2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.
On day 12, CT guided local irradiation in a single high dose (dose rate: 3Gy/min) of the former tumor region, resembling IMRT in human patients, was applied. We monitored animal's health status daily and tumor growth every 3 days by BLI. Results: None of the animals, whether with radiotherapy alone or in combination with cis-fib, showed any signs of pulmonary side effects. None had reduced pulmonary functions, measured by increased breathing or the appearance of blue or white colored ears/extremities/eyes assuming desaturation. No weight loss was observed after 10Gy IR, either alone or in combination with cis-fib. Treatment with a single dose of 20Gy IR or cis-fib+20Gy IR caused weight loss on the day after treatment but all animals regained weight 2 days thereafter. No deterioration of body conditioning or activity score were observed in the immediate postinterventional phase. Regarding efficacy, we detected comparable tumor growth in animals treated with 10Gy IR compared to no IR (cis-fib) group. Thus, we decided to escalate to 20Gy after treating 6 animals/group. Three days after treatment with 20Gy IR (day 15), we detected a significant difference in tumor growth in IR alone compared to cis-fib+IR group (mean tumor growth (%) 539 vs 252; p¼0.04). On day 21, there was a significant difference in tumor growth between cis-fib vs cis-fib+IR treated tumors (mean tumor growth (%) 2295 vs 660; p¼0.01) (figure1). Conclusion:Irradiation alone and in combination with local intracavitary cis-fib application in rats is safe up to a dosage of 20Gy. The administration of local 20Gy radiotherapy in combination with cis-fib enhances tumor control while only minimally (and short term) affecting animal's well-being. These data suggest a promising effect of combined local treatment with cis-fib+IR for MPM.
BackgroundRising antibiotic resistance poses a challenge to the management of febrile neutropenia in patients with haematological malignancies receiving chemotherapy.AimWe studied an alternating first-line antibiotic strategy to determine its impact on all-cause mortality and bacteremia rates in patients with febrile neutropenia.MethodsAn alternating first-line antibiotic strategy was established in mid-2013. Data for 2012 (before strategy implementation) and 2014 (post-strategy implementation) were compared. Antibiotic Heterogeneity Index (AHI) for each of the two time-periods was also calculated.FindingsThere were 2012 admissions (26082 patient-days) in 2012 and 1843 admissions (24331 patient-days) in 2014. There was no significant difference in the baseline characteristics of patients in the two groups. The defined daily doses (DDD) of cefepime (CEF) fell while the DDD of piperacillin-tazobactam (PTZ) rose in 2014 compared with 2012. Vancomycin DDD fell in 2014. The AHI was 0.466 in 2012 and 0.582 in 2014. The difference in all-cause mortality was not statistically significant. There was no difference in rates of bacteremia with CEF-resistant, PTZ-resistant and carbapenem-resistant gram-negative organisms in the two groups. Rates of new cases of Methicillin-resistant Staphylococcus aureus (MRSA) were 2.38/1000 and 2.59/1000 patient-days in 2012 and 2014 respectively. Rates of new cases of Vancomycin-resistant Enterococcus (VRE) were 1.84/1000 and 1.81/1000 patient-days in 2012 and 2014 respectively. There was no Carbapenem-resistant Enterobacteriaceae (CRE) bacteremia in 2012 and 1 in 2014.ConclusionAn alternating first-line antibiotic strategy resulted in an increase in antibiotic heterogeneity, without increasing mortality. There was also no significant increase in bacteremia rates.
Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity.
Background High dose therapy (HDT) followed by autologous stem cell rescue is the standard of care for transplant eligible patients with multiple myeloma (MM). High dose cyclophosphamide (Cy) at 4-7g/m2 with granulocyte colony stimulating factor (GCSF) has been shown to be effective for haematopoietic progenitor cell (HPC) mobilization despite associated haematologic toxicity.Vinorelbine 25mg/m2 in combination with Cy 1500mg/m2 (Vino-Cy) was shown to be comparable to Cy mobilization in a study using historical controls. Vino-Cy is the mobilization regimen of choice at the National University Hospital Singapore (NUH) while Cy mobilization is preferred at the Singapore General Hospital (SGH). We present a retrospective comparison of HPC mobilisation outcomes using Vino- Cy and Cy at these institutions. Methods Medical records for patients undergoing HPC mobilization between 2004 and 2014 at NUH and SGH were analysed. Patients mobilized with Vino -cy received Vinorelbine 25mg/m2 on day 1 followed by cyclophosphamide 1500mg/m2 on day 2, GCSF 10mcg/kg/day was given from day 4 onwards. Alternatively, pegylated GCSF 6mg was given on day 4. Patients mobilized with Cy were given cyclophosphamide 1500mg/m2 on day 1 and 2 and GCSF 10mcg/kg/day from day 5 onwards. Apheresis (using the cobe spectra or optia system at NUH and the Haemonetics MCS+ system at SGH) was commenced once a peripheral blood CD 34+ count of >/= 10 x 10 6/l was achieved. The number of total blood volume exchanges per apheresis was 3 at NUH and 4 at SGH. Apheresis was continued until a minimum target CD 34 collection of 5 x 10 6 per kg/BW was reached. Patients who were successfully mobilized proceeded to HDT with melphalan 200mg/m2. Results 133patients underwent HPC mobilization between 2004 and 2014. The median weight was 62 Kg for Vino Cy and 58Kg for the Cy patients (p=0.03). The groups were evenly matched in terms of age, presence of renal impairment, bone lesions, ISS stage and the use of novel agent based induction. Bortezomib based induction was used in 73% of Vino-Cy and 43% of Cy patients. A higher percentage of Cy patients were mobilized in complete remission (53%) compared to Vino-Cy (21%). Table 1 summarises the mobilization outcomes of the two groups. Although the total CD 34+ collection was greater in the Cy group, the difference in the percentage of patients achieving an adequate HPC collection was not statistically significant, 72/84 (85%) of Vino-Cy patients and 45/47 (95%) of Cy patients achieved a stem cell collection of greater than 5 x 10 6/Kg BW (P=0.07). There were two mobilization failures in each group, one of whom (a Vino-Cy patient) was previously treated with melphalan. The number of days taken to achieve an adequate peripheral blood HPC count was shorter in the Vino Cy group and the date of harvest was also more predictable for Vino Cy with a standard deviation of 0.95 compared to 1.95 for Cy. Grade 3-4 harvest related complications were significantly more common in the Cy group (table 2). There was no significant drop in haemoglobin after harvest in either group. Discussion Our data suggest that HPC mobilization maybe more effective with Cy, differing from data published by Annunziata et al which showed a superior HPC mobilization with Vino-Cy compared to the historical Cy control. Vino-Cy appears superior in terms of the time taken for an adequate peripheral CD34+ count and predictability of the day of harvest. The incidence of harvest related complications is also greater for Cy. These findings are common to our cohort and that reported by Annunziata et al. Data on transfusion requirements, hospitalization rates and survival are being collected. Prospective clinical trials are required to definitively determine which protocol is superior. Table 1. Day of protocol when harvest took place P value Number of days taken to harvest P value CD34+/Kg Collected P value Vino-Cy(n=84) Cy(n=47) Vino-Cy(n=84) Cy(n=47) Vino-Cy(n=84) Cy(n=47) Median 9 13 P=0.000 2 2 P=0.97 8.4 11.3 P=0.009 Mean 8.5 12 2 2 10.0 16.2 Maximum 11 16 5 5 32.5 73.9 Minimum 5 7 1 1 2.2 2.4 SD 0.95 1.9 0.94 0.93 5.7 14.5 Table1. Comparison of Mobilisation Outcomes with Vino-Cy and Cy. Table 2. Mobilisation Chemotherapy P value. Vino-Cy(84) Cyclophosphamide (47) Complications during and after harvest (grade3-4) 2(2.3) 9(19) 0.009 Fluid Overload 1 0 Neutropaenic Fever 1 8 Line related thrombosis 0 1 Table 2. Grade 3-4 Complications during and after stem cell collection, data presented as number (%). Disclosures No relevant conflicts of interest to declare.
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