Transcript BZL 101 Phase I

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
SIO Nov 08
1
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
2
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
SIO Nov 08
3
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 hyperactivation 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 ADPribose) 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
4
BZL101 Phase 1A Results
21
Treated with BZL101
Average # prior
therapies 3.9
In modified RECIST
evaluation, where all
measurable lesions
included as evaluable
16
Were on trial for ≥28 days and
evaluable by RECIST
6/16
(38%)
stable disease for
>90 days
Expected survival 90-120 days
On study, average survival 327.5 days
(Kaplan-Meier Survival Analysis)
3/16
5/16
(19%)
stable disease for
>180 days
(31%)
some degree of objective
tumor regression
1
1mm short of a partial remission
based on RECIST Criteria
1
31% reduction in the
sum of the longest
tumor diameter
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
5
BZL101 Phase 1A vs. BZL101 Phase 1B
BZL-101-001
Phase 1A
Dose
Number of
Participants
Study Drug
SIO Nov 08
Single Dose
12 gm – 350 ml
BZL-102-002
Phase 1B
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)
21
27
• 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
6
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
SIO Nov 08
7
BZL101 Phase 1B Summary
Phase 1B
10g
20g
30g
40g
• 10g/qd
• 10g/bid
• 15g/bid
• 20g/bid
• 11 Enrolled
• 6 Enrolled
• 3 Enrolled
• 7 Enrolled
• 1 DLT
• 1 DLT
• 0 DLT
• 1 DLT
• Average
days on
study: 55
• Average
days on
study: 113
• Average
days on
study: 66
• Average
days on
study: 27
Why 20 grams?
Decision
20g
Phase 2
• Easier to tolerate
• 40g/30g many GI side effects and
difficulty taking BZL101
• Average days on study longest
SIO Nov 08
8
Phase 1B Baseline Characteristics
Age (years)
N=27
Mean (SD)
58.4 (13.9)
Median (Range)
59 (32-78)
Mean (SD)
5.6 (3.7)
Median (Range)
5 (1-19)
Prior Chemo Regimens*
Race/Ethnicity
White/Caucasian
Prior Anticancer Therapies* N=27 (SD)
16 (59%)
Black/African American
6 (22%)
Hispanic
5 (19%)
Baseline ECOG PS
Mean (SD)
2.8 (2.4)
Median (Range)
2 (0-10)
Hormone Receptor Status
N=27 (%)
Positive (either ER or PR +)
14 (63)
Negative (both ER and PR -)
10 (37)
0
16 (60%)
HER2/neu Status
1
9 (33%)
Positive
17 (63)
2
2 (7%)
Negative
10 (37)
*For metastatic disease
SIO Nov 08
9
Phase 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
Disease progression
SIO Nov 08
26 (96)
18 (67)
Patient choice
3 (11)
Adverse event
2 (7)
Serious adverse event
2 (7)
Non-compliance with study procedures
1 (4)
10
Phase 1B Adverse Events Related and Experienced by ≥10%
Adverse Event
By CTCAE
10 g/d
N (n=11)
20 g/d
N (n=6)
30 g/d
N (n=3)
40 g/d
N (n=7)
Total
N (%) (n=27)
0
3
0
3
6 (22)
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)
ALT elevation
2
1
1
0
4 (15)
AST elevation
2
1
0
0
3 (11)
Pain-abdomen
1
1
0
1
3 (11)
Headache
3
1
0
0
4 (15)
Constitutional
Fatigue
Gastrointestinal
Metabolic/Laboratory
Pain
SIO Nov 08
11
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.
SIO Nov 08
12
Phase 1B Dose Limiting Toxicities
ID #
# Days
on
Study
03004
20
10g/day Grade 4 increase in AST with baseline grade 2 AST.
19
Grade 3 diarrhea and fatigue. Note that this
participant had a history of chronic diarrhea and was
taking cholestryramine at baseline to treat this
20g/day condition.
13
Grade 3 rib pain secondary to vomiting. This
participant had bone metastasis in her rib and
40g/day baseline grade 1 rib pain.
05003
05011
SIO Nov 08
Dose
Description
13
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.
SIO Nov 08
14
Phase 1B Compliance with Study Medication
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%
Compliance
*Note: compliance is unknown for 1 participant in 10g/day cohort
SIO Nov 08
15
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
SIO Nov 08
16
Phase 1B Preliminary Efficacy
ID#
Dose
Receptor
Status
ER+
05005
PR10g/d
Her2/neuER+
05006
PR+
20g/d
Her2/neu ND
ER+
03006
PR20g/d
Her2/neu-
SIO Nov 08
# Days
on
# Days
BZL
Stable
54
329
130
Comments
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.
329
Active on study. At Months 6 and 8 there
was a 14% and 16% decrease in total longest
diameter, respectively.
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.
17
Phase 1B Preliminary Efficacy
ID#
Dose
03002
10g/d
Receptor
Status
ERPRHer2/neu-
# Days
# Days
on
Stable
BZL
207
Baseline Bone Scan
SIO Nov 08
564
Comments
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.”
Month 2 Bone Scan
18
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)
SIO Nov 08
19
Phase 2 Enrollment
N = 80
N = 40
N = 40
Hormone
Receptor Positive
Hormone
Receptor Negative
• ER+ / PR+
• ER- / PR-
• ER- / PR+
• ER+ / PR-
•Enrollment open December 2008
•Estimated 1 year to enroll 80 pts
•17 sites across the US
SIO Nov 08
20
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
SIO Nov 08
21
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.
SIO Nov 08
22
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 noncompliance with study procedures.
SIO Nov 08
23