Purpose: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary objectives were to determine biological response rate, time to tumor progression, duration of objective response, health-related quality of life, and safety of Palladia. Experimental Design: Dogs were randomized to receive oral Palladia 3.25 mg/kg or placebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs received open-label Palladia. Results: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7 complete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders (P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events were generally manageable with dose modification and/or supportive care. Conclusions: Palladia has biological activity against canine MCTs and can be administered on a continuous schedule without need for routine planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic index of targeted therapeutics in a clinical setting.

An intravaginal progesterone insert (CIDR insert; 1.38 g of progesterone) was evaluated for synchronization of returns to estrus (SR), conception rate (CR), and pregnancy rate (PR) in dairy cows previously artificially inseminated (AI). Healthy, nonpregnant, lactating Holstein cows, > or = 40 and < or = 150 d postpartum at eight commercial farms were used. Cows detected in estrus and receiving AI 2, 3, or 4 d after one injection of PGF2alpha (25 mg) were assigned as either controls (n = 945), or to receive a CIDR insert (n = 948) for 7 d (14 to 21 +/- 1 d after AI). Cows were observed for returns to estrus from 18 to 26 +/- 1 d after initial AI (resynchrony period) and were reinseminated if in estrus. Vaginal mucus on CIDR inserts (97.3% retention) at removal was scored: 1 = no mucus; 2 = clear; 3 = cloudy; 4 = yellow; and 5 = red or brown. Percentage of cows in estrus (SR) during the 3 d after CIDR insert removal was contrasted to the highest 3-d cumulative percentage in estrus for controls. Cows conceiving to initial AI were omitted in calculations of SR, CR, and PR during resynchrony. Mucous scores of 3 or 4 (mild irritation) were observed in 65% of cows and a score of 5 (more severe irritation) was observed in 2%; otherwise, health was unaffected. The PR to initial AI was lower for cows subsequently receiving CIDR inserts than for controls (32.7 vs. 36.7%). The CIDR insert increased SR (34.1 vs. 19.3% in 3 d) and overall estrus detection (43% in 4 d vs. 36% in 9 d) compared with controls. For the 9-d resynchrony period, CR and PR for CIDR-treated (26.7, 12.2%) and control (30.9, 11.1%) cows did not differ significantly. The CIDR inserts improved synchrony of returns to estrus, slightly reduced PR to initial AI, but did not affect CR or PR to AI during the resynchrony period.

The objectives of the current study were to evaluate the efficacy and field safety of GnRH HCl administered at 3 doses in fixed-time artificial insemination (FTAI) programs (Ovsynch) in dairy cows. A common protocol was conducted at 6 commercial dairies. Between 188 and 195 cows were enrolled at each site (total enrolled = 1,142). Cows had body condition scores ≥ 2 and ≤ 4, were between 32 to 140 d in milk, and were clinically healthy. Within pen and enrollment day (enrollment cohort), cows were assigned randomly in blocks of 4 to each of 4 treatments: (1) 25mg of PGF2α on d 7 with FTAI 72 ± 2 h later (control); (2) 100 μg of GnRH on d 0, d 7 a dose of 25mg of PGF2α, and the second administration of 100 μg of GnRH (T100) administered either at 48 ± 2 h (d 9) after PGF2α with FTAI 24 ± 2 h later or 56 ± 2 h (d 9) after PGF2α and FTAI 17 ± 2 h later; (3) same as T100 with both injections of 150 μg of GnRH (T150); and (4) same as T100 with both injections of 200 μg of GnRH (T200). Three sites selected the first option and 3 sites selected the second option for the timing of the second injection of all doses of GnRH. Cows were observed daily for signs of estrus and adverse clinical signs. Cows not returning to estrus had pregnancy diagnosis between 42 and 65 d following FTAI. Pregnancies per FTAI (P/FTAI) were analyzed as a binary variable (1 = pregnant, 0 = not pregnant) using a generalized linear mixed model with a binomial error distribution and a logit link function. The statistical model included fixed effects for treatment, random effects of site, site by treatment, enrollment cohort within site, and residual. Parity (first vs. second or greater) was included as a covariate. For demonstration of effectiveness, α=0.05 and a 2-tailed test were used. Fifty-two cows were removed from the study because of either deviation from the protocol, injury, illness, culling, or death. Among the remaining 1,090 cows, 33.9% were primiparous and 66.1% were multiparous. Back-transformed least squares means for P/FTAI were 17.1, 27.3, 29.1, and 32.2% for control, T100, T150 and T200, respectively. The P/FTAI for each GnRH dose differed from that of the control. No differences were detected in P/FTAI between GnRH doses. No treatment-related adverse events were observed. Mastitis was the most frequently observed adverse clinical sign, followed by lameness and pneumonia. This study documents the efficacy and safety of doses of 100 to 200 μg of GnRH as the HCl salt when used in Ovsynch programs.

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