Society of Integrative Oncology

SIO Nov 08 1

Society of Integrative Oncology

A Phase I/II Clinical Trial Assessing Safety and Efficacy of BZL101 for Metastatic Breast Cancer

Alejandra Perez, MDCo-Director, Breast Cancer Center

Memorial Cancer Institute

SIO Nov 08 2

What is BZL101?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

SIO Nov 08 3

BZL101- A Novel Mechanism of ActionBZL101- A Novel Mechanism of Action

• 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

Normal Cells

Cancer Cells

SIO Nov 08 4

BZL101- Basis for the Selectivity Towards BZL101- Basis for the Selectivity Towards Cancer CellsCancer 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

SIO Nov 08 5

BZL101 Phase 1A ResultsBZL101 Phase 1A Results

21 Treated with BZL101

16 Were on trial for ≥28 days and

evaluable by RECIST

6/16 (38%)

stable disease for>90 days

3/16 (19%)

stable disease for>180 days

5/16 (31%)

some degree of objective tumor regression

1 1mm short of a partial remission

based on RECIST Criteria

1 31% reduction in thesum of the longest

tumor diameter

Average # prior therapies 3.9

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

SIO Nov 08 6

BZL101 Phase 1A vs. BZL101 Phase 1BBZL101 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

SIO Nov 08 7

BZL101 Phase 1B DesignBZL101 Phase 1B Design

Primary:To determine the maximum tolerated dose of BZL101To 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 survivalDuration of responseChange in participant-reported QOL (EORTC QLQ-C30)

Main eligibility criteria:Histologically confirmed breast cancerMeasurable stage IV diseaseNo more than 3 prior chemotherapies for metastatic disease

SIO Nov 08 8

BZL101 Phase 1B SummaryBZL101 Phase 1B Summary

10g 20g 30g 40g

• 10g/qd

• 11 Enrolled

• 1 DLT

• Average days on study: 55

• 10g/bid

• 6 Enrolled

• 1 DLT


• 15g/bid

• 3 Enrolled

• 0 DLT


• 20g/bid

• 7 Enrolled

• 1 DLT


Phase 1B

20g Phase 2

Decision Why 20 grams?

• Easier to tolerate

• 40g/30g many GI side effects and difficulty taking BZL101

• Average days on study longest

SIO Nov 08 9

Phase 1B Baseline CharacteristicsPhase 1B Baseline Characteristics

Age (years) N=27

Mean (SD) 58.4 (13.9)

Median (Range) 59 (32-78)

Race/Ethnicity

White/Caucasian 16 (59%)

Black/African American 6 (22%)

Hispanic 5 (19%)

Baseline ECOG PS

0 16 (60%)

1 9 (33%)

2 2 (7%)

Prior Anticancer Therapies* N=27 (SD)

Mean (SD) 5.6 (3.7)


Prior Chemo Regimens*

Mean (SD) 2.8 (2.4)


Hormone Receptor Status N=27 (%)

Positive (either ER or PR +) 14 (63)

Negative (both ER and PR -) 10 (37)

HER2/neu Status

Positive 17 (63)

Negative 10 (37)

*For metastatic disease

SIO Nov 08 10

Phase 1B Summary of Study ParticipantsPhase 1B Summary of Study Participants

Study Participants N=27 (%)

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)

SIO Nov 08 11

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

By CTCAE10 g/d

N (n=11)20 g/dN (n=6)

30 g/dN (n=3)

40 g/dN (n=7)

TotalN (%) (n=27)

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)

SIO Nov 08 12

Phase 1B Dose Limiting Toxicities Phase 1B Dose Limiting Toxicities DefinitionsDefinitions

• 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.

SIO Nov 08 13

Phase 1B Dose Limiting ToxicitiesPhase 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.

SIO Nov 08 14

Phase 1B Summary of Adverse EventsPhase 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.

SIO Nov 08 15

Phase 1B Compliance with Study MedicationPhase 1B Compliance with Study Medication

Compliance

10g/day

N=10*

20g/day

N=6

30g/day

N=3

40g/day

N=7

Total

N=26

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

SIO Nov 08 16

Phase 1B Preliminary EfficacyPhase 1B Preliminary Efficacy

Evaluable participants according to RECIST: 17 of 27

6/17 (35%) stable >90 days

3/17 (18%) stable >180 days

RECIST CriteriaComplete 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

SIO Nov 08 17


ID#

DoseReceptor

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 329Active 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.

SIO Nov 08 18


ID#

DoseReceptor

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 patient’s bone scans with less intrusive activity noted in the left anteromedial rib and left acetabular region.”

Baseline Bone Scan Month 2 Bone Scan

SIO Nov 08 19

Phase 2 Outcome MeasuresPhase 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)

SIO Nov 08 20

Phase 2 EnrollmentPhase 2 Enrollment

N = 40

Hormone Receptor Positive

N = 40

Hormone Receptor Negative

• ER+ / PR+

• ER- / PR+

• ER+ / PR-

• ER- / PR-

N = 80

•Enrollment open December 2008

•Estimated 1 year to enroll 80 pts

•17 sites across the US

SIO Nov 08 21

Phase 2 Key Inclusion/Exclusion CriteriaPhase 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

SIO Nov 08 22

SummarySummary• 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.

SIO Nov 08 23

SummarySummary

• 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.

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