Providence Cancer Center, Portland, OR; 2 Oncology Specialists, Chicago, IL; 3 John Wayne Cancer InsPtute, Santa Monica, CA; 4

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1 The MITCI (Phase 1b) study: A novel immunotherapy combina>on of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma pa>ents with or without previous immune checkpoint therapy treatment Brendan Cur> 1, Jon Richards 2, Mark Faries 3, Robert H.I. Andtbacka 4, Sigrun Hallmeyer 2, Gregory A. Daniels 5, Mark Grose 6, Roberta Karpathy 6, Darren R. Shafren 6 1 Providence Cancer Center, Portland, OR; 2 Oncology Specialists, Chicago, IL; 3 John Wayne Cancer InsPtute, Santa Monica, CA; 4 Huntsman Cancer InsPtute, Salt Lake City, UT; 5 UCSD Moores Cancer Center, La Jolla, CA; 6 ViralyPcs Limited, Sydney, Australia, 1

2 Disclosures Informa>on Brendan D. Cur,, MD I have the following financial relationships to disclose: Honoraria - Prometheus Research Funding - Bristol-Myers Squibb (Inst); MedImmune (Inst); Prometheus (Inst); Viralytics (Inst). Travel, Accommodations, Expenses - Agonox; Prometheus I will discuss the following off label use and/or investigational use in my presentation: CVA21 2

Coxsackievirus A21 (CAVATAK ) Proprietary formulapon of the bio- selected oncolypc virus, Coxsackievirus A21 Non- enveloped RNA Picornavirus, common cold virus Not genepcally modified Targeted to

3 Coxsackievirus A21 (CAVATAK ) Proprietary formulapon of the bio- selected oncolypc virus, Coxsackievirus A21 Non- enveloped RNA Picornavirus, common cold virus Not genepcally modified Targeted to specific receptor over expressed on cancer cells (human ICAM- 1) Rapid lypc cell infecpon Destroys local and metastapc cells by oncolypc and immunotherapeupc acpvity PotenPal applicapon across a range of cancer types Generally well tolerated in papents PotenPal combinapon with other immunotherapies ~nm Computer generated capsid structure of CVA21 3

4 CAVATAK : Oncolytic immunotherapeutic modes of action in combination therapy Ipilimumab

5 Intratumoral CVA21- mediated immune cell changes in the tumor micro-environment Pt 4-15 Day : Pre-treatment Day 8: Post-treatment

6 Levels of immune-checkpoint gene expression in progressing and disease control CVA21-injected lesions Progression Disease control Change in RNA expression, relative units at Day 8 compared to Day Change in RNA expression, relative units at Day 8 compared to Day A2AR B7-H3 BTLA CTLA-4 CD27 CD28 CD4 CD4L Patients (n=3) CD122 Patients (n=3) IDO LAG3 PD-1 PD-L1 PD-L2 TIM-3 4-1BB OX-4 OX-4L GITR ICOS A2AR B7-H3 BTLA CTLA-4 IDO LAG3 PD-1 PD-L1 PD-L2 TIM-3 CD27 CD28 CD4 CD4L CD BB OX-4 OX-4L GITR ICOS Change in RNA expression, relative units at Day 8 compared to Day Change in RNA expression, relative units at Day 8 compared to Day A2AR B7-H3 BTLA CTLA-4 Patients (n=6) IDO LAG3 PD-1 PD-L1 PD-L2 TIM-3 CD27 CD28 CD4 CD4L CD BB OX-4 OX-4L GITR ICOS Patients (n=6) A2AR B7-H3 BTLA CTLA-4 IDO LAG3 PD-1 PD-L1 PD-L2 TIM-3 CD27 CD28 CD4 CD4L CD BB OX-4 OX-4L GITR ICOS 1, Hannani et al., Cell Research (215) : CD122 is the β- component of the IL-2 receptor complex Increased expression of CD122, a potential marker for enhanced anti-tumor activity of CTLA-4 blockade 1 6

7 Relevant Melanoma Studies MDX1-2 Ph3: ipilimumab 1 (Q3Wx4) (n=137) Prior anti-pd1 therapy % (/137) ORR mwho 1.9% (15/137; 2CR+13PR) DCR (CR+PR+SD) 28.5% (39/137) KEYNOTE 6 Ph3: Post-Hoc analysis 2, ipilimumab (Q3Wx4) after pembrolizumab (n=97) Prior anti-pd1 therapy 1% ORR RECIST 13% (13/97; 3CR+1PR) DCR (CR+PR+SD) 45% (44/97) CALM Ph 2: Intratumoral CAVATAK 3 (n=57) Prior anti-pd1 therapy % (/57) 6 months irpfs 38.5% ORR irrecist 28.1% (16/57; 8CR+8PR), DRR 21.2% 1. Hodi et al., N Engl J Med 21; 363: ; 2 Long et al.,smr 216 Abstract; 3. Andtbacka et al., ASCO 215: Abstract 93.

MITCI Phase 1b Study Design (MELANOMA INTRA-TUMORAL CAVATAK AND

papents at least 1 injectable lesion CVA21 intralesional 3 x1 8

Ipilimumab 3 mg/kg IV Q3W x 4 Fu>lity Clause: 4 confirmed

Study Objec>ves Primary: Safety and tolerability Secondary: BORR,

8 MITCI Phase 1b Study Design (MELANOMA INTRA-TUMORAL CAVATAK AND IPILIMUMAB) Study popula>on: 26 Stage IIIC and IV melanoma papents at least 1 injectable lesion CVA21 intralesional 3 x1 8 TCID 5 Day 1,3,5,8,22 then Q3W Pll Day 358 Immune induc>on Ipilimumab 3 mg/kg IV Q3W x 4 Fu>lity Clause: 4 confirmed objecpve responses in the first 12 papents Day 1 Day 22 Day 85 Study Objec>ves Primary: Safety and tolerability Secondary: BORR, DCR, 1yr survival and OS, PFS, Dura?on of response Complete enrolment: 14 addiponal papents

9 Key Patient Characteristics* Prior Checkpoint therapy (n=13) Checkpoint therapy naïve (n=12) Median Age (min, max) 65. (28,81) 65. (35,76) Stage of disease IIIC 8% (1/13) IVM1a 8% (1/13) IVM1b 15% (2/13) IVM1c 69% (9/13) IIIC 5% (6/12) IVM1a 8% (1/12) IVM1b 16% (2/12) IVM1c % (3/12) Elevated LDH ULN 23% (3/13) 33% (4/12) Median time between the last checkpoint and first CVA21 dose Median time between the last checkpoint and first ipilimumab dose 5.7 weeks N/A 8.7 weeks N/A Mean prior lines of systemic therapy CVA21 serum neutralizing Antibody titer Negative < 1:16 Positive > 1:16 85% (11/13) 15% (2/13) 1% (12/12) % (/) N/A= not applicable *, Preliminary data

10 Treatment-Emergent Adverse Events Prior Checkpoint therapy (n=13) Total Grade 3+ N(%) N(%) Checkpoint therapy naïve (n=12) Total Grade 3+ N(%) N(%) Preferred Term Any event 13 (1) 4 (31%) 11 ( 92) 7 (58) Any attributable to CVA21 11 ( 85) 8 ( 67) Any attributable to ipilimumab 12 ( 92) 1 (8)* 11 ( 92) 1 (8)* Fatigue 9 ( 69) 7 ( 58) 1 (8) Pruritus 8 ( 62) 1 (8) 6 ( 5) ( ) Diarrhoea 5 ( 38) 3 ( ) Anaemia 4 ( 31) 3 ( ) 1 (8) Headache 3 ( 23) 3 ( ) Injection site pain 4 ( 31) 2 ( 17) Pruritus generalised 2 ( 15) 4 ( 33) Rash 2 ( 15) 4 ( 33) Arthralgia 3 ( 23) 2 ( 17) Nausea 5 ( 38) Pyrexia 3 ( 23) 2 ( 17) Alanine aminotransferase increased 3 ( 23) 1 ( 8) 1 (8) Aspartate aminotransferase increased 2 ( 15) 1 ( 8) 2 ( 17) Back pain 2 ( 15) 2 ( 17) Blood alkaline phosphatase increased 3 ( 23) 1 (8) Chills 3 ( 23) 1 (8) Constipation 1 (8) 3 ( ) Hypertension 1 (8) 3 ( ) 2 (17) Hypokalaemia 2 ( 15) 2 ( 17) Influenza like illness 2 ( 15) 2 ( 17) Pain 2 ( 15) 1 2 ( 17) Pain in extremity 2 ( 15) 2 ( 17) 1 (8) Rash generalised 2 ( 15) 2 ( 17) Weight decreased 3 ( 23) 1 ( 8) Patients completing standard dosing of ipilimumab (3 mg/kg IV Q3W x 4) No DLT s reported. Grade 3+ events in these patients attributed to CVA21: None. *Grade 3+ events in these patients attributed to ipilimumab: fatigue (checkpoint naïve), elevated liver enzymes (prior checkpoint). Prior Checkpoint therapy Checkpoint therapy naïve 92% (11/12) + 82% (9/11) + +, One pa,ent from each group currently in the process of comple,ng standard ipilimumab dosing schedule

11 Best Overall Response: Intent to Treat Popula>on (n=22) 11 Best percentage change in the target lesions IIIC IVM1a IVM1b IVM1c Best overall Response*,+ Per irrc (irrc) n (%) Overall response rate 11 (5) Complete response (CR) 4 (18) Partial response (PR) 7 (32) Stable disease (SD) Progressive disease (PD) 6 (27) 5 (23) Disease control rate (CR+PR +SD) 17 (77), Positive level of neutralizing anti-cva21 serum antibodies at baseline (>1:16) *, irrc criteria: Preliminary data, investigator assessed +, First response assessment at Day 16, Response ongoing but not confirmed at data cutoff date

12 Best Overall Response* 12 Best percentage change in the target lesions Prior Checkpoint therapy (n=11) + * Prior ipilimumab IIIC + Prior anti- PD1 IVM1a + # Prior anti- PD-L1 IVM1b IVM1c * # * Best Overall Response + (irrc) Per irrc n (%) Overall response rate 4 (36) Complete response (CR) 1 (9) Partial response (PR) 3 (27) Stable disease (SD) 5 (46) Progressive disease (PD) 2 (18) Disease control rate (CR+PR+SD) 9 (82) * * * Best percentage change in the target lesions Checkpoint therapy naïve (n=11) Best Overall Response + (irrc) Per irrc n (%) Overall response rate 7 (64) Complete response (CR) 3 (27) Partial response (PR) 4 (36) Stable disease (SD) 1 (9) Progressive disease (PD) 3 (27) Disease control rate (CR+PR+SD) 8 (73) *, irrc criteria: Preliminary data, investigator assessed +, First response assessment at Day 16

13 Pt1351 (Stage IIIC) Complete tumor response Pre- Treatment Day 3 Prior cancer treatments (Best response) 1. BCG (PD) 2. Nivolumab (PD) Best percentage change in the target lesions Pt Study Day Day 9 Day 18 13

Pt1345 (Stage IVM1c) Par>al tumor response

14 Pt1345 (Stage IVM1c) Par>al tumor response Pre- treatment Day 127 Prior cancer treatments (Best response) 1. Ipilimumab/Nivolumab (PR) 2. Nivolumab (PD) 3. Surgery (NE) Best percentage change in target esions Pt Study Day Day 31 14

15 Pt13123 (Stage IVM1c) Par>al tumor response 15 Prior cancer treatments (Best response) 1. IL- 2 (PD) Best percentage change in target lesions Pt Study Day

16 Prior cancer treatments (Best response) 1. Surgery x 2 (NE) 2. gp1 vaccinapon (SD) Pt1342 (Stage IVM1a) Complete tumor response Pre- treatment Day Best percentage change in target lesions Pt Study Day

17 Changes in target lesion burden*,+ by disease stage Prior Checkpoint therapy (n=11) Checkpoint therapy naïve (n=11) Best percentage change in the target lesions IIIC IVM1a IVM1b IVM1c Best percentage change in the target lesions Study Days Study Days *, irrc criteria: Preliminary data, inves>gator assessed +, First response assessment at Day 16, Pa>ent completed study, Pa>ent on study, No further response assessment due to index lesion excision

18 Non- injected individual target visceral lesion response*,+ 18 Best percentage change in individual target lesions Prior Checkpoint therapy Best percentage change in the target lesions Checkpoint therapy naïve Lung lesion Liver lesion Other visceral lesion 46% of non- injected target lesions regressed 5% 67% of non- injected target lesions regressed 5% *, irrc criteria: Preliminary data, investigator assessed +, First response assessment at Day 16

19 Best percentage change in the target lesions Broad ac>vity of intratumoral CVA21 in combina>on with ipilimumab or pembrolizumab in an>- PD1/PD- L1 therapy naïve melanoma pa>ents CVA21 + ipilimumab (n=11) BORR= 64% (7/11) Best percentage change in the target lesions CVA21 + pembrolizumab 1 (n=15) * BORR= 6% (9/15) 19 IIIB IIIC IV M1a IV M1b IV M1c * Prior ipilimumab treatment DCR= 72% (8/11) DCR= 87% (13/15) 1 Silk, Kaufman et al, 217, AACR Abstract CT26/2

20 Detail of Analysis of CD4 T cell Subsets* Lymphocytes+ CD3+CD4++ CD3+CD4++ CCR4++ Non4Treg++ CCR4++ and+ccr44++ CD4++ Non4Treg++ and+ Non4naïve++ CD4++ Non4Treg,+ Non4naïve++ and+non4t=++ CD4++ CD4+ <PerCP-Cy5-5-A>: CD <Alexa Fluor 7-A>: CD3 CD3+ CCR4+ <PE-Cy7-A>: CCR <PerCP-Cy5-5-A>: CD4 CD4+ CD127+ <BV65-A>: CD Treg <BV65-A>: CD CD+ CD45RO+ <APC-H7-A>: CD45RO Na <PerCP-Cy5-5-A>: CD4 CD4+ SSC+ SSC-A K 2K 15K 1K 5K T=+ CCR <BV51-A>: CXCR5 <PE-CF594-A>: CXCR3 <BV785-A>: CCR CXCR5+ CXCR3+ Th17+ Th2+ Th1/+ Th17+ Th1+ * Fresh peripheral blood from a subset of 8 patients at Providence Cancer Centre underwent immune monitoring.

Qualitative Difference: Activation Superior Breadth and Depth of CD4 Activation in Responders HLADR NR R Treg Th17 Tk 1 8 6 4 Th1 2 Th1Th17 Th2 HLADR, CD38, ICOS, OX4, GITR, TIGIT, CD39, 4-1BB and

21 Qualitative Difference: Activation Superior Breadth and Depth of CD4 Activation in Responders HLADR NR R Treg Th17 Tk Th1 2 Th1Th17 Th2 HLADR, CD38, ICOS, OX4, GITR, TIGIT, CD39, 4-1BB and CD69 (total 9 markers) were evaluated. Frequency of marker posipve papents (> 4% increased from baseline in more than two independent Pme points) are displayed in the radar plot. 1 % = all papents show all marker posipve (> 4% increased) at least two Pme points.

22 Quantitative Difference: Expansion Broader CD4 T cell Subsets Expanded in Responders NR R Treg Th Naive (% of subjects) Tk Th1 Th2 Th1Th17 CD4 T cell subsets were considered to be expanded when frequency of CD4 subsets increased > 4% from baseline at more than two Pme points. The radar plot shows the frequency of individuals with expanded CD4 subsets.

23 Conclusions The CVA21-ipilimumab combination immunotherapy treatment is generally well tolerated and has displayed durable antitumor activity in local, regional and distant systemic disease. At present no DLT s have been reported, with surprisingly, only 2 Gr 3 treatment-ae s (ipilimumab-related fatigue and elevated liver enzymes) with an overall study Gr 3/4 treatment-related AE rate of 8% (2/ pts). Preliminary investigator assessed Best Overall Response Rates (BORR): - 5% (11/22 pts) in ITT population; - 36% (4/11 pts) in patients administered prior checkpoint therapy; - 64% (7/11 pts) in patients naïve to checkpoint therapy; - All response rates are higher than published rates for either agent used alone (CVA21: 28.1% and ipilimumab :~11%) in advanced melanoma patients. Objective response rates of 46% (6/13 lesions) and 67% (6/9 lesions) in non-injected visceral target lesions in patients with or without prior checkpoint therapies, respectively. CVA21 + ipilimumab can increase the percentage of activated CD4 and CD8 T cells with effector and memory phenotypes in the peripheral blood. Evidence of broader CD4 T-cell subsets expanded in responding patients. While preliminary, the data suggest that a CVA21-ipilimumab combination may represent a viable treatment option for an unmet need in advanced melanoma patients refractory to prior anti-pd1+/- CTLA-4 therapies.

$Future Direc>ons A focus on an unmet clinical need in advanced melanoma patients refractory to prior immune checkpoint therapies.$

24 Future Direc>ons A focus on an unmet clinical need in advanced melanoma patients refractory to prior immune checkpoint therapies. Expansion Cohort 44 Stage IIIC and IV melanoma patients at least 1 injectable lesion, immune checkpoint refractory Recruitment commenced Primary study Objective Response rate

25 Acknowledgments The invespgators, papents, and study staff who are contribupng to this study; Bernie Fox, Zipei Peng, Christopher PausPan, Carlo Bifulco, Yoshi Koguchi and Will Redmond: Earle A Chiles Research Ins>tute Providence Cancer Center, Portland; Howard Kaufman and Ann Silk: Rutgers Cancer Ins>tute of New Jersey, New Brunswick, New Jersey; ViralyPcs R&D and Clinical Teams.

Disclosures Information Brendan D. Curti, MD

Disclosures Information Brendan D. Curti, MD The MITCI (Phase 1b) study: A novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy