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Abstract # 1099
A Phase I Trial of Scutellaria Barbata (BZL101) for Metastatic Breast Cancer
Perez A1, Shaw HS2, Fleming G3, Hershman D4, Franco S1, Shapiro C5, Neal K6, Caygill K6, Cohen I6, Tagliaferri M6, Tripathy D7.
Memorial Cancer Institute, Hollywood, Florida1; Duke University Medical Center, Durham, NC2; University of Chicago, Chicago, IL3
Columbia University, New York, NY; Ohio State University, Columbus, OH5; Bionovo, Inc, Emeryville, California6;
University of Texas Southwestern, Dallas, Texas7.
Abstract
Background: BZL101 is an aqueous extract from herba Scutellaria Barbata. BZL101
demonstrates in vitro growth inhibitory effects on human breast cancer cell lines and does not
inhibit the growth of normal human mammary epithelium. In a murine xenograph model, oral and
intraperitoneal administration of BZL101 inhibited tumor formation without any observed toxicity.
Treatment of breast cancer cells with BZL101 leads to sustained inhibition of glycolysis, as evident
from the decreased enzymatic activities within the glycolytic pathway and inhibition of lactate
production. Because tumor cells primarily rely on glycolysis for energy production (Warburg
effect), targeting this pathway may lead to novel cytotoxic agents with less toxicity than the
currently available treatments. We are conducting an open-label, dose escalation, phase 1 trial of
BZL101 for the treatment of metastatic breast cancer to determine the maximum tolerated dose.
Methods: Eligible patients had histologically confirmed metastatic breast cancer and measurable
disease. Patients cannot receive any other anticancer treatment on trial. Three patients are
enrolled at each dose level and treated for 28 days. If toxicity is acceptable, 3 additional patients
are enrolled to a higher dose until the MTD is reached. The primary objectives are safety and
toxicity and to determine the maximum tolerated dose. The secondary objectives are tumor
response defined by RECIST, duration of response, survival time and change in patient reported
quality of life.
Results: Twenty patients have been enrolled to the study. The mean number of prior cytotoxic
treatments for metastatic disease was 3.1. There have been no SAEs attributable to BZL101.
There have been 3 DLTs in 2 patients; grade 4 AST elevation, grade 3 diarrhea and grade 3
fatigue. All other BZL101 related AEs were primarily grade 1 and 2, of which the most frequent
were: diarrhea (40%), nausea (30%), headache (20%) and increased ALT (20%). Of the 20
patients enrolled, 12 patients (60%) were on the trial for 28 days or more and evaluable according
to the RECIST criteria. Of those 12 patients evaluable according to RECIST, 5 patients (42%) had
stable disease for >90 days. One patient (ID# 03002) with bone only disease was stable for 12
months and had radiologic evidence of tumor shrinkage. One patient (ID# 05005) had evidence of
tumor shrinkage by physical exam and another patient (ID# 03006) reported complete resolution
of bone pain.
Conclusions: Oral administration of BZL101 has a favorable safety and tolerability profile and
encouraging clinical activity for the treatment of metastatic breast cancer.
Objectives
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Safety and tolerability
Maximum tolerated dose (MTD)
pancreas
Results
Results
(cont.)
Duration of response and
survival time
prostate
breast
Change in patient reported quality of life (EORTC
QLQ-C30)
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The selective cytotoxicity is based on the strong induction by BZL101 of reactive oxygen
species (ROS) in tumor cells leading to extensive oxidative DNA damage.
Oxidative DNA damage induced by BZL101 in breast cancer cells leads to the hyperactivation
of poly ADP-ribose polymerase (PARP), followed by a sustained decrease in levels of NAD and
depletion of ATP, neither of which are observed in non-transformed cells.
BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the
decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate
production.
The promising selectivity of BZL101 towards cancer cells is based on metabolic differences
between highly glycolytic tumor cells and normal cells.
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Women 18 years or older with histologically confirmed diagnosis of breast cancer and
clinical evidence of metastatic involvement
At least one measurable disease site defined by RECIST criteria
No more than 3 prior cytotoxic regimens administered for metastatic breast cancer
Completed prior therapies and had adequate time to recover sufficiently from the toxicities
associated with prior anticancer treatments
A life expectancy of ≥12 weeks
Eastern Cooperative Oncology Group (ECOG) performance stats ≤2
Patients were excluded from the study for clinically significant gastrointestinal abnormalities,
extensive liver involvement (>50% of liver parenchyma), lymphangitic pulmonary
involvement, central nervous system involvement or spinal cord compression not stabilized
by therapy for >3 months and organ or marrow dysfunction
Definition of Dose Limiting Toxicity (DLT)
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Grade 3, 4 or 5 toxicity that is possibly, probably or definitely related to study medication
Grade 2 gastrointestinal toxicity lasting for >3 weeks that is possibly, probably or definitely
related to study medication or less than 70% compliance with study medication due to oral
intolerability
If there were no DLTs at a dose level in which 3 patient reached 28 days with >70%
compliance, the dose was escalated to the next level
Adverse
Event
10g/day
N=11
Grade
(NCI-CTCAE)
I
II
III
20g/day
N=6
ID#
(dose)
Response
IV
I
II
III
30g/day
N=3
IV
Administration of BZL101 Dose
10g/day
10 grams in 100 mls of water or fluid, daily
Hemoglobin
10 grams in 100 mls of water or fluid, twice daily
30g/day
15 grams in 150 mls of water or fluid, twice daily
40g/day
20 grams in 200 mls of water or fluid, twice daily
Constitutional
Fatigue
2 (33)
Sweating
1 (9)
1 (17)
1 (17)
Gastrointestinal
Anorexia
2 (18)
Distension
1 (9)
Dehydration
1 (9)
1 (17) 1 (17)
1 (17)
Dental: teeth
Diarrhea
1 (17)
2 (18) 2 (18)
1 (17)
1 (9)
1 (17)
Flatulence
1 (33)
1 (17)
2 (67)
1 (33)
1 (9)
ER Positive
14 (70)
ER Negative
6 (30)
Prior Number of Cytotoxic Regimens
for Metastatic Disease
HER2/neu Status
Previously completed Phase I trial in 21 patients showed antitumor effects of BZL101 for
patients with advanced breast cancer. Four of the sixteen evaluable patients (25%) had stable
disease for >90 days and 3/16 (19%) had stable disease for >180 days. Five patients had
evidence of tumor shrinkage, one of which was 1mm short of a partial response (PR). Average
expected survival time was 379 days.
Mean (SD)
3.1 (2.7)
Positive
1 (5)
Median (Range)
2 (0-10)
Negative
16 (80)
Unknown
3 (15)
5 (25%)
Latina/Hispanic
4 (20%)
2 (18)
AST
1 (9)
3
05002
(10g/day)
Stable for 8
Months
Lung, local
regional
7
Discontinued due to patient choice at Month 4.
Patient still has stable disease.
05005
(10g/day)
Stable for 4
Months*
Bone, lung liver,
local regional,
contra-lateral
4
Axillary tumor decreased from 2.5cm at baseline to
1.5cm at Month 1 on physical exam; breast tumor
also decreased in size at Month 1 on exam.
Discontinued due to unwillingness to schedule study
procedures.
09002
(20g/day)
Stable for 1
Month
Lung, breast,
chest wall,
axillary lymph
nodes
1
Discontinued at Month 1 due to a new skin lesion on
left breast. Scans demonstrated a decrease in size
of total measurable lesions by 8% (a 55mm chest
wall lesion decreased to 50mm and a 21mm lymph
node decreased to 18mm).
05006
(20g/day)
Stable for 5
Months
Lung, distant
nodes
2
Active patient. Month 4 scans demonstrated two
lymph node tumors decreased in size compared to
Baseline. The total percent change in measurable
disease at Month 4 is 0% from baseline.
1 (33) 1 (33)
5
Despite progression noted in lung lesion at Month 4,
bone scans demonstrated stable disease and patient
reported complete resolution of bone pain and
improved quality of life.
2 (67)
1 (17)
1 (9)
Baseline Bone Scan of 03002
1 (33)
Month 2 Bone Scan of 03002
1 (17)
1 (9)
1 (17)
Pain
Pain-abdomen
1 (9)
Pain-back
Pain-headache
Pain-joint
Pain-vagina
TOTALS
Baseline ECOG PS
0
13 (65)
1
5 (25)
2
2 (10)
1 (17)
1 (9)
2 (18)
1 (17)
1 (33)
1 (9)
1 (9)
14
10
1
13
5
2
9
Summary
1
Average Time on Study Medication
Summary of Study Patients
Number of Days
Study Patients Enrolled
03002
Bone only
(10g/day)
disease
Stable for (not evaluable by
12 Months*
RECIST)
1 (9)
ALT
Watery eye
58 (32-78)
Black/African American
1 (17) 1 (17)
IV
Comments
At Month 2, the radiologist reported “Mild
improvement in the patient’s bone scans with less
intrusive activity noted in the left anteromedial rib
and left acetabular region” (see bone scans below).
Discontinued due to patient choice. Patient still has
stable disease.
N=20 (%)
59.9 (13.3)
11 (55%)
Areas of
Disease
Ocular/Visual
Estrogen Receptor
Status
Median (Range)
White/Caucasian
1 (9)
1 (17)
Alk Phosphate
Mean (SD)
Race/Ethnicity
Number of
Prior
Therapies for
Metastatic
Disease
03006
(20g/day)
Stable for 4
Months
Bone, lung
*Status unconfirmed in database
1 (17)
Total protein
N=20
III
Metabolic
Baseline Patient Characteristics
Age (years)
II
1 (9)
Vomiting
20g/day
I
Blood/Bone
Marrow
Nausea
Dose of BZL101
One patient with bone only disease has been stable for approximately 12 months.
Number of Patients (% in dose level)
Mucositis
Dose-Escalation Schedule
Of the 20 patients enrolled, 12 patients were on the trial for 28 days or more and evaluable
according to RECIST criteria.
Of the 12 patients evaluable by RECIST, 5 patients (42%) had stable disease for >90 days.
Patients Demonstrating Clinical Activity
Adverse Events Classified as Related to BZL101
Key Inclusion/Exclusion Criteria
BZL101 via IP administration prevented tumor formation in a mouse xenograft model. Oral
administration of BZL101 0.5 ml or 1.0 ml three times per week showed significant inhibition of
tumor formation at day 28 (t-test), BZL101 0.5 ml vs. control, p=0.011; BZL101 1.0 ml vs.
control, p=0.014.
1 Breast Cancer Res Treat. 2007 Sep;105(1):17-28. Epub 2006 Nov 17. PMID: 17111207.
2 Cancer Biol Ther. 2008 Jan 7;7(4) [Epub ahead of print] PMID: 18305410
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BZL101 is well tolerated. The most common adverse events are diarrhea (40%), nausea (30%), headache
(20%) and increased ALT (20%).
No serious adverse events were classified as related to BZL101.
The MTD has not yet been determined; the maximum dose of 40g/day is currently being evaluated.
There have been 3 DLTs; grade 4 AST elevation, grade 3 diarrhea and grade 3 fatigue (grade 3 diarrhea
and fatigue occurred in the same patient).
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Heartburn
BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, has a selective cytotoxic
activity towards breast cancer cell lines and does not target non-transformed cells.
Clinical Activity
Summary of Adverse Events Possibly, Probably or
Definitely Related to BZL101
Tumor response (RECIST)
Methods
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Background
Secondary
Primary
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Results
10g/day
N=11
20g/day
N=6
30g/day
N=3
Total
N=20
55
84
53
63
10-207
19-149
49-61
10-207
N=20 (%)
Included in safety analysis
20 (100)
Evaluable by RECIST criteria
12 (60)
Number of patients with DLTs
2 (10)
Total number discontinued
16 (80)
Disease progression
10 (63)
Patient choice
3 (19)
Adverse event
1 (6)
Serious adverse event
1 (6)
Non-compliance with study procedures
1 (6)
Range
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Compliance with Study Medication
10g/day
N=10*
20g/day
N=6
30g/day
N=3
Total
N=19
Mean
93%
93%
96%
93%
Range
73-100%
61-100%
94-98%
61-100%
Compliance
*One patient did not return study drug, compliance unknown.
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The MTD has not yet been reached; the study is continuing at 40g/day.
Extracts of Scutellaria Barbata inhibit the growth of breast cancer cells in vitro.
BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the
decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate
production.
Oral administration of BZL101 is well tolerated. The most common adverse events are: diarrhea
(40%), nausea (30%), headache (20%) and increased ALT (20%).
There have been 3 DLTs: grade 4 AST elevation, grade 3 diarrhea and grade 3 fatigue (grade 3
diarrhea and fatigue occurred in the same patient). There have been no serious adverse events
attributed to BZL101.
On average, compliance with study medication was 93% of prescribed doses taken.
In this heavily pre-treated population, of the patients evaluable according to RECIST, 5 of 12 patients
(42%) had stable disease for >90 days. One patient with bone only disease has been stable for
approximately 12 months. Of the 20 women enrolled, 10 patients discontinued therapy due to
progression, 3 patients discontinued due to patient choice, 1 discontinued due to a non-drug related
SAE, 1 discontinued due to an AE, and 1 discontinued due to non-compliance with study procedures.
Patient 03002 has been stable for 12 months and had radiologic (bone scan) evidence of tumor
shrinkage.
Patient 03006 reported complete resolution of bone pain and improved quality of life.
Patient 05005 had evidence of tumor shrinkage by physical exam.