A Phase I Trial of Scutellaria Barbata (BZL101) for Metastatic Breast Cancer

1
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 1099
Abstract
Objectives
Results
Results (cont.)
Results

• Secondary
• Tumor response (RECIST)
• Duration of response and survival time
• Change in patient reported quality of life
  (EORTC QLQ-C30)

• Primary
• Safety and tolerability
• Maximum tolerated dose (MTD)

Summary of Adverse Events Possibly, Probably or
Definitely Related to BZL101
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 gt90 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.
pancreas
prostate
breast

• 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).

Patients Demonstrating Clinical Activity
Methods
ID (dose) Response Areas of Disease Number of Prior Therapies for Metastatic Disease Comments
03002 (10g/day) Stable for 12 Months Bone only disease (not evaluable by RECIST) 3 At Month 2, the radiologist reported Mild improvement in the patients 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.
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.
03006 (20g/day) Stable for 4 Months Bone, lung 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.
Adverse Events Classified as Related to BZL101

• Key Inclusion/Exclusion Criteria
• 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 (gt50
  of liver parenchyma), lymphangitic pulmonary
  involvement, central nervous system involvement
  or spinal cord compression not stabilized by
  therapy for gt3 months and organ or marrow
  dysfunction
• Definition of Dose Limiting Toxicity (DLT)
• Grade 3, 4 or 5 toxicity that is possibly,
  probably or definitely related to study
  medication
• Grade 2 gastrointestinal toxicity lasting for gt3
  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 gt70 compliance, the
  dose was escalated to the next level

Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level) Number of Patients ( in dose level)
Adverse Event 10g/day N11 10g/day N11 10g/day N11 10g/day N11 20g/day N6 20g/day N6 20g/day N6 20g/day N6 30g/day N3 30g/day N3 30g/day N3 30g/day N3
Grade (NCI-CTCAE) I II III IV I II III IV I II III IV
Blood/Bone Marrow
Hemoglobin 1 (9)
Constitutional
Fatigue 2 (33) 1 (17)
Sweating 1 (9) 1 (17)
Gastrointestinal
Anorexia 2 (18)
Distension 1 (9) 1 (17) 1 (17)
Dehydration 1 (9) 1 (17)
Dental teeth 1 (17) 1 (33)
Diarrhea 2 (18) 2 (18) 1 (17) 1 (17) 2 (67)
Flatulence 1 (9) 1 (17)
Heartburn 1 (33)
Mucositis 1 (17)
Nausea 1 (9) 1 (9) 1 (17) 1 (17) 1 (33) 1 (33)
Vomiting 1 (17) 2 (67)
Metabolic
Alk Phosphate 1 (9)
ALT 2 (18) 1 (17) 1 (33)
AST 1 (9) 1 (9) 1 (17)
Total protein 1 (9)
Ocular/Visual
Watery eye 1 (17)
Pain
Pain-abdomen 1 (9) 1 (17)
Pain-back 1 (9)
Pain-headache 2 (18) 1 (17) 1 (33)
Pain-joint 1 (9)
Pain-vagina 1 (9)
TOTALS 14 10 1 13 5 2 9 1
Background

• 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.
• 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.
•  
• 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, p0.011 BZL101 1.0 ml vs. control,
  p0.014.
• 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
  gt90 days and 3/16 (19) had stable disease for
  gt180 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.
• 1 Breast Cancer Res Treat. 2007
  Sep105(1)17-28. Epub 2006 Nov 17. PMID
  17111207.
• 2 Cancer Biol Ther. 2008 Jan 77(4) Epub ahead
  of print PMID 18305410

Dose-Escalation Schedule Dose-Escalation Schedule
Dose of BZL101 Administration of BZL101 Dose
10g/day 10 grams in 100 mls of water or fluid, daily
20g/day 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
Status unconfirmed in database
Baseline Bone Scan of 03002
Month 2 Bone Scan of 03002
Baseline Patient Characteristics
Age (years) N20
Mean (SD) 59.9 (13.3)
Median (Range) 58 (32-78)
Prior Number of Cytotoxic Regimens for Metastatic Disease Prior Number of Cytotoxic Regimens for Metastatic Disease
Mean (SD) 3.1 (2.7)
Median (Range) 2 (0-10)
Race/Ethnicity Race/Ethnicity
White/Caucasian 11 (55)
Black/African American 5 (25)
Latina/Hispanic 4 (20)
Estrogen Receptor Status N20 ()
ER Positive 14 (70)
ER Negative 6 (30)
HER2/neu Status HER2/neu Status
Positive 1 (5)
Negative 16 (80)
Unknown 3 (15)
Baseline ECOG PS Baseline ECOG PS
0 13 (65)
1 5 (25)
2 2 (10)

Summary
Average Time on Study Medication

• 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 gt90 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.

10g/day N11 20g/day N6 30g/day N3 Total N20
Number of Days 55 84 53 63
Range 10-207 19-149 49-61 10-207
Summary of Study Patients
Study Patients Enrolled N20 ()
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)
Compliance with Study Medication
Compliance 10g/day N10 20g/day N6 30g/day N3 Total N19
Mean 93 93 96 93
Range 73-100 61-100 94-98 61-100
One patient did not return study drug,
compliance unknown.