Recombinant Human Endostatin

Recombinant Human Endostatin Injection


 
Generic Name: Recombinant Human Endostatin Injection
Brand name: ENDOSTAR
Composition:
Recombinant Human Endostatin
Description:
Colorless transparent liquid. pH 5.5±0.5
Indications:
ENDOSTAR + NP chemotherapy regimen is used to treat Stage III/IV NSCLC patients either untreated or
pretreated.This indication is based on a completed multi-center Phase III clinical trial (see Clinical Studies).
Strength:
15mg/2.4×105U/3ml/vial
Dose and administration:
Add ENDOSTAR into 250~500ml NS just before the use, drip intravenously at uniform speed for 3~4h.
At combined administration with NP chemotherapy regimen, ENDOSTAR is administered continuously at
7.5mg/m2 (1.2×105U/m2) once a day during Day 1~14 of treatment cycle, and then continues the next
treatment cycle only after the rest for 1 week (generally 2~4 treatment cycles). The physician is recommended
to properly extend its administration time in clinical application within the tolerance of patients.
Adverse Reactions:
During Phase I~III clinical trial, ENDOSTAR is administered in 470 advanced NSCLC patients. The frequent
adverse reactions (1-10%) mainly occurred on heart, and rare adverse reactions (0.1-1%) mainly occurred in
digestive system and skin/annexa allergy.
1. Heart: At the early stage of administration, few patients have mild fatigue, chest distress and palpitation.
In most cases, these symptoms may improve enough so as not to influence the administration continuation
after the symptomatic treatment. But they can persist to discontinue the administration in very few cases. A
minority of cases had to stop the drug for the continuing above-mentioned symptoms. 30 patients (6.38%)
have Degree I/II or mild/moderate cardiologic adverse reactions of mainly myocardial ischemia within Day
2~7 after the administration and posing no dangers to the patient's life. 6.4‰ of these cases have more
evident but reversible symptoms, which does not influence the administration continuation but can alleviate
without any symptomatic treatment. Only 2.1‰ of the cases stop the treatment due to adverse reactions.
In the patients with previous coronary heart disease and hypertension, ENDOSTAR causes the following
frequent cardiologic adverse reactions: sinus tachycardia, mild ST-T change, AV conduction blocking, atrial
premature beat and rare ventricular premature beat. Thus, to guarantee patient safety, regular ECG
examination is recommended for the patient with cardiologic adverse reactions during clinical application.
Patient with previous serious heart diseases must use ENDOSTAR carefully under the guidance of physicians.
2. Digestive System: Rare diarrhea and liver dysfunction (mainly symptom-free transaminase elevation and
jaundice). All these adverse reactions are mainly mild/moderate but rarely serious. Most are reversible and
mild cases do not require symptomatic treatment; Moderate or serious cases may be alleviated through the
slowing of dripping speed or through the proper symptomatic treatment after drug withdrawal; and only few
cases require symptomatic treatment but generally have no influence on administration continuation.
3. Skin/Annexa: The allergy mainly includes reversible systemic maculopapule accompanied with itching
(relievable after drug withdrawal) and mostly mild/moderate fever and fatigue.No death related to adverse
reactions was observed in this multi-center clinical trial on all 470 ENDOSTAR-treated patients.
Contraindications:
Use carefully in the patient with heart/renal hypofunction.
Precautions:
1. Use carefully for the person with allergic constitution or previous allergy to protein biological products;
2. Use carefully for the patient with existing or previous serious heart diseases, including: congestive heart f
ailure, high-risk uncontrollable arrhythmia, angina pectoris requiring drug treatment, valvular disease of definite
clinical diagnosis, serious myocardial infarction on ECG and persistent hypertension. ECG examination shall
be regularly made during its clinical application, ECG monitoring performed for the patients with cardiologic
adverse reactions;
3. This product is colorless transparent liquid, and must not be used in case of abnormalities (such as turbidity
and sediment), broken packaging vial and expired.
4.When the temperature is interrupted(not more than 20ºC)during storage and transportation,the time should
not exceed 7 days,and freezing,illumination or heating shoule be avoided.
Pregnancy and lactation:
Never used in pregnant and lactating women, no previous animal experiment on its genital toxicity. Thus, use
only under the close supervision of physicians.
Pediatric use:
No previous clinical trial on its administration in pediatric patients. Used only if medication is absolutely needed
and only under the guidance of physicians.
Geriatric use:
Use only under the close observation of physicians for the old tumor patients with previous serious heart disease.
Drug interactions:
No previous systematic research on its interaction with other drugs. During the clinical application, do not mix
with other drugs or solutions possibly influencing its pH value.
Overdose:
In this clinical trial, the above-mentioned adverse reactions occur after the single intravenous drip of 30~210
mg/m2 (4.8×105~33.6×105U/m2) or after the continuous intravenous drip of 7.5~30mg/m2 (1.2×105~4.8×10
5U/m2) for 28d. There is no clinical data of higher dose.
See under section of Adverse Effect.
Clinical studies:
The National Clinical Trial Center for New Drugs (Anti-Tumor) of Cancer Hospital, Chinese Academy of
Medical Sciences, led a research team to jointly conduct a multi-center clinical trial.
Single-drug Administration: Phase II clinical trial (single-drug administration) adopts the randomly controlled,
open-labeled and multi-center research method. It mainly assesses the efficacy of ENDOSTAR, compares
the dose-efficacy relation and safety difference of 7.5mg/m2 (1.2×105U/m2) and 15mg/m2 (2.4×105U/m2),
and thus determines the optimum effective dose for clinical application. All subjects are retreated tumor p
atients pathologically and/or cytologically diagnosed definitely as non-small-cell lung cancer (NSCLC). The
subjects are divided into 7.5mg/m2 and 15mg/m2 dose group at intravenous drip for 3~12h once a day
continuously for 28d respectively. After the completion of administration, the efficacy is assessed according
to the Efficacy Evaluation Criterion on Solid Tumor (WHO). A total of 8 hospitals participates in this trial to o
bserve 68 NSCLC patients, among which 60 patients complete efficacy assessment (Table 1). 



Combination treatment: A randomly controlled, double-blind and multi-center Phase III clinical trial is made on
the combined administration of ENDOSTAR and NP regimen in 493 advanced NSCLC patients.Administration
regimen of test group: 25mg/m2 NVB at Day 1 and Day 5; 30mg/m2 DDP at Day 2, Day 3, and Day 4; and
7.5mg/m2 (1.2×105U/m2) ENDOSTAR continuously during Day 1~14. Administration regimen
of control group: 25mg/m2 NVB at Day 1 and Day 5; 30mg/m2 DDP at Day 2, Day 3, and Day 4; and normal
saline (NS) during Day 1~14. The endpoint research index includes: response rate(CR+PR/total cases×100%)
clinical benefit rate (CR+PR+MR+SD/total cases×100%), TTP, median survive time, one-year survival rate,
quality of life (QOL) and safety. There are 486 cases with evaluable efficacy, i.e. test group: control
group =322:164 (cases), and untreated: pretreated =347:139 (cases). (Table 2) .



Pharmacology and toxicology:
1. Pharmacological action 
Rh-Endostatin is a new angiogenesis-inhibiting biological product. It inhibits the metastasis of angiogenesis
endothelial cells, inhibits the formation of tumor new blood vessel, obstructs the nutrition supply of tumor cells,
and thus inhibits the proliferation or metastasis of tumor.As shown by in vitro test results, ENDOSTAR inhibits
the metastasis of HHEC and the formation of Tube, significantly inhibits the angiogenesis of chicken embryo
allantoic membrane. Thus, ENDOSTAR suppresses angiogenesis in vitro to a certain extent. In addition, it
inhibits the growth of human lung adenocarcinoma cells SPC-A4 to a certain extent.As shown by in vivo test
results, ENDOSTAR has extensive effects of inhibiting the mouse tumor model (S180 sarcoma, H22 liver
cancer) and human xenograft tumor (SPC-A4 lung adenocarcinoma, SGC7901 stomach cancer, Hela cervical
carcinoma, SMMC-7721 and Bel7402 liver cancer).
2. Toxicological action
General Pharmacology: After the intravenous injection of 1.5, 3 and 6mg/kg (2.4×104 - 4.8×104, and 9.6×104
U/kg)(high, medium and low dose group) , such parameters as blood pressure, respiration, and ECG index,
etc. of anaesthetized dog remains same to those before the injection, and the autonomic activity frequency
of mouse is not influenced.Hemolysis, Irritation,Allergy in Animal: There is no hemolysis or hemagglutinationin
during the observationtime after the administration of 0.08mg/ml ENDOSTAR; guinea-pig had no allergic
reactions after first the intraperitoneal injection of 0.5ml/guinea-pig (0.036mg/ml) every other day continuously
for 3 times and then the 1ml/guinea-pig (0.036mg/ml) 14d and 21d after the first administration; and rabbit had
no evident irritant reactions (such as vasodilatation and red swelling) or morphological changes (as vascular
wall thickening) in venous irritation test.
Acute Toxicity: Mouse had a LD50 of more than 450.5mg (7.2×106 U)/kg after the intravenous or
intraperitoneal administration of ENDOSTAR.
Long-term Toxicity: As shown by long-term toxicity test on rat, at the end of 21d after the withdrawal of
continuous intraperitoneal injection of 3, 6, and 12mg/kg/day (4.8×104, 9.6×104, and 19.2×104U/kg/day) for
45d respectively, all these three dose groups are not significantly different from control group in the
pathomorphological changes of internal organs (such as heart, liver, spleen, lung, brain, stomach, small
intestine, uterus and testicle).
As shown by long-term toxicity test on beagle dog, after the continuous intravenous injection of 2, 10 and
25mg/kg/day (3.2×104, 16.0×104, and 40.0×104U/kg/day) for 13 weeks respectively, beagle dog does not
have evident toxic reactions on target organs or delayed toxic reactions, but only have the adverse reaction
of elevated reticuloerythrocyte which is reversible after the drug withdrawal.
As shown by long-term toxicity test on rhesus, after the continuous intravenous injection of 3mg (4.8×104U)/
kg/day (50.4mg/m2), 10mg(1.6×105U)/kg/day (167.9mg/m2), and 30mg (4.8×105U)/kg/day (503.7mg/m2)
continuously for 9 months respectively, each dose group had no evident abnormal change in vital signs,
appearance behavior, and activities; its examination results fluctuated within the range of normal value for
weight, food intake, and hematological/blood biochemical/ECG/urine examination (i.e. no evident impairment
 liver and renal function; it had basically normal protein, fat, and glucose metabolism; and it is not significantly
different in organ coefficient and had no dose-related abnormal change according to the histopathological
results. In brief, no evident toxic reactions occur after the continuous intravenous injection of less than 30mg
(4.8×105U)/kg/day, and thus such dose range is safe for ENDOSTAR.
Pharmacokinetics:
After the single intravenous drip of 30mg (4.8×105U)/m2 and 60mg (9.6×105U)/m2 within 30min (at a speed
of 1 and 2mg/m2/min respectively) and of 120mg (19.2×105U)/m2 and 210mg (33.6×105U)/m2 within 120min
(at a speed of 1 and 1.75mg/m2/min respectively) in health volunteer, ENDOSTAR has a terminal clearance
half-life (t1/2) of about 10h and a systemic clearance rate (CLs) of about 2.8L/h/m2. In normal human body,
ENDOSTAR follows approximately the linear pharmacokinetics within the dose range of 30~120mg/m2 (4.8×
105~19.2×105U/m2). The linear model can be used to predict the blood drug concentration at different total
dose, dripping speed and dripping time, which can influence AUC and maximum concentration level.
In tumor patient, ENDOSTAR shows great inter-individual difference in drug concentration-time curve after the
daily intravenous drip within 2h continuously for 28d.The minimum concentration tends to increase continuously
with the increase in administration times, and both total dose and dripping times can influence both the peak
and trough concentrations.
After the intravenous administration of in normal mouse, the drug concentration is highest in urinary excretory
system, higher in kidney, urine, lung and liver than in plasma, lower in other tissues than in plasma, and lowest
in muscle, fat, and brain. After the intravenous injection in tumor mouse, the systemic distribution ENDOSTAR
is similar to that in normal mouse,  its low distribution in tumor tissue is similar to that in muscle and fat tissue.
Antibody generation:
The antibody IgG  serum is detected through indirect ELISA method the intravenous injection of ENDOSTAR
continuously for 9 months in rhesus. The antibody generated after the administration is related to both dose
and time: the higher dose generates the higher-titer antibody in more rhesuses. The antibody can be detected
1 month after the administration. The antibody titer varies with time: more stable in first 3 months before the
administration, and less and even no at Month 5, 7, 9, and 10. As analyzed through the cell viability detection
method, the ENDOSTAR viability in serum does not change at all, and thus the generated antibody is not
neutralizing antibody.Various ENDOSTAR antibodies (IgA, IgG, IgM, and IgE) and His-tag antibody are
detected through the same above antibody detection method in patient serum. 31 subjects undergo this
detection, including 20 cases from treatment group and 11 cases from control group. In treatment group,
2 cases have positive ENDOSTAR IgA on Day 32 and Month 24 respectively, and 1 case had positive His-tag
IgA, both at a titer of 1:10. In control group, 2 cases have positive IgG at a titer of 1:10. Any other patient does
not have antibody reaction after the treatment. The in vitro test on low-titer (1:10) serum antibody does not
show any biological activity to neutralize ENDOSTAR.
Storage:
Keep at 2~8ºC in a dark place
Package:
Filled in 3.0ml Pre-embedded syringe.
Shelf-life:
18 months