Impact of repeated cycles of EGF bispecific angiotoxin (eBAT) administered at a reduced interval from doxorubicin chemotherapy in dogs with splenic haemangiosarcoma

Abstract

We previously reported that eBAT, an EGF-targeted angiotoxin, was safe and it improved the overall survival for dogs with splenic haemangiosarcoma when added to the standard of care in a single cycle of three administrations in the minimal residual disease setting. Our objective for the SRCBST-2 trial was to assess whether increased dosing through multiple cycles of eBAT would be well tolerated and would further enhance the benefits of eBAT. Eligibility was expanded to dogs with stage 3 haemangiosarcoma, provided that gross lesions could be surgically excised. The interval between eBAT and the start of chemotherapy was reduced, and the experimental therapy was expanded to three cycles, each administered at the biologically active dose (50 μg/kg) on a Monday/Wednesday/Friday schedule following splenectomy, and scheduled 1 week prior to the first, second and fifth doxorubicin chemotherapy. Twenty-five dogs were enrolled; six experienced acute hypotension with two requiring hospitalization. Self-limiting elevation of ALT was observed in one dog. A statistically significant survival benefit was not seen in this study in eBAT-treated dogs compared with a Contemporary comparison group of dogs with stages 1-3 haemangiosarcoma treated with standard of care alone. Our results indicate that repeated dosing cycles of eBAT starting 1 week prior to doxorubicin chemotherapy led to greater toxicity and reduced efficacy compared with a single cycle given between surgery and a delayed start of chemotherapy. Further work is needed to understand the precise mechanisms of action of eBAT in order to optimize its clinical benefits in the treatment of canine haemangiosarcoma and other tumours. IACUC Protocols 1110A06186 and 1507-32804A.

Keywords: canine; epidermal growth factor receptor; haemangiosarcoma; sarcoma; targeted toxin; urokinase plasminogen activator receptor.

Figure 1.

CONSORT diagram for SRCBST-2 study

Figure 2.

Study Protocol Timeline. Numbers indicate days of sample collection, staging and treatment. eBAT starts on Day 1 and is given prior to the 1^st, 2^nd, and 5^th cycle of doxorubicin chemotherapy.

Figure 3.. Effect of multiple cycles of eBAT on survival of dogs with splenic HSA treated with adjuvant doxorubicin chemotherapy when unknown cause of death was considered to be related to HSA.

Kaplan-Meier Curve for all 25 dogs in the SRCBST-2 study versus the comparison dogs. Unknown cause of death in 11 cases (5 eBAT treated and 6 in the Comparison Group) was treated as related to HSA.

Figure 4.. Effect of multiple cycles of eBAT on survival of dogs with splenic HSA treated with adjuvant doxorubicin chemotherapy when unknown cause of death was considered to be unrelated to HSA.

Kaplan-Meier Curve for all 25 dogs in the SRCBST-2 study versus the comparison dogs. Unknown cause of death in 11 cases (5 eBAT-treated and 6 in the Comparison Group) was treated as unrelated to HSA.

Figure 5.. Effect of eBAT on survival of dogs that completed 3 cycles of therapy when unknown cause of death was considered to be related to HSA (A) or unrelated to HSA (B).

Kaplan-Meier Curve for 12 dogs in the SRCBST-2 study that completed all planned eBAT cycles of therapy versus the Comparison Group.

Figure 5.. Effect of eBAT on survival of dogs that completed 3 cycles of therapy when unknown cause of death was considered to be related to HSA (A) or unrelated to HSA (B).

Kaplan-Meier Curve for 12 dogs in the SRCBST-2 study that completed all planned eBAT cycles of therapy versus the Comparison Group.