#CT021
Phase 1b study of a novel immunotherapy combination therapy of intralesional Coxsackievirus A21 and systemic
ipilimumab in patients with advanced melanoma
1
Curti ,
2
Richards ,
3
Faries ,
4
Andtbacka ,
5
Grose ,
5
Karpathy ,
Brendan
Jon
Mark
Robert H.I
Mark
Roberta
Darren R.
1Providence Cancer Center, Portland, OR; 2Oncology Specialists, Chicago, IL; 3 John Wayne Cancer Institute, Santa Monica, CA; 4Huntsman Cancer Institute, Salt Lake City, UT, 5Viralytics Limited, Sydney, Australia, Australia
Introduction
Results
71
28
M
IIIC
1312003
1312004
1312007
67
35
63
M
F
M
IV M1c(2)
IIIC
IV M1c
1312009
54
M
IV M1c
1312010
81
F
IV M1c
1312011
76
M
IV M1b
Safety and
D
8
F
(P
o
x
D
-L P3
1
ne
g.
PD )
-L
1
C
4
16
D
C
C
Day 22
Day 85
1o end-point :
Safety
2o endpoint:
Response
(irWHO
criteria).
Key Inclusion Criteria
1 Patients with metastatic or unresectable stage IIIc or IV melanoma for whom
treatment with ipilimumab is indicated and who have at least one cutaneous,
subcutaneous tumor or palpable lymph node amenable to intratumoral injection.
Histological confirmation of melanoma will be required by previous biopsy or cytology.
2 Patients who have received prior ipilimumab treatment for metastatic melanoma are
eligible, as long as they did not experience any grade ≥ 3 toxicity and have resolution
of any previous toxicity to grade 1 or less.
3 At least one tumor must qualify to be a target lesion for irRC-modified WHO criteria.
4 Patients must be ≥ 18 years of age.
5 ECOG performance status of 0-1
!
AACR 2016, April 16-22, New Orleans USA.
6
5
5
not assessed
yet
irPR
irPR
irSD
4
4
3
7
5
7
1
2
1
not assessed
yet
not assessed
yet
10
2
8
1
not assessed
yet
9
3
Corresponding author, Brendan.Curti@providence.org
*
Toxicity
Related'to'CAVATAK'®'n(%)'
'
'
3
D
C
D
16
3
C
D
8
F
(P
o
x
D
-L P3
1
ne
g.
PD )
-L
1
0
Phase 1b: MITCI study design
(Melanoma Intra-Tumoral Cavatak and Ipilimumab )
Day 1
not assessed
yet
irCR
!
Study Design
ipilimumab 3 mg/kg IV Q3W x 4
chemotherapy,
immunotherapy (MEDI
6020-2)
radiotherapy,
immunotherapy (IL-2)
3000
Figure 1: CVA21 treatment induced notable changes within the tumor microenvironment by inducing
increases in immune cell infiltrates and expression of PD-L1, assessed by multi-spectral imaging.
26 Stage
IIIC and IV
melanoma
patients
at least 1
injectable
lesion
IIIC
1305002
MedDRA'Preferred'Term'
CAVATAK intralesional
3 x108 TCID50 Day 1, 3, 5 ,8 and 22 then Q3W till Day 358
M
IV
irPD
irCR
Related'to'Ipilimumab'n(%)'
'
'
Grade'1'
Grade'2'
Grade'3'
Grade'4C5'
Grade'1'
Grade'2'
Grade'3'
Grade'4C5'
Hypothyroidism'
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ColiIs'
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ConsIpaIon'
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Diarrhoea'
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Chills'
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FaIgue'
2/(18)!
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InflammaIon'
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Influenza'like'illness'
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InjecIon'site'reacIon'
2/(18)!
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Pain'
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Pyrexia'
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ALT'increased'
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AST'increased'
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Blood'ALP'increased'
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Blood'bilirubin'increased'
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Weight'decreased'
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Decreased'appeIte'
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Groin'pain'
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Myalgia'
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tumor'necrosis'
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Dysphonia'
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Achromotrichia'acquired'
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DermaIIs'
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Pruritus'
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Pruritus'generalised'
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Rash'
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ViIligo'
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* preliminary analysis, adverse events from 11 treated patients using Common Terminology Criteria for Adverse Events
(CTCAE), Version 4.0
Patient Response Data*
Best Overall response rate*
BORR (confirmed CR+PR, irWHO):
Disease control Rate (CR+PR+SD)
Median Time to response
irPFS 6 months
66.7%+ (80.0%*) [2CR + 2PR]
83.3% [2CR + 2PR+1SD]
NA
80.0% (4/5 pts)
!
+,patients evaluable for tumor assessment n=6, investigator assessed
*,ipilimumab naïve patients
NA=Not available, all responses have occurred by 3.5 months
IIIC
ipi-N
75
ipi-R
50
IVM1c
25
0
-25
-50
-75
-100
IIIC
IVM1c IVM1a
IIIC
100
ipi-N
75
ipi-R
50
25
0
-25
IIIC
IVM1c
-50
-75
-100
IIIC
IVM1c IVM1a
IIIC
injected
ipi-R
50
25
0
-25
-50
-75
-100
ipi-N=ipilimumab naive
ipi-R=ipilimumab refractory
Non-injected visceral
Changes in tumor burden by disease stage*
100
75
50
IIIC
IV M1a
IV M1c
Ipilimumab
3 mg/kg IV Q3W x 4
25
0
50
-25
100
150
200
250
ipi-N
ipi-N
ipi-R
50
25
0
-25
-50
-75
-100
Best percentage change in the lesions
cross product relative to baseline
1305001
M
surgery
surgery (2), other
(vaccine)
Immunotherapy
(ipilimumab/nivolumab)
immunotherapy
(nivolumab, BCG)
Immunotherapy
(nivolumab)
Immunotherapy (IL-2)
none
immunotherapy
(ipilimumab, interferon,
galectin,
pembrolizumab),
radiotherapy
none
100
ir RECIST criteria
Best percentage change in the lesions
cross product relative to baseline
36
IIIC
IV M1a
ir WHO criteria
Best percentage change in the lesions
cross product relative to baseline
1304005
M
F
Total lesions Number of
present
lesions
(index+non- Injected with
index)
CVA21
5
1
6
2
Best Percentage changes in individual lesion lesions
(ir WHO criteria)
Best percentage change in the lesions
cross product relative to baseline
73
64
Best irWHO
Overall
Response
Best percentage change in the lesions
relative to baseline ir RECIST
1304001
1304002
Previous Lines of
Treatment
6000
C
!
Patient
Age Gender Melanoma
Identification
Stage at
Code
Baseline
Best percentage change in the lesions
cross product relative to baseline
9000
D
• Female: Stage IIIC
with melanoma to legs
• Prior treatment with ipilimumab
and pembrolizumab
Post-treatment
(Day 8)
12000
4
Day!8!(post"treatment)!
Number of positive cells / mm2
Day!0!(pre"treatment)!
Pre-treatment
(Day 0)
Best Overall Response
Patient Characteristics
Best percentage change in the lesions
cross product relative to baseline ir WHO
CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21.
Intratumoral (I.T) CVA21 injection can induce preferential tumor cell infection, tumor immune-cell
infiltration, up-regulation of γ-INF response genes, cell lysis and enhancement of a systemic anti-tumor
immune response (Figure 1). The Phase II CALM study investigated the efficacy and safety of I.T
CVA21 in patients with advanced melanoma. The primary endpoint of the study was achieved with 22
of 57 (38.6%) evaluable patients with irPFS at 6 months, the confirmed response rate was 28.1% (16 of
57), with responses observed in both injected and non-injected melanoma metastases, suggesting the
generation of significant host anti-tumor responses. Ipilimumab is a humanized mAb that blocks
CTLA-4, a receptor that down-regulates the host immune system. In a pivotal study, overall survival of
advanced melanoma patients was longer with ipilimumab treatment alone compared with tumor
vaccine. Pre-clinical studies in an immune-competent mouse model of melanoma have revealed that
combinations of intralesional CVA21 and anti-CTLA-4 or anti-PD-1 mAbs mediated significantly greater
anti-tumor activity and compared to use of either agent alone. Presented are the interim data of the
open-label, multicenter Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of
novel immunotherapy combination Coxsackievirus A21 and ipilimumab in patients with advanced
melanoma
Pt'04C015'
5
Shafren .
ipi-N
ipi-R
50
25
0
-25
-50
-75
-100
Non-injected non-visceral
ipi-N
ipi-R
50
25
0
-25
-50
-75
-100
300
Combination treatments with ipilimumab
Study days
-50
-75
Schedule
-100
Ipilimumab +
1
Nivolumab
(phase 3)
Ipilimumab +
2
Bevacizumab
(phase Ib)
Ipilimumab
3
+ TVEC
(phase Ib)
Ipi 3 mg/kg +
Nivo 1 mg/kg
4 cohorts Ipi
(3 or 10 mg/kg)
+ Beva
46
25.1
79
9
19.6*
67.4
46
Ipi 3 mg/kg
+ TVEC
Ipilimumab
+
CAVATAK
(phase Ib)
Ipi 3 mg/kg
+ CAVATAK
18
NR
72.2
10.6
50*
73
32
11
NR
NR
NA
+
66.7 (80*)
+
83.3
9
*. First tumor response assessment at study day 106
Complete response
in Pt 1305001 Stage IIIC
non-injected
Partial response
in Pt 1312003 Stage IVM1c
Pts population
Median OS
1-year OS (%)
mPFS (months)
BORR (%)
DCR (%)
Grade 3+ Drug related AE (%)
!
314
NR
85
11.5
57.6*
70.8
55
1, N
Engl J Med. 2015;373(1):23
2, Cancer Immunol Res 2014;2:632–42
3, J Clin Oncol.Vol 33, No 15_suppl (May 20 Supplement), 2015: Abstract 9063
+,patients evaluable for tumor assessment n=6:
* Ipilimumab naïve patients:
NR=Not reached
NA=Not available
Conclusions
•  The CVA21-ipilimumab combination immunotherapy treatment is generally well tolerated and has
displayed anti-tumor activity in local, regional and distant systemic disease.
•  At present no DLT’s have been reported, with only 1 Gr 3 treatment-AE (ipilimumab-related
fatigue).
•  The preliminary confirmed overall response rate (80%) in ipilimumab naïve patients is higher
than published rates for either agent used alone (CVA21: 28.1% and ipilimumab:~15-20%) in
advanced melanoma patients.
•  While very preliminary, the presented response data are encouraging compared to that of other
ipilimumab combinations used to treat advanced melanoma patients.
•  Levels and composition of immune infiltrates in serial biopsies are currently being assessed by
multi-spectral IHC and NanoString analysis.
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