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A Summary of Clinical

Application & Research


Progress of BRM

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Outline ( 1

 BRM has a molecular target-taxis diphasic broad spectrum
anti-cancer action, like chemotherapeutic drug, killing
cancer cells directly and enhancing immunity of the body
as well, thus lead to an improvement of the clinical
symptoms

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Outline ( 2 )
Hundreds of study reports published in China indicate that BRM
mainly has following efficacies :
 When BRM is used singly in treating cancers, it has obvious
therapeutic effect to many primary malignant tumours such as lung
cancer, hepatic cancer, gastric cancer, mastocarcinoma, etc, and
can enhance immune function of human body, improve patients’
survival quality and prolong their survival period ;
 When BRM is used in combination with chemotherapy , radiotherapy and
intervening therapy, it can increase the clinical curative effect by about one
time and remit toxic and side effects caused by radio/chemotherapy.

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Preoperative use of BRM may facilitate the liquification and

necrosis of the tumor and raise the curative ratio surgically;

In the treatment of advanced malignant tumor, BRM holds the

cachexia in check effectively, arresting cancerous pain, improving

body weight and survival quality;

As yet no damage to the heart, liver, kidney function and

hematopoietic system and other adverse effects associated with

BRM has been reported.

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(1) A Survey to the Clinical
Trial

Since 1993, BRM has been subjected to

various kinds of clinical trials. Of them


Phase 3 clinical study is the largest one.
Here we will give a introduction to the
study results.

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1. About China phase Ⅲ clinical trial

2. About China phase Ⅰ clinical trial

3. About China phase Ⅱ clinical trial

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1. About China phase Ⅲ
clinical trial

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( 1) BRM used solely in the treatment of primary
lung cancer

The study of “BRM in the treatment of primary bronchial lung cancer” at


Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) revealed
that :
 BRM group effective rate: 12.15% (26/214); chemotherapy group (for
control, MVP and EP program) effective rate: 14.29% (13/91). No significant
difference between the two groups (P > 0.05).
 The results showed BRM has advantage over chemotherapy in the
improvement of symptoms such as cough, bloody sputum, chest pain,
fever, languidness, poor appetite in patients with primary bronchial cancer.

 Assay on immunological function revealed BRM has the effects of raising


the NK cell activity and IL-2 level, improving T-lymphocyte subgroup ratio
and protection of the peripheral blood picture.

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Phase Ⅲ Clinical Trial on
Treatment of Primary Lung Cancer
Comparison of Therapeutic Effect

Group Scheme Case (n) CR PR SD PD Effective


rate
(%)

BRM BRM 214 0 26 165 23 12.15*

Chemothera MVP /EP 91 1 12 62 16 14.29


py

*compared with
chemotherapy P>0.05

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( 2 ) BRM used solely in treatment of primary
hepatic cancer
Cancer Hospital, Chinese Academy of Medical Sciences conducted a BRM treatment of primary
liver cancer patients. The results showed that:
BRM effective rate of 11.43% of liver cancer, chemotherapy group (PAF program) effective rate
of 9.8% between the two groups no significant difference.
Test proved that BRM can significantly improve the symptoms of liver cancer patients and
improve the quality of life and immune function.
Tests also confirmed that, BRM without bone marrow suppression, liver and renal function no
obvious damage.
See only mild adverse reactions of nausea, fever, after stopping their own ease.

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Phase Ⅲ Clinical Trial on
Treatment of Primary Hepatic
Comparison of Therapeutic Effect Cancer

Group Case CR PR MR SD PD Effective


rate
(%)

KLT 105 0 12 36 41 16 11.42*

Chemotherapy 91 1 5 6 20 20 9.80
PAF scheme

* Compared with
chemotherapy P>0.05

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( 3 ) BRM + Chemotherapy in the Treatment of NSCLC

Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) conducted


clinical study on treatment of NSCLC with BRM + Chemotherapy method
( PVM scheme :Cisplatin+Vindesine+Mitomycin C ) with results as
follows :

 The effective rate of BRM+PVM group is 为 45 %( 18/40 ), while that of


PVM chemotherapy group is 22 %( 7/32 ), showing significant difference.
It indicates that BRM in combination with chemotherapy yields synergism
and enhances effect in treatment of NSCLC.

 All examination indices demonstrate that BRM combined with


chemotherapy can obviously improve patients’ common state.

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Phase Ⅲ Clinical Trial on BRM +
Chemotherapy in Treatment of
NSCLC
Comparison of Effective Rate

Group Scheme Case MR SD PD Effective


PR rate
(%)

Trial BRM+PVM 40 18 9 9 4 45*

Control Sole PVM 32 7 2 10 13 22

*Compared with control


group P<0.05

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( 4 ) Combination of BRM and surgery in the treatment of lung

cancer

The study of BRM preoperatively for the treatment of lung cancer was
carried out in Cancer Hospital, Chinese Academy of Medical Sciences
(CAMS) . the results showed:

 The occurrence of large area necrosis of tumor tissue more than 25%
demonstrated by postoperative pathological examination in BRM group
being 62.22% (28/45), and that of the control group being 26.67% (8/30),
significant difference was present.
 Among whom with necrotic area larger than 50% in the BRM group being
28.9% (13/45), and that of the control group being 13.3% (4/30), had
significant difference.

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Phase Ⅲ Clinical Trial on BRM combined with
Surgical Operation in Treatment of Primary Lung
Cancer
Comparison of the necrosis area between the tumor specimen
of the two groups
Group Case Necrotic area Effective
rate ( % )
( necrotic area
<25% 25~50% 50~70% >25% )

BRM 45 17 15 13 62.22*

Control 30 22 4 14 26.67

*Compared with control group P<0.05

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( 5 ) BRM + Radiotherapy in Treatment of Malignant
Tumors

clinical studies on BRM + Radiotherapy in Treatment of Malignant Tumors,


and the result indicates that :

 The effective rate of this combination therapy is 82.2%(83/101) , while

that of treatment merely using radiotherapy is only 60.4%(52/86),


showing a significant difference.

 The grain factor of BRM + Radiotherapy method is

1.36 ( 82.2 % /60.4 %)。

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Phase Ⅲ Clinical Study on BRM +
Radiotherapy in Treatment of Malignant
Tumors
Group Case CR PR SD+PD Effective rate (%)

Therapy 101 50 33 18 82.18 *

Control 86 16 36 34 60.47

*Compared with control group P<0.001

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( 6) Combined BRM intervention therapy in the
treatment of primary hepatic cancer and primary
lung cancer

This treatment in patients with primary lung cancer or primary hepatic cancer,
the results showed:

 Chemotherapy + BRM intervention therapy for the treatment of hepatic cancer,


effective rate: 69.23% (90/130); sole chemotherapy intervention effective rate:
38.23% (26/68), the former was evidently superior to the latter.

 Chemotherapy + BRM intervention therapy for the treatment of lung cancer,


effective rate: 52.11% (74/142); sole chemotherapy intervention effective rate:
28.95% (22/76), the results of combined therapy group was evidently superior to
the sole chemotherapy group and had significant difference between the two
groups

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Phase Ⅲ Clinical Trial on Combined BRM
Intervention Therapy in Treatment of
Primary Hepatic Cancer and Primary
Lung Cancer
Group Scheme Case PR MR SD PD Effective
rate
(%)
Hepatic BRM+ 130 4 86 24 16 69.23*
cancer Chemotherapy

Sole 68 1 25 22 20 38.24
chemotherapy

Lung BRMT+ 142 8 66 55 13 52.11*


cancer Chemotherapy

Sole 76 2 20 43 11 28.95
chemotherapy

* Compared with sole chemotherapy group P<0.05

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( 7 ) BRM Can Control Cancer Pain and Improve the Survival Quality
of Advanced Cancer Patients

BRM can effectively control cancer pains and improve survival quality of advanced cancer
patients :

 By BRM therapy , the pain remission rate among 328 patients with cancer pain
reaches 80.49 %( PR of 56.1 %, CR of 24.39 %) .

 By BRM therapy, among patients with different degree of pains (slight, moderate ,
severe ) , 100 % patients with slight pain can be controlled (62/62) , 86.18 % with
moderate pain ( 131/152 ) is remitted , and 62.28 % with severe pains is
( 71/114 )

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Clinical Trial on Improvement of
Survival Quality of Advanced Cancer
Patients
Effect of BRM to survival quality score of Advanced Cancer Patients

Score of life and survival quality increases after therapy (score )

0 5 10 15 20 25

Case 33 70 97 88 68 20

% 8.78 18.62 25.80 23.40 18.09 5.30

After therapy by BRM, 91.22% ( 343/376 ) of the patients see survival quality score
increase, and those whose score increased by 10 points accounting for
72.61% ( 273/376 )

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Phase Ⅲ Clinical Trial of Cancerous Pain Control
of Advanced Cancer Patient
Relief degree of cancerous pain after BRM therapy
Pain Case Pain-relieving degree Remission
degree rate
0 1 2 3 4 ( 100% )

Slight 62 0 0 0 0 62 100

Moderate 152 21 30 50 36 15 86.18

Severe 114 43 32 21 15 3 62.28

Total 328 64 62 71 51 80 80.49

The overall effective rate of pain control after BRM therapy reaches 80.49% ( partial relief
56.10% , complete relief 24.39% ), and the pain-relieving effect can last about 1-7 days after
withdraw of BRM, and no habituation occur. Therefore, BRM can partially or totally replace
morphine or morphine like analgesics.

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2. About China Phase Ⅰ Clinical
Trial

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China Phase Ⅰ Clinical Trial

Purpose : Investigation on relations of medicine tolerance,


dosage and toxic and side effects

Case involved : 16 patients ( 15 persons are assessable )

Cancer type : NSCLC, esophageal cancer, prostate cancer, colon


cancer, thyroid gland cancer, pancreatic cancer, carcomas,
carcinoid tumor, mesothelial cancer, totally nine kinds.

Grouping : 15 patients were divided into five dosage groups,


each 2-4 persons, the dosage were respectively

2.4g/d, 3.6g/d,4.8g/d, 5.4g/d, 6.0g/d

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Test Results of BRM Toxicity

Dosage group Case Case assessable Number of DLT* toxicity of grade 2

I ( 2.4g/d ) 3 3 0 0
II ( 3.6g/d ) 3 3 0 0
III ( 4.8g/d ) 4 3 0 1
IV ( 5.4g/d ) 3 3 0 0
V ( 6.0g/d ) 2 2 0 0

● DLT ( Dose limiting toxicity ): denotes BRM therapy-

related grade 3 non-blood system toxicity or grade 4


blood system toxicity 25
Follow-up Investigation on BRM
Therapeutic Effect and Patients’ Survival
State.
Among the 15 patients :
SD ( stable disease ) patient : 10 persons
PD ( progress disease ) patient : 5 persons

The follow-up investigation shows:


The stable duration of all 10 SD patients exceeds 6 months;
7 patients survived for more than one year;
1 patient (suffered from pancreas cancer) survived for 25.5 months

 All involved patients suffered from different advanced


cancers, with expected survival period of 3 - 6 months

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3. About China Phase Ⅱ
Clinical Trial

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About China Phase ⅡClinical Trial

Purpose : Investigation on medicine therapeutic


effect and toxic effect to advanced NSCLC

Case involved : 29 patients ( 28 assessable )

Method : 1 ) Merely using BRM solely

2 ) Sequential application of BRM and


chemotherapeutic medicine

3 ) BRM used in combination with


chemotherapeutic medicine

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Summary of China Phase Ⅱ Clinical Trial
Conclusion
● The trial demonstrates the BRM effect in treatment of NSCLC.

● 72.2% ( 17/22 ) of the patients were benefited by the


sole BRM treatment or sequential treatment of BRM
combined with chemotherapy; so far 40.9% ( 9/22 ) of
the patients remain relatively satisfactory living
state though still suffered from tumor , with average
survival period of 352.5 days.

● 100% of the 6 patients subjected to combined treatment of


BRM and GP chemotherapy saw curative effects, and the
time to progress ( TTP ) was 7.3 months.

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2. New progress of domestic
and foreign basic research

Over the years, a series of domestic and foreign basic


studies of BRM was made on basis of the previous study
focusing on current hot issues of tumor study in order to
deepen the academic connotation of BRM and further study

its anti-tumor mechanism, which are briefed as follows.

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1. Previous Study Results
The study results of top research bodies such as Chinese
Academy of Medicine Sciences Tumor Hospital show that the
anti-tumors mechanism of BRM involves the following

aspects :

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BRM 抗癌作用机理研究

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Inhibit of BRM to the Activity of Protein
Kinase C

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containing cell-dissolved products

82
1-
nM

-3
Ro
20

K
K
0K

00
er

uM
50
l
/m
l
/m

st

+1

+1

+2
+
ul

le
ul

e
l

50

e
ro

bo

e
0

id
id

id

id
T1
nt

pt
or

pt
T

pt

pt
Co

KL
KL

Pe
Ph

Pe

Pe

Pe
(-) (non-phosphopeptide)

(phosphopeptide)
(+)

BRM inhibits the activity of protein kinase C induced by Phorbol ester

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BRM Inhibits the Activity of Metalloprotease-9(MMP-9)

20 nM Phorbol

0 0 10 35 50

BRM inhibits MMP-9 MMP-9


mRNA expression
(RT-PCR method) 甘油醛 -3- 磷
酸脱氢酶

20 nM Phorbol

0 0 10 35 50
MMP-9
BRM inhibits MMP-9
Activity (zymogram method)
MMP-2

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BRM Inhibits the Attack of Tumor Cells
on Basement Membrane Matrix
Phorbol (20 nM) PHorbol (20 nM)+
BRM(1.2 ul/ml)

Phorbol (20 nM)+ Phorbol (20 nM)+


BRM(2.4 ul /ml) BRM(3.6 ul / ml)

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BRM Inhibits the Activity of Fatty Acid Synthase
(FAS).

KLT decreases the Expression of MDA-MB-231


Cell FAS Protein

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BRM Inhibits the Activity of Fatty Acid Synthase

Blank control
BRM(2.4g)
14C acetate binding enters lipid

BRM(3.6g)
140
120
(% control)

100
80
60
40
20
0 hour
1 3 6 12 24 36 48 60 72

After action of BRM, the obvious reduction of quantity of


acetate binding entering the lipid is dependent on the
dosage. 37
Study Result of BRM Action Mechanism

Inhibiting Adjusting tumor


Inhibiting formation Adjusting tumor Adjusting tumor Adjusting enzyme
proliferation- nuclear
of nascent blood vessel cell factor gene expression expression
induced apoptosis transcription factor

inhibiting Decreasing Decreasing


Reducin
G2+M cancer- partial
g TNF- Decreasing
Inducing promoting cancer cell
phase a,IL- expression
apoptosi gene bcl-2 strain,
cell, 1leve, of MMP-9
s of expression, especially
reducing increasi (metallopr
tumor increasing breast
percentag ng IL-VI otease-9),
cell cancer- cancer cell
level of COX-2
e of S inhibiting strain NF-
serum, (epoxidase
period, gene P53 κB
improvi -2),PKC
and and expression,
ng (protein
inhibiting Fas/Apo-1 facilitating
cachexi kinase C)
proliferati expression cancer cell
a of and FAS
apoptosis.
on of tumor. (fatty acid
tumor cell synthase)
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