Audit on High Dose Antipsychotic Treatment (HDAT) Monitoring at Rampton Hospital

Aims•High Dose Antipsychotic Treatment defined as 100% of the maximum recommended dose in British National Formulary, either as single agent or in combination.•HDAT and poly-pharmacy may be linked to heightened mortality for psychiatric patients. The Committee on Safety of Medicines, Medicines and Healthcare Products Regulatory Agency recommended ECGs, electrolyte monitoring after each dose escalation, and 6 monthly intervals.•The Royal College of Psychiatrists in 2006 suggested some justifiable cases of temporary poly-pharmacy with careful monitoring.•This audit has been done in past to improve standards, especially in High Secure Setting where prescribing HDAT is a common practice•To audit adherence to “HDAT monitoring guidelines” including regular monitoring of bloods, physical observations and ECG , done after every dose escalation plus at every 6 months.•To monitor compliance with consent to treatment documentation including reasons of being on HDAT, documentation of physical health monitoring resultsMethod•All patients prescribed high dose antipsychotic (regular and as required) were identified by treating Consultants and also going through drug cards.•One year retrospective review of haematological, ECG and physical observations were identified through Electronic notesResult•6 % of patients received HDAT within Rampton Hospital in 2018(12 males’ vs 6 females).•All patients on Regular HDAT had yearly TFT done whereas only 71% had prolactin monitoring done.•Approximately 50-60% of patients had quarterly blood monitoring including glucose, electrolytes, lipids, liver function test and full blood count.•About 40% of patients had quarterly ECG monitoring recorded.•100% patients on regular HDAT had quarterly physical observation monitoring compared to 81% patients on HDAT (including PRN).•Consent forms were completed for all patients on HDAT. 85% patients on regular HDAT has the reasons for treatment documented in the notes compared to 100% patients on HDAT (including PRN).Conclusion•Improvement in monitoring of blood parameters and cardiac function (ECG) 40-60% as compared to 2014 audit (8% to 23%).•Yearly monitoring of TFTs and Prolactin also appeared better (100% and 71%) which was (88% and 72% in 2014).•Quarterly physical observations were recorded in 77% patients on regular HDAT in 2014 which improved to 100% in 2018.•There was slight difference for those who were on PRN (77% to 81%). All prescribers informed about results and reminded of recommended guidelines•Reaudit in 2021-22 to measure change in clinical practice in prescribing HDAT.

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Reducing the use of high dose antipsychotic medication in acute adult inpatient psychiatric units

BJPsych Open ◽

10.1192/bjo.2021.893 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S341-S341

Author(s):

Shay-Anne Pantall ◽

Sarah Warwicker ◽

Lisa Brownell

Keyword(s):

Antipsychotic Medication ◽

Psychiatric Inpatient ◽

Electronic Prescribing ◽

Antipsychotic Treatment ◽

High Dose ◽

Junior Doctors ◽

List Type ◽

Increased Risk ◽

Adult Inpatient ◽

Inpatient Units

AimsTo evaluate the use of antipsychotics, and high dose antipsychotic treatment (HDAT) in psychiatric inpatient unitsBackgroundThe Royal College of Psychiatrists published a consensus statement on high dose antipsychotic medication in October 1993. Such treatment carries an increased risk of adverse effects including towards ventricular tachycardia and sudden death.MethodA retrospective case note review of all male patients on acute adult inpatient units in a psychiatric hospital in South Birmingham on a date in June 2018 (n = 45) including review of electronic patient records and prescriptions. This was compared with the results of an earlier study, with identical methods, undertaken in June 2015.Result•In both 2015 and 2018, only a minority of patients (20% and 11% respectively) were informal.•In both 2015 and 2018, the majority of inpatients had a diagnosis of schizophrenia (54% and 67%)•In both 2015 and 2018, 93% inpatients were prescribed antipsychotic medication.•In 2015, 56% patients were prescribed HDAT. This reduced in 2018 to 16%.•This reduction in use of HDAT was almost entirely due to a reduction in the prescription of PRN antipsychotic medication.•In terms of regularly prescribed antipsychotic medication, in both years, the most commonly prescribed drug was flupentixol, with a range of other second generation oral and long acting medications being prescribed, usually at doses within BNF limits.Between the two years, there was a substantial change in the prescribing of PRN antipsychotics. In 2015, 59% individuals were prescribed at least one PRN antipsychotic (27% were prescribed two). In 2018, this reduced to 40% prescribed at least one, and only 2% being prescribed 2 PRN antipsychotics. In both years, oral quetiapine was a common choice (39% patients in 2015 prescribed oral quetiapine, and 34% in 2018). In 2015, 39% patients were prescribed oral or intramuscular aripiprazole, while this reduced to 7% in 2018.ConclusionThe vast majority of psychiatric inpatients were being prescribed antipsychotic medication. Prescription of high dose antipsychotic medication was common in 2015, and this was largely attributable to high levels of prescribing of PRN antipsychotics. Following an educational programme for junior doctors and ward nurses, and the introduction of electronic prescribing, we achieved a significant change in practice, particularly in the prescribing of PRN antipsychotics, which has reduced our patients’ risk of receiving high dose antipsychotic medication.

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Safety and Pharmacokinetics Of Clofarabine In Combination With High-Dose Cytarabine and Liposomal Daunorubicin In Pediatric AML: Results Of a Phase 1 Combination Study By The ITCC Consortium

Blood ◽

10.1182/blood.v122.21.2693.2693 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2693-2693 ◽

Cited By ~ 1

Author(s):

Christian M. Zwaan ◽

Michael Dworzak ◽

Thomas Klingebiel ◽

Claudia Rossig ◽

Guy Leverger ◽

...

Keyword(s):

Dose Level ◽

Dose Escalation ◽

Fungal Infections ◽

Single Agent ◽

Lung Infection ◽

High Dose ◽

Liposomal Daunorubicin ◽

Candida Sepsis ◽

Pediatric Aml ◽

Dose Levels

Abstract Introduction Relapsed/refractory pediatric AML has a poor prognosis despite salvage therapy including stem-cell transplantation. Chemotherapy using FLAG plus liposomal daunorubicine (FLAG-DNX) is currently considered the standard in 1strelapse in Europe (Kaspers et al, JCO 2013). FLAG is based on potentiation of cytarabine (Ara-C) by fludarabine (Flu) by increasing Ara-CTP levels. Clofarabine (CLO) is a novel purine nucleoside analog, designed to have improved efficacy. Methods We initiated an ongoing phase 1B dose-escalation study using a ‘3x3 design’ to define the optimal dose of CLO, replacing FLU in FLAG-DNX. Dosages consisted of Ara-C 2gr/m2/day (day 1-5), with escalation of DNX from 40, 60 to 80 mg/m2/day (day 1, 3 and 5), and CLO from 20, 30 to 40 mg/m2/day (day 1-5) in 5 dose-levels, without GCSF priming. At day 6 intrathecal Ara-C was administered. Dose-level 1-4 recruited early 1st relapse, refractory 1st relapse and 2nd relapse of AML, and escalated CLO to 40 mg/m2 with DNX 60 mg/m2. Dose level 5 is open to 1st relapse pts and escalates DNX to 80 mg/m2. Responding patients received a 2ndconsolidation with CLARA-DNX or treated by investigator discretion. Other inclusion criteria consisted of performance status ≥60%, and normal liver and renal function. Maximum tolerated dose was the primary endpoint. Hematologic DLTs were defined as count recovery in responding pts >42 days. Serum and CSF were collected for pharmacokinetics (PK), taken at day 1: predose, T=2hrs and T=5 hrs post-infusion, and repeated on day 5, including a T=24 sample on day 6, together with a CSF sample just prior to intrathecal medication. CLO plasma and CSF concentrations were analyzed using LC-MS/MS. Efficacy data are awaiting central review and not released until the end of the study. The study is registered in the Dutch Trial Registry (nr. 1880). Results We here report safety and PK data on the first 4 dose-levels after accrual of 22 AML patients (≥2nd relapse, n=7; refractory 1st relapse, n=9; early 1strelapse, n=6). Patients were treated at dose-level (DL) 1, n=4; 2, n=3; 3, n=12; 4, n=3. Eleven patients had been transplanted prior to enrollment. In total 27 CLARA-DNX courses were administered. Median age was 6.4 years, 14 patients were male. 20 SAEs were reported, consisting of febrile neutropenia (n=11), typhlitis (n=1), lung-infection fungal (n=3), lung-infection bacterial (n=2), candida sepsis (n=1), rash (hand-foot skin reaction) (n=1), and tumor lysis/capillary leak syndrome (n=1). Other grade 3-4 AEs reported in at least 2 patients consisted of abdominal pain, nausea and vomiting, diarrhea, anorexia and allergic reaction. Two patients had bilirubin elevation (max 61 umol/l); six patients had mild transaminase elevation > 100 U/l (max. 330U/l), which was reversible. At dose-level 3, two patients experienced DLTs (fungal infection) halting dose-escalation. Detailed analysis showed that most patients had evidence of subclinical fungal infections prior to enrollment. Therefore a protocol amendment was issued that required screening patients with CT-scan and serum-galactomannan prior to enrollment. After enrolling another cohort of 6 patients at DL3 this appeared to be safe (1 DLT of Candida sepsis out of 6 patients). No DLTs occurred at dose-level 4 in 3 patients. No hematological DLTs occurred. PK samples were available from 19 patients; in 2 patients sampling was repeated at course 2. At day 1 the median AUC was 28 ng/ml.mg.hr (range 6-401), with a mean T1/2 of 1.5 hrs. Day 1 and day 5 results were similar. CSF levels were not measurable in most patients and were 0.1-0.2 ng/ml.mg in the 3 patients with detectable levels. Our PK-data in combination are not significantly different from our data with single-agent CLO in relapsed ALL patients (Joel et al, AACR, 2007), and fit the CLO single agent PK model of Bonate et al (J Clin Pharmacol 2004, 44: 1309-32) . Conclusions The RP2D of CLO in a CLARA/DNX course in relapsed/refractory pediatric AML is 40 mg/m2, excluding patients with evidence of prior subclinical aspergillus. There is no evidence for PK interaction between CLO and the other drugs. We are currently testing the safety of an augmented dose of DNX (80 mg/m2) in 1strelapse AML patients. When tolerable this dose may be randomized against other induction regimens in front-line therapy in pediatric AML. Acknowledgment This study was financially supported by Sanofi and by the KiKa-foundation grant nr. 26. Disclosures: Off Label Use: Clofarabine for pediatric AML.

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Phase I dose-escalation trial of tremelimumab in combination with bicalutamide in patients with recurrent prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.174 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 174-174 ◽

Cited By ~ 1

Author(s):

J. M. Lang ◽

M. J. Staab ◽

G. Liu ◽

G. Wilding ◽

D. G. McNeel

Keyword(s):

Prostate Cancer ◽

Phase I ◽

Dose Escalation ◽

Clinical Stage ◽

Hot Flashes ◽

Maximum Tolerated Dose ◽

High Dose ◽

Common Grade ◽

Grade 3 ◽

One Year

174 Background: Antibodies targeting CTLA-4 have demonstrated anti-tumor efficacy in human clinical trials. The mechanism of this effect is presumably in part mediated by the expansion of tumor-specific T cells. Androgen deprivation (AD), the cornerstone of treatment for patients with metastatic prostate cancer, has been demonstrated to cause prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with AD, followed by an anti-CTLA-4 antibody, could have benefit by augmenting a tumor-specific immune response elicited with AD. We report the initial results from the dose-escalation portion of a phase I trial evaluating tremelimumab in combination with high-dose bicalutamide. Methods: Eligible patients were those with clinical stage D0 prostate cancer (rising serum PSA but no evidence of metastatic disease). Subjects were treated in two courses, 3 months apart, in which they received bicalutamide 150 mg daily for 28 days and tremelimumab on day 29. Patients were treated in cohorts of six, defined by tremelimumab dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg). The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose (MTD). Results: Eleven patients were enrolled and completed the dose-escalation portion of the trial and at least one year of follow up. Dose-limiting toxicities (DLTs) were observed in 2/5 subjects treated at 6 mg/kg, and included grade 3 diarrhea and a grade 3 skin rash. One of six subjects treated at 3 mg/kg tremelimumab required hospitalization for colitis. No other grade 3 or grade 4 events were observed. Common grade 1/2 events included fatigue, hot flashes, diarrhea, abdominal discomfort, rash, pruritis, and gynecomastia. Two patients experienced a prolongation in PSA doubling time detectable months after completing treatment. Conclusions: Tremelimumab, administered at 3 mg/kg every 3 months in combination with AD, was found to be the MTD and with reasonable safety in this population. The identification of patients with prolonged stable disease following treatment suggests that future studies could explore repetitive administration of this combination. [Table: see text]

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800 A phase I dose escalation and expansion study of intratumorally administered CV8102 as a single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0800 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A849-A849

Author(s):

Thomas Eigentler ◽

Lucie Heinzerling ◽

Jürgen Krauss ◽

Carsten Weishaupt ◽

Peter Mohr ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Phase I ◽

Cell Carcinoma ◽

Adenoid Cystic Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Dose Escalation ◽

Single Agent ◽

List Type ◽

Adenoid Cystic

BackgroundCV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system.1 2 An ongoing phase I trial is investigating i.t. CV8102 either as a single agent or in combination with systemic anti-PD-1 antibodies in patients with advanced melanoma (MEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC).MethodsAn open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies.8 intratumoral injections of CV8102 are being administered initially over a 12 week period, while patients benefiting from the single agent therapy may receive further treatment. In an initial dose escalation part the maximum tolerated dose and recommended phase 2 dose for subsequent cohort expansion will be defined.ResultsAs of September 16, 2020, 29 patients have been treated with CV8102 as a single agent (25-900 µg) and 21 patients have received CV8102 (25-900 µg) in combination with anti-PD-1 antibodies. Most frequent treatment related adverse events were mild to moderate fever, fatigue, chills and headache. One patient treated at the 900 µg single agent experienced a dose limiting toxicity (G3 transaminase increase in the context of G2 cytokine release syndrome).Regression of injected and distant noninjected lesions was observed in several patients in the single agent and the anti-PD-1 combination cohorts. Updated safety and efficacy results will be presented.ConclusionsCV8102 showed an acceptable tolerability and preliminary evidence of clinical efficacy as single agent and in combination with anti-PD-1- antibodies.Trial RegistrationNCT03291002Ethics ApprovalThe study was approved by the Central Ethics Committees in Tuebingen, Germany under 785/2016AMG1, in France under 19.05.17.64111, in Barcelona, Spain under the EudraCT number.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesZiegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzmán CA, Kallen KJ, Fotin-Mleczek M, Kalinke U. A new RNA-based adjuvant enhances virus-specific vaccine responses by locally triggering TLR- and RLH-dependent effects. J Immunol 2017;198(4):1595-1605. doi:10.4049/jimmunol.1601129Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, Scheel B, Voss S, Kallen KJ, Fotin-Mleczek M. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer 2015 Jul 15;137(2):372-84. doi: 10.1002/ijc.29402

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Final Results from a Phase I Trial Combining Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2018-99-120244 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4073-4073

Author(s):

Amy Wang ◽

Howard Weiner ◽

Richard A. Larson ◽

Olatoyosi Odenike ◽

Andrew S Artz ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Remission Induction ◽

High Dose ◽

Hematologic Toxicity ◽

Induction Phase ◽

Advisory Committees ◽

Count Recovery

Abstract Background: Selinexor, an exportin 1 (CRM1/XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent and in combination with anthracyclines and DNA damaging agents. HiDAC/Mito is an effective induction regimen for patients with relapsed/refractory (R/R) AML and has a reported overall response rate (ORR) of 55% at our institution. We hypothesized that adding selinexor to HiDAC/Mito would be feasible and have synergistic anti-leukemic effects. Early results of the trial were previously reported (Wang et al., J Hematol Oncol, 2018), and here we present more mature data on survival and relapse. Methods: We performed a phase 1 dose escalation trial with cohort expansion in patients with AML. This study tested increasing doses of selinexor combined with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of the regimen. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase. HiDAC (1.5 to 3 g/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) were only evaluated during dose escalation and was defined as any grade 3 or greater non-hematologic toxicity, except transient (<48 hours) nausea/vomiting or liver function abnormalities, or by persistent bone marrow aplasia lasting >56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: The study enrolled a total of 28 patients from October 2015 to October 2017. Selinexor dose levels were 60mg (n=3) and 80mg (n=25). Median age = 61 (range 37 - 76). De novo AML = 15 (54%); secondary AML = 12 (43%), and therapy-related AML = 1 (3%). Of these, 13 patients had R/R disease (6 primary refractory, 6 in first relapse, 1 in second relapse). Fifteen (54%) patients were previously untreated. Molecular/genetic subgroup profiles by European Leukemia Net 2010 criteria included favorable = 6 (21%), intermediate I = 9 (32%), intermediate II = 5 (18%), and adverse = 8 (29%). No DLTs were observed in dose escalation. Myelosuppression was universal. Median time to count recovery (ANC >1.0 x 109/L, platelet count >100 x 109/L for the 16 responding patients was 46 days. Febrile neutropenia occurred in 21 (75%) patients. Common selinexor-related adverse effects included diarrhea (32%), electrolyte disturbances (32%), bacteremia (32%), anorexia (29%), nausea/vomiting (29%), fatigue (25%), and acute kidney injury (25%). One patient from the expansion cohort died from hemorrhagic stroke prior to completing induction. The ORR was 64% (18/28 pts): complete remission (CR) = 46% (13 pts), CR with incomplete count recovery (CRi) = 14% (4 pts), partial remission (PR) = 4% (1 pt), and treatment failure (TF) = 36% (9 pts). ORR was 87% (9 CR, 3 CRi, 1 PR, 2 TF) for newly diagnosed pts and 38% (4 CR, 1 CRi, 8 TF)) for R/R pts. Of the responders, 6 proceeded to consolidation without allo-SCT, 10 eventually underwent allo-SCT, and 2 relapsed prior to either. The 10 non-responding patients proceeded to another line of therapy, and 3 eventually underwent allo-SCT. Eleven (40%) patients are alive with a median observation period of 13 months (range 8 days to 34 months). The median relapse free survival (RFS) and overall survival (OS) was 11 and 16 months, respectively. The 1-year PFS and OS was 44% and 61%, respectively. Median OS was 9 months for non-responders and 19 months for responders (HR 1.8, 95% CI 0.6 - 5.7, p=0.2); 1-year OS rates were 50% vs 67%, respectively. One CR patient completed consolidation and maintenance without allo-SCT remains in remission 33 months later. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. This regimen yields an ORR of 64% based on currently available data. We had previously reported molecular correlatives demonstrating the effect of selinexor. The recommended phase 2 dose is 80mg of selinexor. Figure. Figure. Disclosures Larson: Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Odenike:Agios: Research Funding; Astex: Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; NS Pharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; ABBVIE: Honoraria, Research Funding; Janssen: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Liu:BMS: Research Funding.

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Seven Weeks of High-Dose Vitamin D Treatment Reduces the Need for Infliximab Dose-Escalation and Decreases Inflammatory Markers in Crohn’s Disease during One-Year Follow-Up

Nutrients ◽

10.3390/nu13041083 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1083

Author(s):

Mia Bendix ◽

Anders Dige ◽

Søren Peter Jørgensen ◽

Jens Frederik Dahlerup ◽

Bo Martin Bibby ◽

...

Keyword(s):

Vitamin D ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Dose Escalation ◽

Inflammatory Markers ◽

High Dose ◽

One Year ◽

Group D ◽

High Dose Vitamin

Background: Seven weeks of high-dose vitamin D treatment decreases intestinal IL17A and IFN-γ mRNA expression in active Crohn’s disease (CD). In this follow-up study, we investigated whether seven-week vitamin D treatment affected the infliximab response in the following 45 weeks compared to placebo. Methods: CD patients (n = 40) were initially randomised into four groups: infliximab + vitamin-D; infliximab + placebo-vitamin-D; placebo-infliximab + vitamin-D; and placebo-infliximab + placebo-vitamin-D. Infliximab (5 mg/kg) or placebo-infliximab was administered at weeks 0, 2 and 6. Vitamin D (5 mg bolus followed by 0.5 mg/day for 7 weeks) or placebo-vitamin D was handed out. After the 7-week vitamin D period, all patients received infliximab during follow-up. Results are reported for Group D+ (infliximab + vitamin-D and placebo-infliximab + vitamin-D) and Group D- (infliximab + placebo-vitamin-D and placebo-infliximab + placebo-vitamin-D). Results: Group D- patients had greater needs for infliximab dose escalation during follow-up compared to group D+ (p = 0.05). Group D+ had lower median calprotectin levels week 15 (p = 0.02) and week 23 (p = 0.04) compared to group D-. Throughout follow-up, group D+ had 2.2 times (95% CI: 1.1–4.3) (p = 0.02) lower median CRP levels compared with group D-. Conclusions: Seven weeks high-dose vitamin D treatment reduces the need for later infliximab dose-escalation and reduces inflammatory markers. EudraCT no. 2013-000971-34.

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Association Between Antipsychotic Treatment and Neurological Adverse Events in Pediatric Patients: A Population-Based Cohort Study in Korea

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.668704 ◽

2021 ◽

Vol 12 ◽

Author(s):

Soo Min Jeon ◽

Susan Park ◽

Soonhak Kwon ◽

Jin-Won Kwon

Keyword(s):

Adverse Effects ◽

Adverse Events ◽

Movement Disorders ◽

Pediatric Patients ◽

Psychiatric Patients ◽

Cumulative Exposure ◽

Antipsychotic Treatment ◽

High Dose ◽

Initial Exposure ◽

Time Varying Covariates

Background: Potential adverse effects might be caused by increasing the number of antipsychotic prescriptions. However, the empirical evidence regarding pediatric psychiatric patients is insufficient. Therefore, we explored the antipsychotic-induced adverse effects focusing on the neurological system.Method: Using the medical information of pediatric patients retrieved from the claims data of Health Insurance Review and Assessment in Korea, we identified those psychiatric patients who were started on antipsychotic treatment at age 2–18 years between 2010 and 2018 (n = 10,969). In this study, movement disorders and seizures were considered as major neurological adverse events. The extended Cox model with time-varying covariates was applied to explore the association between antipsychotic medication and adverse events.Findings: Total 1,894 and 1,267 cases of movement disorders and seizures occurred in 32,046 and 33,280 person-years, respectively. The hazard risks of neurological adverse events were 3–8 times higher in the exposed to antipsychotics period than in the non-exposure period. Among the exposure periods, the most dangerous period was within 30 days of cumulative exposure. High doses or polypharmacy of antipsychotics was associated with increased risks of neurological adverse events. Among individual antipsychotics, haloperidol showed the highest risk of developing movement disorders among the examined agents. Quetiapine showed a lower risk of developing movement disorders but a higher risk of developing seizures than risperidone.Conclusion: These findings suggest that antipsychotics should be used with caution in pediatric patients, especially regarding initial exposure, high dose, and polypharmacy.

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470 A phase 1/2, open-label, dose escalation and expansion study of GI-101 as a single agent and in combination with a pembrolizumab, lenvatinib or local RT in advanced solid tumors (KEYNOTE-B59)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.470 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A499-A499

Author(s):

Byoung Chul Cho ◽

Sang Joon Shin ◽

Jae-Lyun Lee ◽

Byoung Yong Shim ◽

Hyung Soon Park ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Phase 1 ◽

Single Agent ◽

Interleukin 2 ◽

List Type ◽

Advanced Solid Tumors ◽

Part D ◽

Anti Tumor Activity

BackgroundGI-101 is a novel bispecific fusion protein containing CD80 and interleukin-2 (IL-2) variant, designed to exhibit high affinity to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and preferential binding to IL-2Rβ subunit. In various animal models, GI-101 exerted strong anti-tumor efficacy, accompanied by robust stimulation of CD8+ T and NK cell proliferation without a significant increase in regulatory T cells. GI-101 also elicited synergistic anti-tumor efficacy when used in combination with pembrolizumab (anti-PD1 agents), lenvatinib (tyrosine kinase inhibitor) and radiation in in vivo.1 Given the complementary mechanisms of action of GI-101 via blocking CTLA4 with IL-2 activity to enhance the proliferation and activation of effector T and NK cells, it was hypothesized that GI-101 as a single agent or in combination with other immunotherapies, VEGF inhibitors or RT may exert anti-tumor activity in cancers with high unmet needs.MethodsKEYNOTE-B59 (NCT04977453) is an ongoing phase 1/2 study composed of 4 parts. This study is planned to enroll approximately 374 patients across the indications. Patients assigned to Part A and B receive either GI-101 monotherapy (Part A) or GI-101 + 200 mg of pembrolizumab (Part B) via IV infusion on every 3 weeks (q3w). In Part C, patients will receive GI-101 q3w in combination with lenvatinib (oral, once daily). In Part D, patients will be given GI-101 q3w in combination with local tumor irradiation. Each part is initiated with dose-escalation/optimization phases which will enroll patients with advanced solid tumors, except Part D that enrolls advanced melanoma and sarcoma only. This phase utilizes conventional 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of GI-101 as a monotherapy and in combination. Once RP2D is determined, patients will be enrolled in dose-expansion phases of each part that includes specific tumor types, such as solid cancers failed on standard of care, treatment-naïve unselected or CPI-treated solid tumors. Patients with advanced solid tumors and recovered from prior therapy will be enrolled. This study will assess safety, tolerability, dose-limiting toxicities, MTD, RP2D, preliminary anti-tumor activity, and pharmacokinetics/pharmacodynamics of GI-101 as a single agent and in combination.ResultsThis study is currently enrolling patients with advanced or metastatic solid tumors.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by GI Innovation, Inc.Trial RegistrationNCT04977453ReferencePyo KH, Synn CB, Koh YJ, et al. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeuticantibody candidate with bispecific immuno-oncology target. Cancer Res 2021;81(13_Suppl).Ethics ApprovalThis study was approved by Severance hospital institutions’ Ethics Review Board (IRB); approval number 4-2021-0185, Asan Medical center‘s IRB; approval number 2021-0669.

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Short Course Infliximab and Extracorporeal Photopheresis As Therapy For Steroid-Refractory Acute Gvhd In Matched Related and Unrelated Allogeneic Hematopoietic Cell Transplant (HCT)

Blood ◽

10.1182/blood.v122.21.4590.4590 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4590-4590

Author(s):

Jared Klein ◽

James L Slack ◽

Lisa Sproat ◽

Veena Fauble ◽

Nandita Khera ◽

...

Keyword(s):

Conflicts Of Interest ◽

Single Agent ◽

Published Data ◽

High Dose ◽

Cell Transplant ◽

Post Transplant ◽

Allogeneic Hct ◽

One Year ◽

Grade Iii ◽

Steroid Refractory

Background Steroid-refractory (SR) acute graft-versus host disease (aGVHD) is a serious complication of allogeneic HCT, for which there is no established standard treatment. Both ECP and cytokine inhibitors such as Infliximab have apparent single agent activity in the therapy of SR aGVHD, but there are no published data that address the efficacy of combination anticytokine therapy and ECP in this setting. We report here results in 18 adult patients (pts) with grade III or IV SR aGVHD who were treated with concurrent Infliximab and ECP. Patients All pts underwent allogeneic HCT (first transplant, n=15, second transplant, n=3) for a hematologic malignancy at Mayo Clinic Arizona between March 2012 and May 2013. The median age was 61 (range 22-70), and the median follow-up of 6 surviving pts is 263 days (range 79-433). Donors were related in 3, matched unrelated in 8, and mismatched unrelated in 7. GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil in 13 pts and tacrolimus/methotrexate in 5; in addition, 17 pts received in vivo T-cell depletion with Thymoglobulin 2.5 – 7.5 mg/kg. All pts developed grades III-IV aGVHD at a median day 27 post-transplant (range 10-107) and failed to respond to a course of high-dose corticosteroids (methylprednisolone or equivalent 2 mg/kg daily) for at least 5 days. Treatment Regimen At diagnosis of SR aGVHD, pts were scheduled to receive weekly Infliximab 10 mg/kg (maximum 4 doses), concurrent with ECP performed twice or thrice weekly for one month, followed by a pre-specified taper schedule (anticipated total treatment duration of 6-9 months). To minimize infectious risk and morbidity, corticosteroids were tapered rapidly after the start of Infliximab/ECP therapy. Results Thirteen pts (72%) responded to the Infliximab/ECP combination; complete response (CR; resolution of all GVHD symptoms for at least 30 days and able to discontinue corticosteroids) was observed in 6 pts (33%), and partial response (PR; improvement in GVHD symptoms, partial taper of corticosteroids, and no additional agent for at least 30 days) in 7 pts (39%). At the time of this report, 6 pts are alive, and the Kaplan-Meier estimate of one-year survival is 22.5 % (95% CI, 8.8%-47%). Only pts who achieved CR had good outcomes (5/6 surviving and clinically well); among 13 pts with PR (7) or no response/progression (6) to Infliximab/ECP, 12 have died and one is day 79 post transplant and remains on ECP and low-dose prednisone. Eleven of the 12 deaths were related to GVHD or complications of its treatment (infection, multi-organ failure). Conclusions In this retrospective study of adult pts with severe (grade III/IV) SR aGVHD, treatment with 4 doses of weekly Infliximab and concurrent ECP resulted in an overall response rate of 72%, with one-third of pts achieving CR; the regimen was well-tolerated and facilitated early taper and rapid discontinuance of corticosteroids. Unfortunately, the overall survival of 22.5% at one year does not appear superior to other single agent or combination therapies reported in the literature, or to historical data from our program. Although a small percentage of pts appear to be long-term survivors, the majority of pts succumb to complications of progressive GVHD or infection. Given poor results with available therapies, and the dismal prognosis of pts with SR aGVHD, future research should focus on better preventative strategies for this devastating complication of allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

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