Summary
1. Primary clinical tolerance study of Jilifen at four dosages(75ug,150ug,300ug,450ug)showed that Jilifen exhibited few adverse reaction at low dosage, and as dose intensity increased, mild osteodynia and abnormality of hepatic function appeared in some patients. But 7 days continuous administration of Jilifen was tolerable at each dosage(75-450ug) applied. Severe adverse reaction or dose restricted toxicity was not found.

2.Jilifen had fine action of elevating granulocyte at either dosage, and the action enhanced as dosage increased.

Key words: Jilifen granulocyte colony stimulating factor tumor chemotherapy phase I

From Nov.1995 to Jul.1996, we performed phase I clinical tolerance trial of human recombinant colony stimulating factor injection(commercial name:Jilifen) produced by Hangzhou Jiuyuan Gene Engineering Co., Ltd. The primary purpose of the study is to investigate and evaluate its human body tolerance at dosage of 75ug,150ug,300ug and 450ug, and help to find the basis for a rational clinical dose setting of the drug in phase II clinical trial. The results are reported below:

1.Patients and method

1.Chemical:Jilifen was provided by Hangzhou Jiuyuan Gene Engineering Co., Ltd., which was a colorless, transparent liquid,1.2ml per ampoule, contained 300ug rhG-CSF, number of sample:950508.

2.Patient:12 patients of pathologically diagnosed later stage malignant tumors were engaged in the trial. Among which were 9 with non-Hodgkin’s lymphoma, 1 with small cell lung cancer, 1 with nasopharyngeal cancer and 1 with osteoblastosarcoma, aged 14-62, median age 38 years. 11 males and 1 female,performance status 0-2 grade(WHO/ECOG), their ECG and hepatic, renal function were within the normal range. All patients were at recovery phase of chemotherapy, 48 hours after the last administration of chemotherapeutic drugs, with no acute toxic reaction of chemotherapy or systemic symptoms such as fever, osteodynia, muscular pain, headache.

3.Dosage: Since rhG-CSF was broadly applied clinically abroad with clinical doses at 75ug,150ug,300ug, we planned to perform human body tolerance study of Jilifen at dosages of 75ug,150ug,300ug and 450ug. With the permission of National Public Health Bureau ,the above plan was carried out.

4.Clinical method: In 3 cases(defined as group 1),75ug was employed as primary dose, injected subcutaneously, continued for 7 consecutive days, no severe side effect was shown. Thereafter the dosage was increased gradually to 150ug,300ug or 450ug, subcutaneously injected once daily for 7 days for the rest.

5.Investigation of effects and toxicity: Before the use of Jilifen, electrocardiogram, hepatic and renal function, blood electrolytes, serum bilirubin, liposaccrides, blood routine examination, body temperature and blood pressure were measured. During the administration of Jilifen, blood routine examination was done every two days, determined body temperature twice daily, patient condition was inquired and physical examination was performed daily, side effects were recorded in detail. All the items examined before the therapy were re-examined after the therapy.

6.System of toxicity evaluation according to WHO toxicity reaction grading standard.

7.Evaluation of therapeutic effect: exam blood routine at the day before treatment and once every two days after treatment. Take the average number of neutrophil at the same time points of the 3 cases in a same group and plotted ANC versus time so as to investigate the tendency of its change after administration of Jilifen. Meanwhile observe the changes of erythrocyte and platelet.

Results

12 cases at different 4 dosages that totally received 84 times of subcutaneous injections, none of them withdrew from the study because of adverse reactions.

1) Adverse reactions

Jilifen exhibited no detectable adverse reaction at low dosage (75-150ug);and when dosage reached 300-450ug, some of the patients complained mild osteodynia .At dosage of 300ug, a patient complained pain of tibial bone and bilateral hip bones,at dosage of 450ug,2 patients complained pain of waist and sacrum(grade I),which were all disappeared after withdrawal of Jilifen. In addition, at dosage of 300 and 450ug, hepatic function damage emerged in some patients. At dosage of 300ug,1 patient showed elevation of serum alkaline phosphorylatase (ALP) and lactic dehydroxygenase (LDH) (grade I); At 450ug,another patient showed elevation of s-GTP, s-GOT and ALP(grade I), all those adverse reactions were tolerable and disappeared spontaneously after withdrawal of Jilifen(see tab.1). Adverse reactions like fever, skin rash, local pain at injection region, nausea,abdoman pain or blood pressure decrease were not found. Examinations of electrocardiogram, renal function and other blood biochemical indexes showed no abnormality.

Table 1.adverse reactions of Jilifen at different dosages

2) Effectiveness

Jilifen increased the peripheral neutrophil count at each dosage employed(75ug,150ug,300ug,450ug),with no obvious adverse effect, and as dose increased its action of elevating granulocyte counts also enhanced. We also found that Jilifen acted rather rapidly, in general, 2 days after injection of Jilifen, neutrophil count increased to reach its peak, and then decreased gradually, but still maintained at a relatively high level. After withdrawal of Jilifen, ANC recovered to normal level(see fig1). RBC and platelet level were not significantly affected at either dosage(see fig2,fig3).

Discussion

1. In this study, Jilifen showed few adverse reactions at low dosage(75ug, 150ug). As dose increased to 300ug and 450ug, mild bone pain arose in some cases. All these

adverse reactions were tolerable and disappeared after withdrawal of Jilifen. The results were similar with that of rhG-CSF produced by foreign companies.

2. At dosage of 300ug and 450ug, some individuals showed grade I elevations of transaminase, alkaline phosphatase and lactate dehydrogenase, which disappeared after the withdrawal of Jilifen. Jaundice or hepatic dysfunction was not found.

3. Allergic reactions like fever, decrease of blood pressure or edema was not found.

4. Jilifen exhibited obvious action of elevating granulocyte level at low dosage, and the action enhanced as dose increased. Due to the limited case number of this study, a controlled phase II clinical trial is needed to evaluate the potency of Jilifen further.

Head Institute: Tumor Hospital of Zhongshan Medical University

Primary documents kept in: Tumor Hospital of Zhongshan Medical University

Discussion

1. In this study, Jilifen showed few adverse reactions at low dosage(75ug, 150ug). As dose increased to 300ug and 450ug, mild bone pain arose in some cases.All these adverse reactions were tolerable and disappeared after withdrawal if Jilifen. The results were similar with that of rhG-CSF produced by foreign companies.

2.At dosage of 300ug and 450ug, some individuals showed grade I elevations of transaminase, alkaline phosphatase and lactate dehydrogenase, which disappeared after the withdrawal of Jilifen. Jaundice or hepatic dysfunction was not found.

3.Allergic reactions like fever, decrease of blood pressure or edema was not found.

4.Jilifen exhibited obvious action of elevating granulocyte level at low dosage, and the action enhanced as dose increased. Due to the limited case number of this study, a control phase II clinical trial is needed to evaluate the potency of Jilifen further.