Download THE MEDICAL SCHOOL 1 Massachusetts General Hospital, Boston

Tumor Responses and Preliminary Survival Data in A Phase 2 Trial of Ofranergene Obadenovec (VB-111)
Combined with Paclitaxel in Patients with Recurrent Platinum-Resistant Ovarian Cancer
CANCER CENTER
1
BACKGROUND
VB-111 is A Novel, First-in-class Anti-cancer
Gene Therapy
• First-in-class, novel, targeted anti-angiogenic gene-therapy agent
with applicability for multiple solid tumor indications
• Mechanism:
»» Based on an Ad5 viral vector that targets angiogenic
endothelium, leading to apoptosis
»» Broad anti-angiogenic activity - leads to tumor starvation and
immune response
»» Effective in combination therapy
• Efficacy signal demonstrated in three tumor-specific Phase 2 trials
• Safe and well tolerated in over 170 cancer patients
• Convenience - simple IV infusion, once every 2 months
• Regulatory Incentives: SPA, Fast Track, Orphan Drug Status
Ovarian Cancer
• Ovarian cancer is diagnosed in approximately 22,000 American
women each year, and is the leading cause of death from
gynecologic cancers; Disease is difficult to detect, and often only
diagnosed when advanced
• Most patients ultimately develop platinum-resistant relapse
• Anti-angiogenic therapy has been shown to be efficacious in
ovarian cancer. Bevacizumab was recently shown to improve PFS
(but not OS) in combination with chemotherapy, in platinumresistant recurrent ovarian cancer (AURELIA trial*)
* J Clin Oncol. 2014;32(13):1302-8
HARVARD
2
1
1
MEDICAL SCHOOL
2
Massachusetts General Hospital, Boston, Massachusetts, Dana Farber Cancer Institute, Boston, Massachusetts, VBL Therapeutics, Or Yehuda, Israel
2
3
RESULTS
Efficacy Signal in Ovarian Cancer Doubled,
Compared with Historical Data
Patient Characteristics
Efficacy Signal GCIG CA-125 – 60% Response Rate
• 21 patients with recurrent Platinum-Resistant Müllerian
cancer, enrolled at Massachusetts General Hospital and
Dana Farber Cancer Institute, Boston, MA and received
up to 7 doses of treatment
• All patients had measurable disease
• Intra-patient dose escalation was allowed
• 2 treatment groups: low dose vs. therapeutic dose
treatment
9 of the 15 evaluable patients (60%) at the therapeutic dose level CA-125 response (defined as 50% reduction): VB-111 + paclitaxel
had a CA-125 response (defined as 50% reduction in CA-125)
vs. chemotherapy ± bevacizumab (AURELIA trial)
Low Dose
Treatment
N=4
3x1012 VPs
+
40mg/80 paclitaxel
Therapeutic Dose
Treatment
N=17
1x1013 VPs
+
80 paclitaxel
Characteristic
Characteristic
No. (%)No. (%)
Age
Age
Median Median
65
65
Range Range
41-79 41-79
Grade at
Grade
diagnosis
at diagnosis
IA
IA
1 (5%) 1 (5%)
IB
IB
1 (5%) 1 (5%)
IC
IC
1 (5%) 1 (5%)
IIIC
IIIC
12 (57%)
12 (57%)
IV
IV
6 (29%)6 (29%)
Histology
Histology
PapillaryPapillary
serous serous
9 (43%)9 (43%)
Adenocarcinoma
Adenocarcinoma
4 (19%)4 (19%)
Carcinosarcoma
Carcinosarcoma
3 (14%)3 (14%)
Clear cell
Clear cell
2 (10%)2 (10%)
Clear cell/Serous
Clear cell/Serous
1 (5%) 1 (5%)
Transitional/Serous
Transitional/Serous
1 (5%) 1 (5%)
Serous/Serous/
1 (5%) 1 (5%)
Mixed mullerian
Mixed mullerian
tumor components
tumor components
Characteristic
Characteristic
No. (%)No. (%)
PROGNOSTIC
PROGNOSTIC
FACTORS
FACTORS
ECOG performance
ECOG performance
status status
0
0
10 (48%)
10 (48%)
1
1
11 (52%)
11 (52%)
Platinum
Platinum
free interval
free interval
(months)
(months)
< 3 (platinum
< 3 (platinum
refractory)
refractory) 10 (48%)
10 (48%)
≥3
≥3
11 (52%)
11 (52%)
Measurable
Measurable
disease,
disease,
SLD, cm
SLD,
(n=20)
cm (n=20)
1 to < 5 1 to < 5
9 (45%)9 (45%)
≥5
≥5
11 (55%)
11 (55%)
Baseline
Baseline
CA-125 CA-125
≥ 100 U/ml
≥ 100 U/ml 14 (67%)
14 (67%)
Prior VEGF
Prior VEGF
Bevacizumab
Bevacizumab
9 (43%)9 (43%)
Cederanib
Cederanib
2 (10%)2 (10%)
Prior lines
Prior
oflines
therapy
of therapy
MedianMedian
(range)(range)
3 (1-4) 3 (1-4)
Mean Mean
2.6
2.6
% Patients with CA-125 Response
% CA-125 Change- Best Response
200%
185%
150%
Non-refractory, Therapeutic Dose
Refractory, Therapeutic Dose
Non-refractory, Low Dose
Refractory, Low Dose
127%
110%
100%
VB-111
+ paclitaxel
VB-111
+ TAX
atattherapeutic
therapeuticdose
dose
60.0%
AURELIA trial*
50%
50%
40%
14%
chemotherapy
Chemotherapy
70%
60%
103%
bevacizumab + chemotherapy
BEV + Chemotherapy
31.8%
30%
0%
-4%
-50%
-13%
-27%
20%
-41% -44%
-55%
-64% -69%
-100%
11.6%
10%
-79%
-92% -96% -96%
-98% -98%
0%
* J Clin Oncol. 2014;32(13):1302-8
Durable Disease Control & Responses
% Change in CA-125
% Change RECIST (sum of longest diameters)
Study VB−111−157
VB−111+ Paclitaxel: % change in CA−125
10
Low−Refractory
300
Safety
Low−Non−Refractory
Therapeutic−Refractory
VB-111 was found to be safe and well tolerated:
• 8 serious adverse events were reported, 2 were considered by the investigator to be possibly related to VB-111
• Most frequent AEs included: fatigue, fever, neutropenia, diarrhea
• No dose limiting toxicities were reported at any dose level
VB-111 Induced Antitumor Immune-Response
Cytotoxic CD8 T-cells and apoptotic cancer cells detected
following treatment with VB-111
STUDY DESIGN
• Design: A Phase 1/2, dose escalation study
• Study objectives:
»» Evaluate safety and tolerability and identify dose limiting
toxicity in combination of VB-111 and weekly paclitaxel
»» Explore efficacy (RECIST response, CA-125 response, PFS and
OS) in an expanded cohort of the optimally tolerated dose of
combination VB-111 and weekly paclitaxel
• Patient population: Recurrent Platinum-Resistant Müllerian
Cancer
12
13
• Intervention: VB-111 3x10 - 1x10 VPs q2m I.V. in combination
with weekly paclitaxel, until disease progression
THE
Richard T Penson , Suzanne Berlin , Ashley M Hanbury , Amalia N Gonzalez , Siobhan A. Collins ,
1
2
3
3
Michael J Birrer , Suzanne M Campos , Andi Lubitz , Yael C. Cohen
1
VB-111 Pt 1
VB-111 Pt 2
Control Pt 1
Control Pt 2
CD8
(x400)
H&E
(x400)
Biopsies were obtained from patients with Recurrent Platinum-Resistant Müllerian Cancer. H&E and
Immunohistochemistry staining with anti-CD8 show regions of apoptotic tumor cells (red circles) and increased
tumor infiltrating CD8 lymphocytes in VB-111 treated patients.
Significant Increase in Overall Survival
Median OS: 810 vs. 172 days
therapeutic dose (n=17) vs. low dose (n=4)
P=0.042
% change from baseline
MASSACHUSETTS
GENERAL HOSPITAL
200
Therapeutic−Non−Refractory
16
1
7
100
2
4
0
21
20
13
11
8
12
−100
0
3
18
5
100
19
9
Time
14
(days)
15
17
200
6
300
400
SUMMARY AND CONCLUSIONS
• VB-111 was safe and well tolerated in patients with recurrent Platinum-Resistant Müllerian cancer in
combination with paclitaxel, toxicity was similar to that expected with antiangiogenics and taxanes in
this patient population
• Efficacy signal:
In a population with 50% platinum refractoriness and 52% prior antiangiogenics »» CA-125 response seen at a favorable rate of 60% (9/15) with a dose response pattern at the therapeutic
dose level
»» significant increase in OS at therapeutic vs. low dose level (810 vs. 172 days, p=0.042)
• Immunotherapeutic effect: cytotoxic CD8 T-cells and apoptotic cancer cells detected following
treatment with VB-111