hikarigaoka, Fukushima

TEL

024-547-1254

Homepage URL

Email

a-kenjo@fmu.ac.jp

Institute

Department of Hepato-Biliary-Pancreatic and Transplant Surgery

Institute

Department

Personal name

Organization

Not applicable

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Department of Gastroenterology

Name of secondary funder(s)

Organization

Independent Ethics Committee of Fukushima Medical University

Address

1 Hikarigaoka Fukushima, Japan

Tel

0245471825

Email

rs@fmu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

福島県立医科大学附属病院

Date of disclosure of the study information

2015

Year

06

Month

15

Day

URL releasing protocol

https://www.umin.ac.jp/

Publication of results

Unpublished

URL related to results and publications

https://www.umin.ac.jp/

Number of participants that the trial has enrolled

11

Results

None of the patients achieved CR, but 3 patients (27.3%) achieved PR and six patients (54.5%) showed SD. The ORR was 27.3% and the DCR was 81.8%. The overall median PFS was 5.6 months and the overall median OS was 11.4 months.
Chemotherapy-related grade 3 hematological toxicities were leukopenia, neutropenia, and anemia. The grade 3 non-hematological toxicities were elevated liver enzymes, interstitial pneumonia, and anorexia. No patients experienced grade 4/5 toxicity during follow-up periods.

Results date posted

2019

Year

11

Month

06

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Patient characteristics
Between March 2013 and November 2015, a total of 11 patients were enrolled in this study. Although the sample size estimated for our clinical trial was 30, the trial terminated early because of poor recruitment. The baseline characteristics of the patients are shown in Table 1. The median age was 66 years (range 61-75 years). The ratio of male to female patients was 8:3, and almost all patients had a good PS (9 patients (81.8%) with ECOG PS 0 and 2 patients (18.2%) with ECOG PS 1). Six patients (54.5%) had locally advanced lesion and 5 patients had metastatic disease (45.5%). In 7 of 11 patients (63.6 %), pancreatic tumors were located in the head of the pancreas. The sites of metastasis were liver, peritoneum, intra-abdominal lymph nodes, and lung. No patients had previous medical history for pancreatic cancer.

Participant flow

Patients treated with biweekly GS therapy. GEM 1,000 mg/m2 was administered intravenously on day 1. S-1 was administered orally twice daily on the fixed days of the week: Monday, Wednesday, Friday, and Sunday. The appropriate dose of S-1 was calculated according to the body surface area (BSA) as follows: <1.25, 1.25 < BSA < 1.5, and > 1.5 m2 received 80, 100, and 120 mg/day, respectively. Treatment was interrupted in cases of grade 2 or higher toxicity (with the exception of alopecia, nausea, vomiting, and anemia) and was not resumed until the adverse event resolved or had improved to grade 1. Dose reduction was required when patients experienced any grade 3 or higher toxicity. The dose of gemcitabine was reduced by 20 % and the dose of S-1 was reduced by 20 mg/day if related toxicity occurred. All treatments were given until disease progression or unacceptable toxicities or refusal by patients.

Adverse events

The observed adverse events are listed in Table 3. Chemotherapy-related grade 3 hematological toxicities were leukopenia (9.1 %), neutropenia (9.1 %), and anemia (9.1 %). The grade 3 non-hematological toxicities were elevated liver enzymes (18.2 %), interstitial pneumonia (9.1 %), and anorexia (9.1 %). No patients experienced grade 4/5 toxicity during follow-up periods.

Outcome measures

None of the patients achieved CR, but 3 patients (27.3%) achieved PR and six patients (54.5%) showed SD. The ORR was 27.3% and the DCR was 81.8% (Table 2).
The median follow-up period was 11.4 months, and 9 of 11 patients had died at the time of analysis. One patient had been alive with tumor progression and the other patient who had locally advanced tumor could perform pancreatectomy without residual tumor and had been alive without tumor. The overall median PFS was 5.6 months (95% CI 1.0-10.1 months; Fig. 2A) and the overall median OS was 11.4 months (95% CI 2.4-20.5; Fig. 2B).

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2013

Year

06

Month

19

Day

Date of IRB

2013

Year

06

Month

15

Day

Anticipated trial start date

2013

Year

06

Month

20

Day

Last follow-up date

2018

Year

05

Month

31

Day

Date of closure to data entry

2018

Year

05

Month

31

Day

Date trial data considered complete

2018

Year

05

Month

31

Day

Date analysis concluded

2018

Year

05

Month

31

Day

Other related information

Registered date

2015

Year

06

Month

14

Day

Last modified on

2019

Year

11

Month

06

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000020386