287 Effects of ruxolitinib cream on pruritus in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease that has phenotypic differences across race and can be more severe in Black patients. In two phase 3 identical design studies (TRuE-AD1/TRuE-AD2), patients (≥12 years old with AD for ≥2 years, Investigator’s Global Assessment [IGA] score 2/3, 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (Janus kinase [JAK]1/JAK 2 inhibitor) cream or vehicle for 8 weeks. Here we describe the effect of ruxolitinib cream on itch in Black patients using pooled data from the 2 studies (n=292). Mean itch numerical rating scale (NRS) score at baseline was 5.3/5.4 for ruxolitinib cream (0.75%/1.5%) and 5.7 for vehicle. Reductions in mean itch NRS score with ruxolitinib cream (0.75%/1.5%) were evident within approximately 12 hours of first application (–0.6/–0.7 vs −0.2 for vehicle), with statistically significant reductions by Day 4 vs vehicle (–1.4/–1.6 vs –0.6; both P\u3c0.05). For those with baseline itch NRS ≥4 (n=187; 64.0%), more patients achieved ≥4-point itch NRS improvement vs vehicle by Day 2 (6.1%/16.4% vs 0%); this increased to 15.9%/26.6% vs 3.0% on Day 7 and 30.1%/43.2% vs 17.5% at Week 8 (P=0.212/P=0.009). More patients applying 0.75%/1.5% ruxolitinib cream vs vehicle reported no days of itch per question 1 of the Patient-Oriented Eczema Measure (POEM) at Week 2 (19.0%/19.4% vs 5.3%); this increased at Week 8 (34.0%/30.8% vs 12.2%). In summary, ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black patients with AD

275 Effects of ruxolitinib cream on sleep and quality of life over 52 weeks in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease with phenotypic differences across race and can affect sleep and quality of life (QoL). In 2 phase 3 studies of identical design (TRuE-AD1/TRuE-AD2), patients (pts; ≥12 y with AD for ≥2 y; Investigator’s Global Assessment score 2/3; 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (RUX; Janus kinase [JAK]1/JAK2 inhibitor) cream or vehicle for 8 wk (continuous treatment), followed by a long-term safety period (LTS; as-needed treatment) up to Wk 52. Pts randomized to RUX cream remained on their regimen during the LTS; pts on vehicle were rerandomized to either RUX cream strength. For Black pts who were initially randomized to the 0.75% RUX cream/1.5% RUX cream/vehicle to 0.75% RUX cream/vehicle to 1.5% RUX cream groups and continued in the LTS (n=91/97/25/22), sleep-related impairment and sleep disturbance scores per Patient-Reported Outcomes Measurement Information System at baseline (BL) were 16.3/16.4/15.0/17.5 and 18.9/19.7/17.9/19.8, respectively. Scores had decreased (less impairment) at LTS start in the RUX cream groups (Wk 8; 14.2/14.7/16.1/15.5 and 16.7/17.5/19.0/19.4) and were below BL at Wk 52 in all groups (14.3/14.8/13.9/14.4 and 18.0/18.0/17.4/16.3). Dermatology Life Quality Index (DLQI) scores were decreased at Wk 8 (mean change from BL, −7.4/−6.6/−3.8/−4.8); decreased scores were maintained to Wk 52 (−7.1/−6.5/−5.6/−8.8). Results were similar for children’s DLQI (Wk 8, −4.0/−6.9/−4.0/−3.0 [n=12/9/1/3]; Wk 52, −5.6/−11.6/−12.0/−7.3 [n=9/7/1/4]). In summary, sleep and QoL improved with RUX cream; improvements were maintained for 44 wk with as-needed use in Black pts

A Phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR in advanced hepatocellular carcinoma (HCC)

This journal suppl. is Abstract Book of The International Liver Congress™ 2011Poster SessionBACKGROUND AND AIMS: Foretinib is an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR. HGF/MET signaling plays a pivotal role in tumour cell proliferation, migration and invasion, and circulating levels of HGF correlate with poor prognosis in HCC. This phase I/II trial (MET111645) is evaluating oral foretinib as first line therapy in advanced Asian HCC patients. METHODS: Patients with measurable unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0–1, adequate organ function and Child–Pugh grade A are eligible for enrolment. Phase I is a standard 3+3 design using increasing doses of oral foretinib to evaluate safety and determine the maximum tolerated dose (MTD). Secondary objectives include antitumour activity and pharmacokinetics. RESULTS: As of November 16, 2010, 13 patients have been enrolled: median age 57 years (range 31–78 years), M/F = 9/4. BCLC stage 0/A/B/C at screening: 0/0/3/10. Prior lines of therapy including local treatment: unknown/1/2/3/4: 1/3/5/2/1. Drug-related adverse events (AE) were reported in 10 patients (77%). The most common AEs were hypertension (54%), diarrhoea (31%), thrombocytopenia (23%), and peripheral oedema (23%). Serious treatment-emergent toxicities were reported in 54% of patients. Two dose-limiting toxicities (renal failure, proteinuria) were observed in 2/6 patients at 45mg OD but no DLTs were observed in 6 patients at 30mg OD. Nine patients were evaluable for response according to RECIST 1.0; 2 patients had a best response of partial response (PR); objective response rate (ORR) 22%. When tumour response was assessed according to modified RECIST criteria for HCC, 1 patient showed a complete response and 3 patients had a PR; ORR 44%. Exposure of 30- and 45-mg OD foretinib was overlapping and similar to higher doses in other tumour types. CONCLUSION: The foretinib MTD was determined to be 30mg OD. The early promising signal of activity observed in this phase I trial needs to be confirmed in phase II.The 46th Annual Meeting of the European Association for the Study of the Liver (International Liver Congress 2011), Berlin, Germany, 30 March-3 April 2011. In Journal of Hepatology, 2011, v. 54 suppl. 1, p. S268, abstract no. 66

A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia

Purpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9). Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789

A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC)

This journal suppl. contain 2012 ASCO Meeting AbstractsOpen Access JournalBACKGROUND: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in …link_to_OA_fulltex

A phase I/II study of Foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR in advanced hepatocellular carcinoma (HCC)

Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting