Society of Integrative Oncology

1. 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

2. 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

3. BZL101- A Novel Mechanism of Action Cancer Cells Normal Cells • Normal cells depend on citric acid cycle (>85%) and glycolysis (<7%) for energy production • Cancer cells depend on glycolysis (>85%) 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

4. 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 7;7(4) [Epub ahead of print] PMID: 18305410

5. 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 Sep;105(1):17-28. Epub 2006 Nov 17. PMID: 17111207 Accepted in 5 days and highlighted as critical trial

6. BZL101 Phase 1A vs. BZL101 Phase 1B

7. 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

8. Phase 1B 10g 20g 30g 40g • 10g/qd • 11 Enrolled • 1 DLT • Average days on study: 55 • 10g/bid • 6 Enrolled • 1 DLT • Average days on study: 113 • 15g/bid • 3 Enrolled • 0 DLT • Average days on study: 66 • 20g/bid • 7 Enrolled • 1 DLT • Average days on study: 27 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

9. Phase 1B Baseline Characteristics *For metastatic disease

10. Phase 1B Summary of Study Participants

11. Phase 1B Adverse Events Related and Experienced by ≥10%

12. 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 >3 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.

13. Phase 1B Dose Limiting Toxicities

14. 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.

15. Phase 1B Compliance with Study Medication *Note: compliance is unknown for 1 participant in 10g/day cohort

16. 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 >90 days 3/17 (18%) stable >180 days

17. Phase 1B Preliminary Efficacy

18. Baseline Bone Scan Month 2 Bone Scan Phase 1B Preliminary Efficacy

19. 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)

20. N = 40 Hormone Receptor Positive N = 40 Hormone Receptor Negative N = 80 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

21. 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 (>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

22. 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.

23. 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 >90 days and 3/17 (18%) were stable for >180 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.