Society of Integrative Oncology

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• Society of Integrative Oncology
• A Phase I/II Clinical Trial Assessing Safety and
  Efficacy of BZL101 for Metastatic Breast Cancer
• Alejandra Perez, MD
• Co-Director, Breast Cancer Center
• Memorial Cancer Institute

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What is BZL101?

• An oral extract of Scutellaria Barbata
• Pin Yin name Ban Zhi Lian (BZL)
• The aerial parts (leaves stems) are used for
  BZL101
• Delivered in a packet with excipients to mask the
  bitter taste of the herb
• Powder is mixed with liquid to make a tea

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BZL101- A Novel Mechanism of Action
Cancer Cells
Normal Cells

• Normal cells depend on citric acid cycle (gt85)
  and glycolysis (lt7) for energy production
• Cancer cells depend on glycolysis (gt85) for
  energy production
• BZL101 inhibits energy production by inhibiting
  glycolysis
• BZL101 causes DNA damage and cancer cell death
• BZL101 does NOT cause normal cell death

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BZL101- Basis for the Selectivity Towards
Cancer Cells

• Tumor cells rely on glycolysis for energy
  production. This is associated with increased
  endogenous levels of ROS. Normal cells rely on
  oxidative phosphorylation for their energy needs.
• BZL101 treatment further increases ROS levels in
  tumor cells leading to hyper-activation of PARP
  and massive oxidative DNA damage. In normal cells
  BZL101 treatment results only in mild increase of
  ROS levels and moderate DNA damage without PARP
  activation.
• Activation of PARP depletes NAD/NADH (substrate
  for synthesis of poly ADP-ribose) and ATP stores.
  
• Glycolysis uses cytosolic NAD as a substrate to
  generate ATP and is inhibited by lack of NAD.
  (Oxidative phosphorylation uses mitochondrial
  NAD to generate ATP and is generally not
  affected by PARP activation).
• Depletion of NAD and ATP by BZL101-induced PARP
  activation leads to inhibition of glycolysis,
  further reduction in ATP levels and cell death.

. Cancer Biol Ther. 2008 Jan 77(4) Epub ahead
of print PMID 18305410
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BZL101 Phase 1A Results
In modified RECIST evaluation, where all
measurable lesions included as evaluable
Expected survival 90-120 days On study, average
survival 327.5 days (Kaplan-Meier Survival
Analysis)
Breast Cancer Research and Treatment (2006),
Rugo H, et al. 2007 Sep105(1)17-28. Epub 2006
Nov 17. PMID 17111207 Accepted in 5 days and
highlighted as critical trial
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BZL101 Phase 1A vs. BZL101 Phase 1B
BZL-101-001 Phase 1A BZL-102-002 Phase 1B
Dose Single Dose 12 gm 350 ml Multiple Ascending Doses 10 gm 100 ml 20 gm 100 ml 30 gm 150 ml 40 gm 200 ml (note 20, 30, and 40 grams were taken twice/day)
Number of Participants 21 27
Study Drug High volume of insoluble plant fiber Taste bitter Liquid form Reduced volume of insoluble plant fiber Taste bitter taste has been modified and masked Freeze-dried to be mixed with liquid
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BZL101 Phase 1B Design

• Primary
• To determine the maximum tolerated dose of BZL101
• To provide preliminary data on safety and
  efficacy of BZL101
• Secondary
• Tumor response as defined by Response Evaluation
  Criteria In Solid Tumors (RECIST)
• Overall and progression-free survival
• Duration of response
• Change in participant-reported QOL (EORTC
  QLQ-C30)
• Main eligibility criteria
• Histologically confirmed breast cancer
• Measurable stage IV disease
• No more than 3 prior chemotherapies for
  metastatic disease

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BZL101 Phase 1B Summary

• Why 20 grams?
• Easier to tolerate
• 40g/30g many GI side effects and difficulty
  taking BZL101
• Average days on study longest

Decision
20g
Phase 2
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Phase 1B Baseline Characteristics
Age (years) N27
Mean (SD) 58.4 (13.9)
Median (Range) 59 (32-78)
Race/Ethnicity Race/Ethnicity
White/Caucasian 16 (59)
Black/African American 6 (22)
Hispanic 5 (19)
Baseline ECOG PS Baseline ECOG PS
0 16 (60)
1 9 (33)
2 2 (7)
Prior Anticancer Therapies N27 (SD)
Mean (SD) 5.6 (3.7)
Median (Range) 5 (1-19)
Prior Chemo Regimens
Mean (SD) 2.8 (2.4)
Median (Range) 2 (0-10)
Hormone Receptor Status N27 ()
Positive (either ER or PR ) 14 (63)
Negative (both ER and PR -) 10 (37)
HER2/neu Status HER2/neu Status
Positive 17 (63)
Negative 10 (37)
For metastatic disease
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Phase 1B Summary of Study Participants
Study Participants N27 ()
Included in safety analysis 27 (100)
Evaluable by RECIST criteria 17 (63)
Number of participants with DLTs 3 (11)
Number of active participants 1 (4)
Total number discontinued 26 (96)
Disease progression 18 (67)
Patient choice 3 (11)
Adverse event 2 (7)
Serious adverse event 2 (7)
Non-compliance with study procedures 1 (4)
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Phase 1B Adverse Events Related and Experienced
by 10
Adverse Event By CTCAE 10 g/d N (n11) 20 g/d N (n6) 30 g/d N (n3) 40 g/d N (n7) Total N () (n27)
Constitutional
Fatigue 0 3 0 3 6 (22)
Gastrointestinal
Abdominal distension 1 2 0 0 3 (11)
Anorexia 2 0 0 1 3 (11)
Diarrhea 4 2 2 5 13 (48)
Flatulence 1 1 0 1 3 (11)
Nausea 2 2 2 5 11 (41)
Vomiting 0 1 2 4 7 (26)
Metabolic/Laboratory
ALT elevation 2 1 1 0 4 (15)
AST elevation 2 1 0 0 3 (11)
Pain
Pain-abdomen 1 1 0 1 3 (11)
Headache 3 1 0 0 4 (15)
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Phase 1B Dose Limiting Toxicities Definitions

• Grade 3, 4, or 5 toxicity based on the NCI CTCAE
  V 3.0 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.
• Baseline laboratory or medical conditions that
  worsen to grade 3 or above that is possibly,
  probably or definitely related to study
  medication.

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Phase 1B Dose Limiting Toxicities
ID Days on Study Dose Description
03004 20 10g/day Grade 4 increase in AST with baseline grade 2 AST.
05003 19 20g/day Grade 3 diarrhea and fatigue. Note that this participant had a history of chronic diarrhea and was taking cholestryramine at baseline to treat this condition.
05011 13 40g/day Grade 3 rib pain secondary to vomiting. This participant had bone metastasis in her rib and baseline grade 1 rib pain.
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Phase 1B Summary of Adverse Events

• Oral administration of BZL101 is well tolerated.
  The most common treatment emergent, related
  adverse events are diarrhea (48), nausea (41),
  vomiting (26) and fatigue (22).
• There were 12 serious adverse events on the
  study, only 1 deemed related to study medication
  hospitalization for grade 3 rib pain secondary to
  vomiting at the 40 g/day dose.
• There were 3 participants with dose limiting
  toxicities.

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Phase 1B Compliance with Study Medication
Compliance 10g/day N10 20g/day N6 30g/day N3 40g/day N7 Total N26
Mean 92 89 92 85 90
Range 73-100 61-100 85-100 79-100 61-100
Note compliance is unknown for 1 participant in
10g/day cohort
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Phase 1B Preliminary Efficacy
RECIST Criteria Complete Response (CR)
Disappearance of all target lesions Partial
Response (PR) At least 30 decrease in the sum
LD of target lesions from the sum at
baseline Progressive Disease (PD) 20 increase
in the sum LD of target lesions or appearance of
one or more new lesions Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD, taking
as reference the smallest sum LD since the
treatment started

• Evaluable participants according to RECIST 17
  of 27
• 6/17 (35) stable gt90 days
• 3/17 (18) stable gt180 days

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Phase 1B Preliminary Efficacy
ID Dose Receptor Status Days on BZL Days Stable Comments
05005 10g/d ER PR- Her2/neu- 54 376 Axillary tumor decreased from 25.0mm at baseline to 15.0mm at Month 1 on physical exam breast tumor also decreased in size at Month 1 on exam. Pending independent radiology review to determine disease status.
05006 20g/d ER PR Her2/neu ND 329 329 Active on study. At Months 6 and 8 there was a 14 and 16 decrease in total longest diameter, respectively.
03006 20g/d ER PR- Her2/neu- 130 104 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.
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Phase 1B Preliminary Efficacy
ID Dose Receptor Status Days on BZL Days Stable Comments
03002 10g/d ER- PR- Her2/neu- 207 564 Bone only disease (not evaluable by RECIST). 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.
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Phase 2 Outcome Measures

• Primary Outcomes
• Obtain preliminary estimate of efficacy based on
  tumor response rate using RECIST criteria
• Adverse events assessed at each clinic visit by
  self-report, physical exam and lab results
• Secondary Outcomes
• Tumor response clinical benefit rate, complete
  response, partial response, progression of
  disease
• Duration of response and survival time duration
  of overall response, complete response and
  partial response, overall survival, and
  progression-free survival
• Change in participant-reported quality of life
  (EORTC QLQ-C30)

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Phase 2 Enrollment

• ER- / PR-

• ER / PR
• ER- / PR
• ER / PR-

• Enrollment open December 2008
• Estimated 1 year to enroll 80 pts
• 17 sites across the US

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Phase 2 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 2 prior cytotoxic regimens
  administered for metastatic breast cancer
• Life expectancy of 12 weeks
• Eastern Cooperative Oncology Group (ECOG)
  performance status 2
• Participants are 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

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Summary

• The Maximum Feasible Dose (MFD) reached in the
  Phase 1B trial was 40g/day. Phase 2 will move
  forward with 20g/day enrolling 80 participants
  (40 HR and 40 HR-).
• BZL101 treatment leads to the inhibition of
  glycolysis as evident from the decrease in the
  enzymatic activities within the glycolytic
  pathway.
• BZL101 invokes selective cancer cell death.
• Oral administration of BZL101 is well tolerated.
  The most common adverse events are diarrhea
  (48), nausea (41), vomiting (26) and fatigue
  (22).
• There were 3 participants with dose limiting
  toxicities.

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Summary

• One SAE was attributed to BZL101 hospitalization
  for the grade 3 rib pain secondary to vomiting at
  40g/day.
• On average, compliance with study medication was
  90 of prescribed doses taken.
• In this heavily pre-treated population, 6/17
  (35) were stable for gt90 days and 3/17 (18)
  were stable for gt180 days.
• There has been radiographic evidence of tumor
  regression.
• Of the 27 women enrolled, 18 discontinued due to
  progression, 3 due to participant choice, 2 due
  to an AE, 2 due to an SAE, and 1 due to
  non-compliance with study procedures.