#5577 phase 1b study of oncolytic vaccinia virus gl-onc1 ......direct lysis: virus colonized and...
TRANSCRIPT
❖ GL-ONC1 treatments are well tolerated, with transient overnight flu-like
symptoms. Daily i.v. hydration during treatment relieved symptoms
and prevented dehydration.
❖ Mechanisms of Action are demonstrated:
➢ Direct lysis: Virus colonized and replicated in the tumor, killing of
tumor cells in ascites, and reduced circulating tumor cells.
➢ Immunotherapy: Virus-induced immune activation with enhanced
tumor infiltration of CD8+ T cells and generation of tumor-specific T-
cell response were observed.
❖ Clinical significant disease control (including objective response) and
extended PFS were documented at both dose levels.
❖ Phase 2 trial (VIRO-15) in ROC pts with adequate nutritional & immune
status is currently enrolling at Cohort 1 dose level.
#5577 Phase 1b Study of Oncolytic Vaccinia Virus GL-ONC1 in Recurrent Ovarian Cancer
RESULTS
❖ Primary
Analysis of adverse events
❖ Secondary
Anti-tumor response by RECIST1.1 & survival (PFS/OS)
❖ Translational
Evaluate virus-encoded transgene expression, tumor biomarkers, circulating
tumor cells (CTCs), TILs in tumor biopsy, tumor-specific T-cell response in
peripheral blood, cytology in ascites, immunohistochemistry of PD-L1 expression
in tumor biopsies pre- and post-GL-ONC1 Tx.
OBJECTIVES
CONCLUSIONS
Acknowledgement: All staff at Genelux for support; Prof. Lisa Butterfield
lab at Univ. of Pittsburg for ELISPOT analysis. Funding for this research
was provided by Genelux Corporation, San Diego, California, USA
June 1-5, 2018; Chicago, IL, USA; Corresponding author: [email protected]
Patient CharacteristicsEleven heavily pretreated end-stage ROC pts were enrolled:
❖ Characteristics related to prior platinum Tx:
Platinum-resistant (n=9; 82%), Platinum-refractory (n=1;
9%), Intermediate platinum-sensitive (n=1; 9%)
❖ # of prior lines therapy: 3-4 (n=3; 27%), ≥ 5 (n=8; 73%)
❖ ECOG 0 (n=7; 64%) or 1 (n=4; 36%)
❖ With ascites/pleural effusion at baseline (n=9; 82%)
❖ Progressive disease (PD) at baseline (n=10; 91%)
❖ Cohort 1: 3 × 109 pfu (n=6); Cohort 2: 1 × 1010 pfu (n=5)
Protocol #: GL-ONC1-015; ClinicalTrials.gov Identifier: NCT02759588; Copyright © 2018 Genelux Corp. All rights reserved.
ABSTRACT
Safety
Tumor Infiltrating Lymphocytes (TILs)
Anti-Tumor Response & Disease Control Observed
Distal Anti-tumor Effects from i.pe. Route of Delivery
Case Report (Ch1: #15A-05): OR & Tumor-specific T-cell Response
Clinical trial design considerations:
➢ I.pe. route of drug delivery is relevant
to ovarian cancer (OC)
➢ OCs are immunogenic → VACV is
excellent adjuvant for tumor antigen
presentation
➢ High tumor-infiltrating lymphocytes
(TILs) favors survival → Oncolytic
VACV stimulates TILs
➢ Oncolytic VACV may overcome
chemo- and/or radiation-resistance
➢ For patients with chemo resistant
ovarian cancer that would otherwise
consider palliative care or use of drugs
with poor Response Rate
❖ Disease Control Rate (DCR = OR + SD≥15 wks) = 55 % in 6/11 evaluable
pts (4 in Ch1, 2 in Ch2).
❖ Extended PFS of 23, 35, 59 (with confirmed PR) & 71 wks observed in 4
pts (3 in Ch1, 1 in Ch2).
❖ More than doubling of PFS compared to the last chemotherapy regimen
was recognized in 4/11 (36%) pts (2 in Ch1, 2 in Ch2).
❖ Heavily treated w/ 9 prior regimens of chemo; no Tumor-specific T-cell response at baseline
❖ Documented Objective Response (OR) from GL-ONC1 Tx after Failure of Last Chemotherapy
❖ Favorable & long-lasting Tumor-specific T-cell Response (TSTcR) by ELISPOT analysis
Exemplary IHC analysis - pt.#15A-06, with PFS of 71 weeks:
Significant infiltration of CD8+ cytotoxic T cells into tumors
after virus treatment indicates activation of immunosurveillance
Clinically Significant Results
Immune Modulation
peritoneal fluid
Prior to 1st dose
W2D17
W2D12
pleural fluid
W2D9
W2D15
W2D17
Robust lymphocyte count increase
(immune activation)
Direct lysis of cancer cells &
immune activation in different
cavities
Tumor cell clusters present
Tumor cell clusters absent
Decrease of
Circulating Tumor
Cells (CTCs)
may indicate systemic
effect against metastases
Baseline 5-mon post Tx
Objective response (OR) of metastatic lesions
pancreatic met.
liver met.
No any other Tx in the meantime0
5
10
15
20
25
30
35
40
45
CT
C C
OU
NT P
RE-
& P
OST T
X
baseline post Tx
Flu-like symptoms in general;
lasting a few hours overnight
post each Tx
No DLT; MTD not reached
No discontinuation due to
treatment-related AEs
Summary:
GL-ONC1 Tx is well tolerated.
baseline Week 36
CD3 CD8
Baseline 2.94 0.58
Week 36 5.06 3.54
0
1
2
3
4
5
6
Cel
l Co
un
ts P
er
80
x Fi
eld
Immune Cell Counts in Tumor biopsies
p<0.001
CD3+
CD8+
p<0.001
Acute inflammatory responses and PD-L1 upregulation in tumors by oncolytic
virus GL-ONC1 can sensitize tumors to PD-1/PD-L1 blockade.
Adverse Events # of Pts (n=11)
Grades 1 & 2 AEs (occurred in ≥ 3 patients)
Chills 7 (63.6%)
Nausea 7 (63.6%)
Fever 6 (54.5%)
Abdominal distention 4 (36.4%)
Abdominal pain 4 (36.4%)
Vomiting 3 (27.3%)
Grade 3 AEs (occurred in the same patient)
Nausea 1 (9.1%)
Vomiting 1 (9.1%)
No Grade 4 AEs
Robert W Holloway1, James E Kendrick1, Amanda J Stephens1, Jessica A Kennard1, Jeremy Burt2, Jane LeBlanc3, Karen Sellers3, Jamie Smith3, and Susan Coakley3
1Gynecologic Oncology Program, Florida Hospital Cancer Institute, Orlando, Florida; 2Department of Radiologic Services, Florida Hospital, Orlando, Florida; 3Office of Clinical Research, Florida Hospital Cancer Institute, Orlando, Florida
0 10 20 30 40 50 60 70 80 90 100
Swim Lane Plot of Survival & Tumor Response by RECIST 1.1
PRSDPDAlive
WEEKS
1Y
ear
Wee
k 2
4
15A-0515A-0615A-0915A-0415A-1515A-0215A-0115A-1015A-0315A-1315A-07
Cohort 1
Cohort 2
(Data cut off: April 17, 2018)
Prophylactic hydrations given
daily to avoid dehydration, and
to reduce symptoms
Background: Immunotherapy can trigger immune activation including tumor-infiltrating
CD8+ T cells, leading to antitumor response and survival benefits. Immunotherapeutic
GL-ONC1 (modified vaccinia virus (VACV)) causes oncolysis, immune activation and
durable anti-cancer memory.
Methods: Intraperitoneal (i.pe.) infusion of GL-ONC1 monotherapy was given at high
repeated doses in patients (pts) with platinum refractory/resistant disease. Primary
endpoint: adverse events; Secondary endpoints: anti-tumor response by RECIST1.1 &
survival. Eleven heavily pretreated pts with end-stage recurrent ovarian cancer (ROC)
were enrolled: 3-4 prior lines (n=3), ≥ 5 lines (n=8), ECOG 0 (n=7) or 1 (n=4),
ascites/pleural effusion (n=9) & progressive disease (PD) at baseline (n=10). There
were two dose cohorts: 3 × 109 (Cohort 1: n=6) or 1 × 1010 (Cohort 2: n=5) plaque
forming units/day on 2 consecutive days.
Results: (1) Adverse reactions included Grade 1-2 chills (n=7), nausea (7), fever (6),
abdominal pain/distention (4), & vomiting (3). There were no differences in toxicity for
the two dose levels. (2) GL-ONC1 colonized and replicated in the tumor, as indicated by
a virus-encoded glucuronidase (GusA) assay. (3) Clearance of tumor cells in ascites
with induction of lymphocyte infiltration was shown in 5 pts with ascites. (4) Reduction of
circulating tumor cells (CTC) was identified in 6/8 (75%) pts who had baseline CTC,
ranging 1-42 per 7.5 mL blood. (5) Enhanced infiltration of CD8+ T cells into tumor
tissue was demonstrated by repeat biopsy. (6) A tumor-specific T cell response was
absent at baseline but confirmed at Week-30 in patient with objective response (OR) by
IFN-γ ELISPOT assay. (7) Disease Control Rate (DCR = OR + stable disease (SD) ≥ 15
weeks) was 6/11 (55%). (8) Extended progression-free survival (PFS) of 23, 35, 59
(with confirmed PR) & 71 weeks were observed in 4 pts, respectively. (9) More than
doubling of PFS compared to the last chemotherapy regimen was recognized in 4/11
(36%) pts.
Conclusions: Promising safety data, anti-tumor activity, and immune activation
mechanisms were documented in this Ph1b trial, and a Ph2 trial (VIRO-15) is currently
enrolling. Future studies combining GL-ONC1 and other immune therapies and/or
chemotherapy are under consideration.Biomarkers
1.0E-04
1.0E-03
1.0E-02
1.0E-01
1.0E+00
1.0E+01
1.0E+02
0 2 4 6 8 10 12 14
Gu
sA a
ctiv
ity
in b
loo
d [
un
its/
mL]
DaysLOD: limit of detection
Virus-encoded glucuronidase
LOD
-70
-60
-50
-40
-30
-20
-10
0
10
20
Be
st c
han
ge o
f C
A-1
25
fro
m
bas
elin
e (
%)
9/11 (82%) pts experienced
CA-125 reduction
Cohort 1Cohort 2
Tumor shrinkage observed
by RECIST1.1
-40
-30
-20
-10
0
10
20
30
40
Be
st c
han
ge o
f SL
D f
rom
bas
elin
e (
%)
Partial response
Progressive disease
Individual target lesion changeTarget lesion SLD change overtime
➢ 17/38 (45 %) individual target lesions had size
reduction
➢ In 4 pts with SLD reduction, all individual target
lesions had reduction in size
-70-60-50-40-30-20-10
0102030405060708090
100
13
15 7 7
15
10 3
15 7 3 7 6 9
10 3 7
10
15
13
13 2
13
10 4 4 4
13 4 2 2 1 5 1 5 4 5 5 5
Be
st c
han
ge o
f in
div
idu
al t
arge
t le
sio
n s
ize
fro
m b
ase
line
(%
)
Patient ID #
Progressive disease
Partial response
-40
-30
-20
-10
0
10
20
30
40
0 5 10 15 20 25 30 35 40 45
Ove
rtim
e c
han
ge o
f SL
D f
rom
bas
elin
e (
%)
WEEKS
PDSDPRCohort 1
Cohort 2
Strong PD-L1 staining at the
tumor-stromal interface
Baseline
GL-ONC1 Upregulates
Immunomodulatory Target
Proteins, such as PD-L1
20 days post Tx
SLD: sum of longest diameters
120
140
160
180
200
220
240
260
280
300
SLD
(m
m)
SLD of target lesions over time
pemetrexed
GL-ONC1 Tx
+ 90% PD
- 34% PR
Wks
Last Chemotherapy: Pemetrexed
3/30-5/18/2016
Progressive disease (PD)
(CT scans on 6/30/2016 & 8/30/2016)
GL-ONC1 Tx
Partial response
(confirmed on Week 24 & 36; durable)
Stable disease @ Week 48
(-27% compared to baseline)
Confirmed
TSTcR
No TSTcR
0 18 36-24