Slide 1: Phase I study of formulated IL-12 plasmid IP with neoadjuvant chemotherapy in ovarian cancer
Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer P.H. Thaker, W. Bradley, C. A. Leath III, C. Gunderson, N. Borys, K. Anwer, L. Musso, R. D.
Slide 2: Treatment Landscape Overview for Advanced Ovarian Cancer
Treatment Landscape Overview for Advanced Ovarian Cancer Surgical goal is complete cytoreduction of all macroscopic visible disease1 Standard adjuvant chemotherapy is an IV or IP taxane/platinum combination1 Despite optimal upfront surgery and adjuvant chemotherapy, approximately 80% of patients wil
Slide 3: IL-12: Four Distinct Mechanisms of Action
IL-12: Four Distinct Mechanisms of Action
Slide 4: IL-12: Four Distinct Mechanisms of Action
IL-12: Four Distinct Mechanisms of Action Shift of TME from Immune Suppression to Activation
Slide 5: Clinical Experience with rhIL-12
Clinical Experience with rhIL-12 • Hurteau et al. – GOG trial of recombinant human IL-12 in recurrent platinum resistant or refractory ovarian cancer – rhIL-12 250 ng/kg IV bolus on D#1 followed by a 2 week rest period, with subsequent daily dosing x 5 days – 26 evaluable patients with median of 2 c
Slide 6: GEN-1: Designed for IP Administration
GEN-1: Designed for IP Administration • Plasmid vector encoding the p35 and p40 subunits of human IL-12 gene • Synthetic lipopolymer delivery system GEN-1 intraperitoneally (IP) produces durable local levels of IL-12 and related cytokines after a single injection and is delivered safely for several
Slide 7: GEN-1 Design Concepts
GEN-1 Design Concepts • PEI condenses DNA into nanoparticle to escape endosomes • Cholesterol is designed to facilitate uptake by cellular membrane • PEG improves in vivo stability (weekly dosing)
Slide 8: Hypothesis
Hypothesis • GEN-1 when added to standard doublet chemotherapy may stimulate a potent immune response in ovarian cancer patients. – resulting in improved R0 resection rates – reduced immunosuppression in the tumor microenvironment – enhanced T cell anti-tumor activity
Slide 9: Phase I Study Design
Phase I Study Design Newly Diagnosed EOC Standard Neoadjuvant Chemotherapy (C) AUC of 6 mg/mL min IV q 3 weeks and (T) 80 mg/m? . IV weekly treatments +8 weekly cycles of GEN-1 IP starting at a dose of 36 mg/m? => Debulking Surgery GEN-1 planned increments: 36, 47, 61, and 79 mg/m? Ml ¢ © ry Surgery
Slide 10: Study Endpoints
Study Endpoints • To determine safety, feasibility and dose in targeted patient population • Secondary Objective: pathological CR, PFS • Translational Objectives: IFN-γ, IL-12, VEGF and tumor- specific T-cell response of CD4+ and CD8+
Slide 11: Study Population
Study Population Patients Dates of Age Histology Stage Performance Baseline CA-125 C1D1 (yrs.) Status: (U/mL) Range: Median: Serous: 0: 34% 18 05Oct2015 63 95% IIIC: 67% Median: 565 1: 55% (ITT) – Range: Clear Cell: IV: 33% Range: 78 - 2252 2: 11% 17May2017 48-79 5% Range: Median: 0: 36% 14 Median:
Slide 12: Results: Safety (n=15)
Results: Safety (n=15) Most Common AEs Attributed to GEN-1 Total (n, %) Grade 1 & Grade 2 Grade 3 (n,%) Grade 4 (n, %) Grade 5 (n, %) (n,%) Nausea 9, 60% 9, 60% 0, 0% 0, 0% 0, 0% Abdominal Pain/ Cramping 6, 40% 5, 33% 1, 6% 0, 0% 0, 0% Fatigue 6, 40% 6, 40% 0, 0% 0, 0% 0, 0% Vomiting 6, 40% 5, 33% 1
Slide 13: Response Data
Response Data 36 47 61 79 Response Total n mg/m2 mg/m2 mg/m2 mg/m2 CR 2 1 0 0 1 RECIST (Prior to IDS) PR 10 0 3 3 4 (n = 14) SD 2 2 0 0 0 R0 9 2 0 2 5 Debulking R1 3 1 2 0 0 Status (n = 14) R2 2 0 1 1 0 cPR 1 1 0 0 0 Pathologic Micro 8 1 2 1 4 (n = 14) Macro 5 1 1 2 1
Slide 14: Follow-up Data: PFS
Follow-up Data: PFS Patients Stage Largest PFS (months) tumor 18 IIIC: 67% Median: 17.1 150 mm (ITT) IV: 33% Range: .1 – 26.9 14 Median: 21 IIIC: 71% (Per 150 mm Range: 9.3 – 26.9 IV: 29% Protocol)
Slide 15: Translational Data: Changes in TME
Translational Data: Changes in TME Low doses (n=4) High doses (n=8) • Changes in immunosuppressive markers in response to low and high dose GEN-1 • Density of markers measured in tissue sections via immunohistochemistry staining Presented by: 15
Slide 16: Ratio of CD8+ Cells to Immunosuppressive Cell Signals
Ratio of CD8+ Cells to Immunosuppressive Cell Signals% Change in Cells/mm3 Increased ratio following treatment in 60-80% of patients CD8+ : FOXP3+ CD8+ : IDO‐1+ CD8+ : PD‐1+ CD8+ : PD‐L1+ • Ratio of CD8+ cells to FoxP3, IDO-1, PD-1 or PD-L1 T-cells in tumor sections counted • % change in the ratio b
Slide 17: Conclusions
Conclusions • Adding GEN-1 to doublet treatment is safe and appears to be active in EOC patients receiving NAC. • Dose limiting toxicity was not reached. • GEN-1 appears to change the tumor microenvironment.
Slide 18: OVATION 2
OVATION 2 • Phase I/II randomized clinical trial for neoadjuvant stage III/IV ovarian cancer patients • Primary Endpoint: PFS
Slide 19: OVATION Study Group
OVATION Study Group P.H. Thaker, Washington University School of Medicine W. Bradley, Medical College of Wisconsin C. A. Leath III, University of Alabama at Birmingham Hospital C. Gunderson, Stephenson Cancer Center The University of Oklahoma N. Borys, Celsion Corporation K. Anwer, Celsion Corporati