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Dogs with Naturally-Occurring Incurable Hemangiosarcoma

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Dogs with Naturally-Occurring Incurable Hemangiosarcoma ＃1694 Genetically Engineered Targeted Toxin Enhances Survival in Dogs with Naturally-occurring Incurable Hemangiosarcoma Antonella Borgatti1,2,3, Joseph S. Koopmeiners4, Amber L. Winter1,5, Kathleen Stuebner1,5, Deborah Todhunter3,6, Jerry Froelich7, Michael Henson1,2,3, Jaime F. Modiano1,2,3, Daniel Vallera3,6 1Animal Cancer Care and Research (ACCR) Program, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; 2Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA; 3Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; 4Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA; 5Clinical Investigation Center, College of Veterinary Medicine, St. Paul, MN 55108; 6Department of Therapeutic Radiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA; 7Department of Diagnostic Radiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA Abstract Clinical study patients EGFuPA was well-tolerated in all dose escalation groups Introduction: EGFuPA is a de-immunized bispecific ligand-targeted toxin (BLT) Table 3: Estimated probability of experiencing at least one dose limiting toxicity (DLT) by treatment group consisting of epidermal growth factor (EGF) and urokinase (uPA) on the same Dose Level N N with DLTs Probability of DLT– empirical (95% CI) Probability of DLT – from model (95% CI) molecule with truncated Pseudomonas exotoxin. EGFuPA simultaneously targets EGF receptors (EGFR) and/or urokinase receptors (uPAR) on tumor cells and 1 (25 ug/kg) 3 0 0.0% (0.0%, 70.8%) 5.3% (0.1%, 24.9%) uPAR in the microenvironment. EGFuPA is safe and effective in laboratory 2 (50 ug/kg) 15 2 (3 total DLTs) 13.3% (1.7%, 40.5%) 15.3% (3.5%, 32.5%) animals and has excellent in vitro activity against sarcomas. Because EGFuPA 3 (100 ug/kg) 3 2 66.7% (9.4%, 99.2%) 51.1% (10.2%, 92.6%) crosses species platforms, an adaptive Phase I/II study (SRCBST) was DLTs consisted of four reversible hypotensive events (two in Dose-2 group and two in Dose-3 group) during or undertaken using canine hemangiosarcoma (HSA) as a model of a highly at the end of drug infusion, and 1 acute episode of grade 3 liver toxicity in Dose-2 group following first infusion aggressive, metastatic, vascular sarcoma. Canine HSA is an incurable tumor with normalization of liver enzymes within one week. derived from blood vessel forming cells, which can overexpress both uPAR and EGFR. It bears similarity to human angiosarcoma. Median survival (MS) of dogs treated with standard of care (SOC) surgery and chemotherapy is ~ 6 months and Pharmacokinetics and Neutralizing Antibody (NA) <10% live ≥1 year due to the development of metastasis. We hypothesized that The presence of EGFuPA in serum was measured by the ability of diluted serum to inhibit proliferation of RD EGFuPA would be safe and effective when combined to SOC for the treatment of (human rhabdomyosarcoma) indicator cells and then extrapolating EGFuPA concentration using standard canine HSA and that median survival at 6 months would exceed 50% in treated curve comparison, as described previously (Kreitman R.J. et al, J Clin Onc, 2012; 30(15):1822-8). Finally, the dogs. Our aim was to determine the activity, toxicity, and optimal dose (i.e. safe presence of neutralizing antibodies was measured using patient serum to block the activity of EGFuPA in vitro and effective dose) of EGFuPA in a relevant, large animal model of a highly Study patient with concurrent (Vallera D. et al, Clin Cancer Res, 2005; 11(10):3879-3888). Serum samples were collected pre-treatment aggressive sarcoma. cardiac and splenic HSA, long-term survivor (time 0) and post-treatment at 5, 15, 30, 45, and 60 minutes on days 1 and 6. A single serum sample was Methods: Dogs with histologically confirmed, non-metastatic stage-I or II splenic Table 2: Baseline characteristics for all dogs and by dose summarized by N (%) or mean (SD) collected on days 8 and 21, when available. HSA presenting to the University of Minnesota (UMN), Veterinary Medical Center Bioassay for EGFATFKDEL (VMC) were eligible after splenectomy. EGFuPA was administered intravenously Variable Level/Unit All Dogs Dose 1 Dose 2 Dose 3 Breed Mix Breed 2 (9.6%) 1 (33.3%) 1 (6.7%) 0 (0%) on Days 1, 3, and 5 followed by standard adjuvant doxorubicin starting on day 21. 50 Labrador 5 (23.8%) 1 (33.3%) 4 (26.7%) 0 (0%) Figure 2: Correlation between NA and EGFuPA Day 1 Results: EGFuPA was detectable in the systemic circulation 5 minutes post- Day 6 Retriever n=10 n=7 infusion with clearance by 15 minutes. It was well-tolerated with self-limiting, detection in the serum. The area under the curve (AUC) 40 English Setter 1 (4.8%) 1 (33.3%) 0 (0%) 0 (0%) generated by EGFuPA detection was measured on day 1 n=7 reversible hypovolemia in 4 dogs and acute, reversible, grade 3 liver toxicity in 1 Brittany Spaniel 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) and day 6 for all dogs. The graph illustrates the AUC 30 dog. The optimal dose was 50 µg/kg. When compared to a Control group of dogs Airedale Terrier 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) C intensity in relation to three group categories: dogs with U Bichon Frise 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) A treated at the UMN with SOC therapy, MS was longer for all 21 dogs treated with 20 no antibody (pre-existing or drug-induced; N=10), dogs n=10 EGFuPA (SRCBST group) and for the 15 dogs in the Optimal Dose group (4.9 Newfoundland 1 (4.8%) 0 (0%) 0 (0%) of 1 (33.3%) with pre-existing antibody (N=4), and dogs who developed A n=4 months for the Control group versus 7.5 and 8.7 months for the SRCBST group Viszla 1 (4.8%) 0 (0%) 0 (0%) 1 (33.3%) 10 Goldendoodle 1 (4.8%) 0 (0%) 0 (0%) 1 (33.3%) antibody following the first dose (N=7). AUC is expressed and the Optimal Dose group, respectively). Six-month survival was 38.7% for the n=3 Control group, 66.6% for the SRCBST group, and 77% for the Optimal Dose English Springer 2 (9.5%) 0 (0%) 2 (13.3%) 0 (0%) as µg/ml x minute. 0 Spaniel Study patient, alive No Antibody Antibody After Pre-existing Antibody group. Outcomes were not affected by the presence of neutralizing antibodies First Dose Cairn Terrier 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) > 1yr after diagnosis (NA) nor by drug detection on pharmacokinetics assays. Papillon 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) Conclusions: A safe and biologically active dose of EGFuPA was established in Dachshund 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) EGFuPA increases survival in treated dogs compared to controls companion dogs with HSA in the minimal residual disease setting. The unique Golden Retriever 1 (4.8%) 0 (0%) 1 (6.7%) 0 (0%) nature of its bispecific targeting and the observed significant, biologic activity Age Years 9.3 (1.7) 9.2 (1.6) 9.4 (1.8) 8.7 (1.8) Table 4: Summary of survival for dogs enrolled in the SRCBST study and control cohort warrants consideration of EGFuPA for a Phase I study for drug-refractory Sex MN 9 (43.2) 1 (33.3) 7 (46.9) 1 (33.3) Group N Median Survival 6-month Survival: KM 6 – month Survival: Model sarcomas in human patients. MI 1 (4.8) 0 (0) 1 (6.7) 0 (0) Months Support: Angiosarcoma Awareness Foundation; NIH K01 grant # OD017242-01; FS 11 (52.4) 2 (66.7) 7 (46.7) 2 (66.7) GREYlong; and University of Minnesota ACCR Program. BCS 1-9 5.7 (1) 5.7 (0.6) 5.6 (1.1) 6.3 (0.6) SRCBST study – all dogs 21 7.5 (4.9, Inf) 66.6% (47.8%, 92.9%) Hemoabdomen Y 18 (85.7) 2 (66.7) 13 (86.7) 3 (100) Study patient still alive SRCBST study – dose 1 3 4.6 (3.8, Inf) 27.2% (6.7%, 100.0%) 53.1% (18.3%, 82.7%) Methods N 3 (14.3) 1 (33.3) 2 (13.3) 0 (0) > 1 year after diagnosis Stage 1 2 (9.5) 0 (0) 2 (13.3) 0 (0) We conducted a Phase I/II dose finding study called SRCBST. The trial was 2 18 (85.7) 2 (66.7) 13 (86.7) 3 (100) SRCBST study – dose 2 15 8.7 (7.5, Inf) 77.0% (56.8%, 100.0%) 66.7% (43.5%, 87.5%) 3 1 (4.8) 1 (33.3) 0 (0) 0 (0) approved by the UMN IACUC and owner consent was obtained prior to dog Time from Days 22.1 (11.2) 15 (5.2) 24.3 (12.4) 18 (2) Study patient, survival SRCBST study – dose 3 3 6.8 (3.0, Inf) 66.7% (30.0%, 100.0%) 74.8% (29.9%, 97.9%) enrollment. Inclusion criteria: histopathologic diagnosis of splenic HSA removed surgery to tx >500 d after diagnosis via splenectomy; no evidence of metastatic disease on thoracic radiography and abdominal ultrasonography; no herbal treatments or supplements; Karnofsky PET-CT imaging shows higher sensitivity in metastasis detection compared to SRCBST control 28 4.9 (4.3, 8.0) 38.7% (24.1%, 62.0%) performance score of 0 or 1; life expectancy ≥12 weeks; adequate organ function. PET-CT scans were optional and results were not exclusionary.
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