Safety of TCMCB07, a melanocortin-4 antagonist peptide, in dogs with naturally occurring cachexia.

BACKGROUND: The melanocortin 4 antagonist TCMCB07 is safe and effective in reversing cachexia caused by sepsis or cancer in rodents. The safety and pharmacokinetics of TCMCB07 are demonstrated in healthy beagle dogs. HYPOTHESIS/OBJECTIVES: The objectives of this study were to investigate the safety, peak plasma concentrations, and potential for efficacy of TCMCB07 in pet dogs with naturally occurring cachexia over a 4-week time period. ANIMALS: Fourteen dogs with cachexia of any underlying cause, except cancer of the oral cavity or gastrointestinal tract, were eligible for enrollment with informed client consent. METHODS: This study was a prospective, 1-armed open-label trial. Physical examination, complete blood count, chemistry panel, and owner-assessed quality of life surveys were checked at weeks 1, 2, and 4. Due to potential for bradycardia and hypotension, Holter monitoring and blood pressure evaluations were scheduled at pre-enrollment and week 4. RESULTS: Fourteen dogs completed the trial. Significant changes detected included increased mean body weight (18.6-19.5 kg, P < .02), increased body condition score (median Tufts 5-point thin dog scale score P < .004 and WSAVA muscle condition score P < .02) and increased mean blood urea nitrogen (21.79-30.43 mg dL-1 , P < .004). On quality of life surveys, pet owners perceived their dog appeared to be panting less (P < .002) and that the general health improved (P < .03). Four dogs had a change in coat pigmentation. The peak plasma concentration of TCMCB07 in cachectic dogs was similar to that in healthy beagle dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: TCMCB07 was safe and has potential efficacy in pet dogs with cachexia.

Autologous cancer cell vaccination, adoptive T-cell transfer, and interleukin-2 administration results in long-term survival for companion dogs with osteosarcoma.

BACKGROUND: Osteosarcoma (OSA) in dogs is an aggressive bone tumor with frequent chemotherapy failure and translational relevance for human health. HYPOTHESIS/OBJECTIVES: We hypothesized that dogs with OSA could be treated safely by ex vivo activated T-cells that were generated by autologous cancer vaccination and supported by interleukin-2 (IL-2) treatment with survival more than twice that reported for amputation alone. ANIMALS: Osteosarcoma-bearing dogs (n = 14) were enrolled in a single-arm prospective trial after complete staging before amputation. Four healthy dogs also were treated in a safety study. METHODS: Autologous cancer cell vaccinations were administered intradermally and dogs underwent leukapheresis. Mononuclear cell products were stimulated ex vivo with a T-cell-activating agent. Activated product was transfused and 5 SC IL-2 injections were administered q48h. Dogs were monitored for metastasis by thoracic radiography every 3 months. RESULTS: Autologous cancer cell vaccine and activated cellular therapy (ACT) products were successfully generated. Toxicity was minimal after premedicants were instituted before ACT. With premedication, all toxicities were grade I/II. Median disease-free interval for all dogs was 213 days. One dog developed cutaneous metastasis but then experienced spontaneous complete remission. Median survival time for all dogs was 415 days. Five dogs survived >730 days. CONCLUSIONS AND CLINICAL IMPORTANCE: This immunotherapy protocol without cytotoxic chemotherapy is safe and tolerable. Compared to historical amputation reports, survival was notably prolonged in this group of patients. Additional prospective studies are warranted to elucidate active immunologic mechanisms and further improve disease response and survival.

Readability of consent forms in veterinary clinical research.

BACKGROUND: "Readability" of consent forms is vital to the informed consent process. The average human hospital consent form is written at a 10th grade reading level, whereas the average American adult reads at an 8th grade level. Limited information currently exists regarding the readability of veterinary general medical or clinical research consent forms. HYPOTHESIS/OBJECTIVES: The goal of this study was to assess the readability of veterinary clinical trial consent forms from a group of veterinary referral centers recently involved in a working group focused on veterinary clinical trial review and consent. We hypothesized that consent forms would not be optimized for client comprehension and would be written above the National Institutes of Health-recommended 6th grade reading level. ANIMALS: None. METHODS: This was a prospective study assessing a convenience sample of veterinary clinical trial consent forms. Readability was assessed using 3 methods: the Flesch-Kincaid (F-K) Grade Level, Flesch Reading Ease Score (FRES), and the Readability Test Tool (RTT). Results were reported as mean (±SD) and compared across specialties. RESULTS: Fifty-three consent forms were evaluated. Mean FRES was 37.5 ± 6.0 (target 60 or higher). Mean F-K Grade Level was 13.0 ± 1.2 and mean RTT grade level was 12.75 ± 1.1 (target 6.0 or lower). There was substantial agreement between F-K and RTT grade level scores (intraclass correlation coefficient 0.8). CONCLUSIONS AND CLINICAL IMPORTANCE: No form evaluated met current health literacy recommendations for readability. A simple and readily available F-K Microsoft-based approach for evaluating grade level was in substantial agreement with other methods, suggesting that this approach might be sufficient for use by clinicians and administrators drafting forms for future studies.

Hyaluronan-Lysine Cisplatin Drug Carrier for Treatment of Localized Cancers: Pharmacokinetics, Tolerability, and Efficacy in Rodents and Canines.

The purpose of this study was to develop a safe and efficacious drug delivery platform for sustained release of cisplatin after locoregional administration. We successfully synthesized hyaluronan-cisplatin nanoconjugates (HA-Lys-Pt) using an N-Ac-lysine linker, which formed a thermodynamically stable five-membered ring with the platinum. The conjugate was characterized for release kinetics, in vitro anti-proliferative activity, degradability, impurity content, formation of Pt-DNA adducts, pharmacokinetics, tolerability in rodents and canines, and for efficacy in rodents. The 75 kD HA-Lys-Pt (75HA-Lys-Pt) sustained release of platinum with a 69 h half-life in phosphate buffered saline without substantial burst release. Compared to intravenous cisplatin, subcutaneously injected 75HA-Lys-Pt formed 3.2-fold more Pt-DNA adducts in rat peripheral blood mononuclear cells compared to intravenous cisplatin over 96 h. Subcutaneous 75HA-Lys-Pt was tolerable in rats at 40 mg/kg (4 × LD50 of conventional cisplatin) and resulted in 62.5% partial response and 37.5% stable disease in murine xenografts of head and neck squamous cell cancer (20 mg/kg/wk × 3 weeks). 75HA-Lys-Pt demonstrated extended tmax and improved area-under-the-curve compared to cisplatin in rats and canines. Canine safety was demonstrated by liver enzyme and electrolyte levels, complete blood count, and urinalysis.

Gum arabic-coated radioactive gold nanoparticles cause no short-term local or systemic toxicity in the clinically relevant canine model of prostate cancer.

INTRODUCTION: Gum arabic-coated radioactive gold nanoparticles (GA-(198)AuNPs) offer several advantages over traditional brachytherapy in the treatment of prostate cancer, including homogenous dose distribution and higher dose-rate irradiation. Our objective was to determine the short-term safety profile of GA-(198)AuNPs injected intralesionally. We proposed that a single treatment of GA-(198)AuNPs would be safe with minimal-to-no evidence of systemic or local toxicity. METHODS: Nine dogs with spontaneously occurring prostatic cancer were treated. Injections were performed with ultrasound or computerized tomography guidance. Complete blood counts, chemistry panels, and urinalyses were performed at weekly intervals for 1 month and imaging was repeated 4 weeks postinjection. Planar scintigraphic images were obtained within 30 minutes of injection. RESULTS: No statistically significant difference was found in any hematologic or biochemical parameter studied, nor was any evidence of tumor swelling or abscessation found in eight dogs with repeat imaging; one dog died secondary to urethral obstruction 12 days following injection. At 30 minutes postinjection, an average of 53% of injected dose in seven dogs was retained in the prostate, with loss of remaining activity in the bladder and urethra; no systemic uptake was detected. CONCLUSION: GA-(198)AuNP therapy had no short-term toxicity in the treatment of prostatic cancer. While therapeutic agent was found in the prostate immediately following injection, some loss of agent was detected in the bladder and urethra. Localization of radioactivity within the prostate was lower than anticipated and likely due to normal vestigial prostatic ducts. Therefore, further study of retention, dosimetry, long-term toxicity, and efficacy of this treatment is warranted prior to Phase I trials in men.