A first-in-human phase I study of VGX-100, a selective anti-VEGF-C antibody, alone and in combination with bevacizumab in patients with advanced solid tumors. G.S Falchook 1 , J.W.Goldman 2 , J. Desai 3,4 , I.M. Leitch 4 , D.S. Hong 1 , V. Subbiah 1 , R. Kurzrock 1 , L.S. Rosen 2 1 University of Texas MD Anderson Cancer Center, Houston, TX; 2 UCLA Hematology-Oncology, Santa Monica, CA; 3 Royal Melbourne Hospital, Melbourne, Australia; 4 Ceres Oncology / Vegenics, Melbourne, Australia; INTRODUCTION STUDY DESIGN CONCLUSIONS VGX-100 (anti-VEGF-C) • VGX-100 is an investigational first-in-class fully human IgG1λ neutralizing monoclonal antibody targeting VEGF-C, inhibiting its receptor activation of VEGFR-2 & VEGFR-3. • VEGF-C is a pro-angiogenic / lymphangiogenic growth factor that may modulate tumoral escape / resistance to anti-VEGF therapy and allow regrowth of tumor vasculature. 1-2 • VEGF-C is associated with: • Increased vascular density • melanoma, breast, pancreatic, colorectal, lung • Poor outcomes including reduced survival • Gastric, lung, colorectal, lung, breast, pancreatic, ovarian 3-6 • In preclinical xenograft models, addition of VGX-100 to bevacizumab +/- chemotherapy or tyrosine kinase inhibitors prolongs tumor regression. 7-9 • Clinical combination of VGX-100 with bevacizumab (Avastin ® ) may result in synergistic effects by targeting multiple VEGF signalling pathways that mediate angiogenesis and lymphangiogenesis. Targeted CoTherapy • Bevacizumab is a humanized monoclonal anti-VEGF-A antibody that binds to and inhibits the biologic activity of human VEGF-A. VEGF C induces angiogenesis via activation of both VEGFR-2 and VEGFR-3, and lymphangiogenesis via activation of VEGFR -3. VGX-100 is a fully human neutralizing monoclonal antibody directed against human VEGF C. VGX-100 Inhibition of VEGF-C Signaling In Tumors. Study Design • Open label, phase 1 a / 1b “3+3” dose escalation study (NCT01514123) • The study has an accelerated two arm design: • Arm A: VGX-100 mono-therapy • Arm B: VGX-100 in combination with bevacizumab OBJECTIVES Primary Objectives •To evaluate the safety and establish the recommended dose of VGX 100 alone and co-administered with bevacizumab. Secondary Objectives •To assess: o the pharmacokinetic profile of VGX-100 alone and co-administered with bevacizumab o the incidence of anti-VGX-100 antibody formation o potential biomarkers o preliminary tumor response Cohort` VGX-100 (mg/kg, QW) Bevacizumab (mg/kg, Q2W) Patients N Patients with DLT N (%) DLT’s in 28 day Cycle 1 Arm A: VGX-100 A1 1 - 4 a 0 A2 2.5 - 3 0 A3 5 - 3 0 A4 10 - 3 0 A5 20 - 3 0 A6 30 - 3 0 Arm B: Bevacizumab + VGX-100 B1 2.5 5 6 1 G3 hypertension B2 2.5 10 3 0 B3 5 10 6* 0 B4 10 10 3 0 B5 20 10 6* 0 VGX-100 +/- bevacizumab administration schedule •Arm A (VGX 100 mono-therapy) o Each 28 day treatment cycle consists of VGX 100 given weekly as an intravenous (IV) infusion at D1, D8, D15 and D22. •Arm B (VGX 100 plus bevacizumab) o Treatment with bevacizumab is given first, followed by VGX-100. For each subject, each 28 day treatment cycle consists of: • bevacizumab given as an IV infusion every 2 weeks at D1 and D15. • VGX 100 given as an IV infusion weekly at D1, D8, D15 and D22. •Patients received treatment until disease progression or intolerable toxicity. Key Eligibility Criteria •Adult patients (≥ 18 years) with advanced solid tumors. •Adequate hematologic, renal and hepatic function. •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 •Evaluable OR measurable disease by RECIST 1.1 criteria. •Patients excluded with CNS / cerebrovascular haemorrhage, myocardial infarction or reversible posterior leukoencephalopathy syndrome associated with prior anti-VEGF/anti-VEGFR therapy. DLT Criteria •A DLT is defined as any AE of ≥ grade 3 up to day 28 despite optimal supportive care, unless there is a clear alternative explanation that the AE was not caused by either VGX-100 or bevacizumab, except for the following: - alopecia; fatigue; or grade 3 hypertension controlled within 72 hrs. •The maximum tolerated dose (MTD) is defined as the highest dose level with an observed incidence of DLT in < 33% of subjects enrolled in a cohort dose level. Abstract # 2524 RESULTS (continued) Patient Disposition and Dose Limiting Toxicities Demographics and Patient Characteristics Arm A: VGX-100 (N=19) Arm B: Bevacizumab + VGX-100 (N=24) Females, n (%) 10 (53) 12 (46) Males, n (%) 9 (47) 12 (54) Age, mean years (SD) 59.6 (14) 57.2 (13) Min, Max 20, 76 28, 85 Race, n (%) White 12 (63) 19 (79) African American 2 (10.5) 2 (8) Latino 3 (16) 3 (13) Asian 2 (10.5) 0 (0) ECOG score, n (%) 0 2 (11) 7 (29) 1 17 (89) 17 (71) Prior Therapy, n (%) ≥ 1 line of Chemotherapy 17 (90) 24 (100) Bevacizumab 9 (47) 9 (38) Radiotherapy 8 (42) 17 (71) Primary Tumor Type, n (%) Breast 0 (0) 2 (8) Cervical 0 (0) 2 (8) Colon 5 (26) 4 (17) Pancreatic 2 (11) 1 (4) Renal cell carcinoma 0 (0) 2 (8) Urothelial 0 (0) 2 (8) Other 12 (63) 11 (46) Arm A (all other tumor types n=1 [5%]): Adnexal, Aveolar soft tissue sarcoma, Cholangiocarcinoma, Endometrial, Gastroesophageal junction, Lacrymal duct carcinoma, Melanoma, Ovarian, Pancreatic neuroendocrine Tumor, Prostate (Undifferentiated), Rectal, Submandibular salivary gland. Arm B (all other tumor types n=1 [4%]): Adrenal, Appendiceal, Gastric, Inflammatory breast cancer, Lung, Melanoma, Mixed Mullerian, Neuroendocrine Tumor of cervix, Sarcoma, Thymic, Uterine. VGX-100 (N =19) Bevacizumab + VGX-100 (N = 22) Patients with any treatment related AE, n (%) 9 (47) 17 (77) Worst grade of 1 7 (37) 8 (33) Worst grade of 2 7 (37) 12 (55) Anorexia 0 (0) 2 (9) Anemia 1 (5) b 1 (5) Back pain 0 (0) 1 (5) d Chills 0 (0) 1 (5) Deep vein thrombosis 0 (0) 1 (5) Dermatitis allergic 2 (11) b 0 (0) Fatigue 1 (11) a 0 (0) Headache 0 (0) 1 (5) Hypersensitivity 2 (11) 2 (9) c Hypertension 0 (0) 4 (18) d Infusion related reaction 1 (5) 0 (0) Infusion site reaction 1 (5) a 0 (0) Thrombosis 0 (0) 1 (5) c Worst grade of 3 0 (0) 2 (9) Cardiac failure congestive* 0 (0) 1 (4) Hypertension # 0 (0) 1 (4) Worst grade of 4 0 (0) 0 (0) Worst grade of 5 0 (0) 0 (0) Treatment-Related Adverse Events Anti-VGX-100 Antibodies Patients N Binding Antibodies N Neutralizing Antibodies N Arm A: VGX-100 single agent 19 0 0 Arm B: Bevacizumab + VGX-100 24 1* 0 Overall incidence rate 2% (1/43) 0% (0/43) *One patient had a “low positive” for pre-existing binding antibodies to VGX-100 at baseline prior to receiving VGX-100 and tested negative at subsequent post-dose timepoints. Serum Concentration versus Time Profiles VGX-100 (N=19) Bevacizumab + VGX-100 (N=24) Evaluable Patients 17 22 Stable Disease, n (%) 6 (35) 8 (36) Progressive Disease, n (%) 11 (65) 14 (64) References • VGX-100 at weekly doses up to 30 mg/kg alone or up to 20 mg/kg in combination with bevacizumab 5 or 10 mg/kg, Q2W was safe and tolerable in patients with advanced solid tumors. No MTD was reached. • Preliminary PK data for VGX-100 support weekly dosing and combining treatments did not markedly affect the profiles of VGX-100 or bevacizumab. • Weekly dosing with VGX-100 ≥20 mg/kg exceeded predicted human circulating VEGF-C levels and efficacy exposures in xenograft models. • There were no findings of altered safety or pharmacokinetic profiles due to development of anti-VGX-100 binding or neutralizing antibodies. • Five patients had durable stable disease ≥ 16 weeks (2 colon, 1 ovarian, 1 RCC and 1 cervical). • The combination of inhibiting both VEGF-C and VEGF-A ligand signaling pathways with VGX-100 and bevacizumab appears promising. • Further clinical evaluation of VGX-100 in combination with VEGF-A inhibitors, chemotherapy and other targeted agents is warranted. At the time of the data cut-off, safety data was available for 22 subjects enrolled in Arm B cohorts a,b,c,d Occurred in the same patient *Observed in Cycle 3 for Cohort B2 (VGX-100 2.5 mg/kg, QW + bevacizumab 10 mg/kg, Q2W) # Observed in Cycle 1 for Cohort B1 (VGX-100 2.5 mg/kg, QW + bevacizumab 5 mg/kg, Q2W) AE, Adverse event • All patients had treatment emergent adverse events of ≥ Grade 1. • Grade 3 treatment emergent adverse events occurred in 1 patient each with either hyperbilirubinemia, hypophosphatemia, dyspnoea, lipase increased, intestinal obstruction, syncope, or abdominal cramps; and 1 patient with abdominal pain, syncope vasovagal and pleural effusion • 1 patient had a treatment-emergent grade 4 adverse event: visual disturbance (Cohort B5: VGX-100 20 mg/kg, QW + bevacizumab 10 mg/kg, QW) • 2 patients had treatment-emergent grade 5 events: of progressive disease (Cohort A5: VGX-100 20 mg/kg, QW) and aspiration (Cohort B3: VGX-100 5 mg/kg, QW + bevacizumab 10 mg/kg, Q2W). • None of these AEs were considered related to VGX-100 or bevacizumab. Treatment-emergent Adverse Events Best Post Dose Tumor Response by RECIST a • A best response of stable disease was seen in 14 of 39 (36%) evaluable patients. • Five patients (13%) had durable stable disease ≥ 16 weeks as follows: • 2 patients with colon cancer • Cohort A3: VGX-100 monotherapy 5 mg/kg, QW • Cohort B1: VGX-100 2.5 mg/kg, QW + Bevacizumab 5 mg/kg, Q2W • 1 patient with ovarian cancer • Cohort A5: VGX-100 monotherapy 20 mg/kg, QW • 1 patient with renal cell carcinoma (RCC) • Cohort B2: VGX-100 2.5 mg/kg, QW + Bevacizumab 10 mg/kg, Q2W • 1 patient with cervical cancer • Cohort B5: VGX-100 20 mg/kg, QW + Bevacizumab 10 mg/kg, Q2W • A patient with triple negative breast cancer had a 16% decrease in disease at all sites (bone, lung, LN and skin) at the end of cycle 2 (Cohort B2:VGX-100 2.5 mg/kg, QW + bevacizumab 10 mg/kg, Q2W) but discontinued in cycle 3 (SAE). • Four patients discontinued prior to post-dose tumor assessment (1 clinical progression, 1 withdrawal of consent and 2 SAE’s). VEGF-B PIGF VEGF-A VEGF-C VEGF-D VGX-100 Bevacizumab RESULTS STUDY DESIGN a One pt in cohort A1 withdrew consent @ D18 after 2 doses of VGX-100 and was replaced per protocol *Enrollment into cohorts was expanded to gain additional safety experience with VGX-100 RESULTS - IMMUNOGENICITY RESULTS – SAFETY AND TOLERABILITY • The increases in C max and AUC 0-168 for VGX-100 appear to be dose proportional over the available dose range and support weekly dosing • Preliminary PK for VGX-100 appears to be similar alone and when co- administered with bevacizumab. • Bevacizumab PK appears to be comparable to historical data. • Weekly i.v doses of VGX-100 ≥ 20 mg/kg, had C min values at Day 15 (Mean 128000 ng/mL, SD 27495 ng/mL) that exceeded: • maximal serum VEGF-C levels (6 - 32 ng/mL) reported in cancer patients 10 • In vivo PK exposures of VGX-100 (~≥100000 ng/mL) associated with efficacy in xenograft tumor models in mice (data on file). • In vitro VGX-100 IC50 values of (26 ng/mL and 19 ng/mL) to inhibit VEGF- C binding to VEGFR-2 and VEGFR-3 receptors respectively in BAF/3 cell assays (data on file). Mean VGX-100 Concentration-Time Profiles on Days 1 and 15 (Cycle 1) for Arm A Cohorts A1-A5 Mean VGX-100 Concentration-Time Profiles on Days 1 and 15 (Cycle 1) for Arm B Cohorts B1-B3 (after co-administration with Bevaacizumab) Mean Bevacizumab Concentration-Time Profiles on Days 1 and 15 (Cycle 1) for Arm B Cohorts B1-B3 (after co-administration with VGX-100) a In patients with measurable disease at baseline and one follow-up assessment who received at least one dose of VGX-100 (Arm A cohorts n=17; Arm B cohorts n=22). RESULTS – SAFETY AND TOLERABILITY RESULTS - PHARMACOKINETICS RESULTS – TUMOR RESPONSE ACKNOWLEDGEMENTS • We thank all patients and their families. We acknowledge all study personnel at the 2 study sites: MD Anderson and UCLA Hematology – Oncology. 1. Lieu, C. et al., Plos One, 8,(10), e77117. 2014 2. Li, D. et al., Cancer Lett, 28 (346), 45-52. 2013 3. Joukov, EMBO J, 15, 290, 1996 4.. Adams and Alitalo, Cell Biol, 8, 464. 2007 5. Jubb, A. et al., Clin Can Res., 17(2):372-81, 2011 6. Fan, F. et al., British J Cancer, 1-8, 2011 7. Baldwin et al., AACR (Abstract # LB-284), 2011. 8. Tester et al., AACR (Abstract # 2442), 2010. 9. Tester et al, EORTC (abstract #36), 2012. 10. Mitsuhashi, A et al., Cancer, 103, 724-730. 2005 ECOG, Eastern Cooperative Oncology Group Solid tumors (advanced or metastatic) VGX-100 QW Bev Q2W “3+3” design 28 day DLT window Imaging every 8 weeks 2 sites US VGX-100 5 mg/kg VGX-100 2.5 mg/kg VGX-100 1 mg/kg Arm A: VGX-100 (QW) single agent Dose escalation Arm B: VGX-100 (QW) + Bevacizumab (Q2W) Dose escalation VGX-100 30 mg/kg, QW VGX-100 20 mg/kg VGX-100 10 mg/kg Bev + VGX-100 10 + 5 mg/kg Bev + VGX-100 10 + 2.5 mg/kg Bev + VGX-100 5 + 2.5 mg/kg Bev + VGX-100 10 + 20 mg/kg Bev + VGX-100 10 + 10 mg/kg A1 A2 A3 A4 A5 A6 B1 B2 B3 B4 B5 Safety Follow Up Visit / End of Study DLT window 28 d