First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours.

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.

Current joint therapy usage in equine practice: a survey of veterinarians 2009.

REASONS FOR PERFORMING STUDY: Medications are frequently employed to treat intra-articular (IA) problems in the performance horse. Actual usage of the different IA medications in horses is not available. OBJECTIVES: To determine the most common usage of these medications, members of the American Association of Equine Practitioners (AAEP) were surveyed. METHODS: An email link to an online survey was electronically sent to 6305 AAEP members and the responses tabulated and analysed with a logistic regression model. RESULTS: A total of 831 survey responses were submitted and tabulated. Eighty per cent of the respondents indicated that they see 100% equine cases in their practice. The majority of respondents (77%) use triamcinolone acetonide (TA) to treat high motion joints and 73% use methylprednisolone acetate (MPA) to treat low motion joints. Veterinarians treating the Western performance and Sport horse were significantly more likely to use TA in high motion joints compared to MPA (P = 0.0201 and P<0.0001, respectively). Triamcinolone acetonide use compared to MPA in high motion joints by racehorse veterinarians was significantly lower compared to other veterinarians (P<0.0001). Polysulphated glycosaminoglycan (Adequan) and hyaluronate sodium (Legend) were the most commonly used disease modifying products (63 and 57% of respondents, respectively). Sport horse practitioners were significantly more likely than race or show horse veterinarians to utilise IRAP products (P = 0.0035 and P = 0.04, respectively). Respondents who had been in practice for more than 10 years were significantly less likely to use antimicrobials in their joint injections compared to those in practice for less than 10 years (P<0.0001). CONCLUSIONS: Significant differences existed in usage of medications related to primary discipline treated and years practicing. POTENTIAL RELEVANCE: The results of this study aid in defining the current usage of different joint therapy medications within equine practice. This knowledge can guide further research as well as education.

Autologous conditioned serum in the treatment of orthopedic diseases: the orthokine therapy.

The common strategies for the treatment of patients with orthopedic diseases do not address the underlying pathogenesis. Several biologically based, local therapies aiming to influence the cytokine imbalance are either in development or in the initial stages of clinical use. A method based on exposure of blood leukocytes to pyrogen-free surfaces (e.g. glass spheres) elicits an accumulation of anti-inflammatory cytokines, including interleukin-1 receptor antagonist, and several growth factors, including insulin-like growth factor-1, platelet-derived growth factor, and transforming growth factor-beta(1), in the liquid blood phase. Based on these observations, a new therapy using cell-free, autologous conditioned serum (ACS) from the incubation of whole blood with glass spheres was developed. The injection of ACS into affected tissue(s) has shown clinical effectiveness and safety in animal models and studies, as well as in human clinical studies, for the treatment of osteoarthritis, lumbar stenosis, disc prolapse, and muscle injuries.