A Summary of Clinical Application

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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 ? clinical trial
• 2. About China phase ? clinical trial
• 3. About China phase ? clinical trial

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1. About China phase ? 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
  (Pgt0.05).
• 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 ? Clinical Trial on Treatment of Primary
Lung Cancer
compared with chemotherapy Pgt0.05
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• (2)BRM used solely in treatment of primary
  hepatic cancer
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Phase ? Clinical Trial on Treatment of Primary
Hepatic Cancer
Compared with chemotherapy Pgt0.05
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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 MSCLC with BRM Chemotherapy method
  (PVM scheme )with results as follows
• The effective rate of BRMPVM group is
  ?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 ? Clinical Trial on BRM Chemotherapy in
Treatment of NSCLC
Compared with control group Plt0.05
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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 ? Clinical Trial on BRM combined with
Surgical Operation in Treatment of Primary Lung
Cancer
Compared with control group Plt0.05
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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 ? Clinical Study on BRM Radiotherapy in
Treatment of Malignant Tumors
Compared with control group Plt0.001
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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 ? Clinical Trial on Combined BRM
Intervention Therapy in Treatment of Primary
Hepatic Cancer and Primary Lung Cancer
Compared with sole chemotherapy group Plt0.05
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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
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 ? Clinical Trial of Cancerous Pain Control
of Advanced Cancer Patient
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 ? Clinical Trial
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China Phase ? 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

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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 ? Clinical Trial

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About China Phase ?Clinical 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 ? 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????????
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Inhibit of BRM to the Activity of Protein Kinase
C
containing cell-dissolved products
Peptide 2uM Ro-31-8220
Phorbol ester 20nM
Peptide 100K
Peptide 50K
KLT 50 ul/ml
Peptide 10K
KLT10 ul/ml
Control
(-)
(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)

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BRM Inhibits the Attack of Tumor Cells on
Basement Membrane Matrix
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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
140
120
100
14C acetate binding enters lipid ( control)
80
60
40
20
hour
0
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.
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Study Result of BRM Action Mechanism
Inhibiting proliferation- induced apoptosis
Inhibiting formation of nascent blood vessel
Adjusting tumor cell factor
Adjusting tumor gene expression
Adjusting tumor nuclear transcription factor
Adjusting enzyme expression
Decreasing partial cancer cell strain, especially
breast cancer cell strain NF-?B expression,
facilitating cancer cell apoptosis.
Decreasing cancer-promoting gene bcl-2
expression, increasing cancer-inhibiting gene P53
and Fas/Apo-1 expression
Reducing TNF-a,IL-1leve, increasing IL-VI level
of serum, improving cachexia of tumor.
inhibiting G2M phase cell, reducing percentage
of S period, and inhibiting proliferation of
tumor cell
Decreasing expression of MMP-9 (metalloprotease-9)
, COX-2 (epoxidase-2),PKC (protein kinase C) and
FAS (fatty acid synthase)
Inducing apoptosis of tumor cell