A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS.

Cancer Treat Res Commun. 2020 Apr 20;23:100174

Authors: Riess JW, Jahchan NS, Das M, Zach Koontz M, Kunz PL, Wakelee HA, Schatzberg A, Sage J, Neal JW

Abstract
BACKGROUND: A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.
METHODS: In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.
RESULTS: Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).
CONCLUSIONS: No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.
MICROABSTRACT: A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.

PMID: 32413603 [PubMed - as supplied by publisher]

A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment.

Invest New Drugs. 2020 May 14;:

Authors: Delord JP, Argilés G, Fayette J, Wirth L, Kasper S, Siena S, Mesia R, Berardi R, Cervantes A, Dekervel J, Zhao S, Sun Y, Hao HX, Tiedt R, Vicente S, Myers A, Siu LL

Abstract
Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

PMID: 32410080 [PubMed - as supplied by publisher]

Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment.

Aliment Pharmacol Ther. 2019 08;50(4):407-415

Authors: Kreijne JE, de Veer RC, de Boer NK, Dijkstra G, West R, Moorsel SAW, de Jong DJ, van der Woude CJ, de Vries AC, of the Dutch Initiative on Crohn, Colitis (ICC)

Abstract
BACKGROUND: Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.
AIM: To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.
RESULTS: In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.
CONCLUSION: LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.

PMID: 31359480 [PubMed - indexed for MEDLINE]

Earlier discontinuation of TNF-α inhibitor therapy in female patients with inflammatory bowel disease is related to a greater risk of side effects.

Aliment Pharmacol Ther. 2019 08;50(4):386-396

Authors: Schultheiss JPD, Brand EC, Lamers E, van den Berg WCM, van Schaik FDM, Oldenburg B, Fidder HH

Abstract
BACKGROUND: In rheumatoid arthritis and psoriasis female sex has been shown to be associated with discontinuation of anti-tumour necrosis factor-α (TNF-α) therapy.
AIM: To retrospectively assess the association between sex and TNF-α drug persistence in patients with inflammatory bowel disease (IBD).
METHODS: All IBD patients on anti-TNF-α therapy with a minimum follow-up of 12 months in a single tertiary centre were identified. Patient and treatment characteristics and reasons for anti-TNF-α discontinuation were recorded. Overall and cause-specific drug persistence was analysed with Kaplan-Meier followed by Cox proportional hazards regression models.
RESULTS: We included 529 patients (49.9% male) with 631 treatment episodes (2280 anti-TNF-α treatment years) and 289 discontinuations of therapy. Female sex (adjusted hazard ratio [aHR] 1.42, 95% confidence interval [CI] 1.16-1.74), greater age at start of therapy per decade (aHR 1.15, 95% CI 1.04-1.27] and dose escalation (aHR 3.74, 95% CI 2.78-5.02) were associated with TNF-α inhibitor discontinuation. Total cohort cause-specific analysis identified female sex to be associated with side effects (aHR 4.05, 95% CI 2.36-6.98) but not to other discontinuation reasons. Adalimumab (aHR 1.70, 95% CI 1.11-2.60) and golimumab (aHR 4.97, 95% CI 2.30-10.74) use and dose-escalation (aHR 7.71, 95% CI 5.28-11.26) were associated with secondary loss of response.
CONCLUSION: Drug persistence of anti-TNF-α therapy is lower in females as compared to males, mainly because of higher rates of side effects in females. Understanding the sex specific differences in effectiveness and safety of anti-TNF-α compounds can aid physicians in clinical decision-making.

PMID: 31310690 [PubMed - indexed for MEDLINE]

No increased risk of nephrotoxicity associated with 5-aminosalicylic acid in IBD: a population-based cohort and nested case-control study.

Aliment Pharmacol Ther. 2019 08;50(4):416-424

Authors: Jairath V, Hokkanen SRK, Guizzetti L, Boxall N, Campbell-Hill S, Patel H

Abstract
BACKGROUND: There is conflicting evidence about nephrotoxicity risk associated with 5-aminosalicylates for treatment of IBD.
AIMS: To determine population-based temporal trends for 5-aminosalicylates and estimated risk of nephrotoxicity associated with 5-aminosalicylate use for ulcerative colitis (UC) and Crohn's disease (CD).
METHODS: Retrospective cohort and nested case-control study, using the Health Improvement Network primary care database linked to hospital discharge coding for patients in England, 1996-2017. Nephrotoxicity risk analysis was a first recorded renal impairment diagnosis adjusted for key variables and was assessed between 2008 and 2017.
RESULTS: A total of 35 601 patients with prevalent UC or CD were included. The proportion of patients prescribed 5-aminosalicylates fell from 83% in 1996-1999 to 71% in 2012-2015 for UC patients and 64% to 45% for CD patients. Thirty per cent of patients had prolonged 5-aminosalicylate use. Between 2008 and 2017, the incident rate of nephrotoxicity was similar and stable for UC (12.6/1000 person-years) and CD (10.9/1000 person-years) patients. Multivariate analysis showed no evidence for association between current prescription of 5-aminosalicylate and nephrotoxicity in UC or CD patients, comparing ≤ 30 days prescription prior to index vs 31-≤180 days. However, active disease, disease duration, concomitant cardiovascular disease or diabetes and nephrotoxic drug use were independently associated with development of nephrotoxicity in UC and CD.
CONCLUSIONS: Despite the paucity of evidence for their benefit, 5-aminosalicylates were prescribed to approximately half of CD patients (30% prolonged therapy). Nephrotoxicity was rare in this patient cohort, and was not associated with 5-aminosalicylate use, but rather with disease status, comorbidity and use of nephrotoxic drugs.

PMID: 31298421 [PubMed - indexed for MEDLINE]

Healthcare and associated costs related to type 2 diabetes in youth and adolescence: the TODAY clinical trial experience.

Pediatr Diabetes. 2019 09;20(6):702-711

Authors: Songer TJ, Haymond MW, Glazner JE, Klingensmith GJ, Laffel LM, Zhang P, Hirst K, TODAY Study Group

Abstract
The economic issues related to medical treatments in youth with type 2 diabetes (T2D) are rarely reported and thus not fully understood. The Treatment Options for type 2 Diabetes in Adolescents and Youth clinical trial of youth recently diagnosed with T2D collected healthcare and related cost information from the largest cohort studied to date. Costs related to medical treatments and expenses faced by caregivers were identified over a 2-year period from 496 participants. Data were collected by surveys and diaries to document frequency of use of diabetes care (excluding study laboratory tests), non-diabetes care services and treatments, caregiver time, and expenses related to exercise and dietary activities recommended for patients. Economic costs were derived by applying national cost values to the reported utilization frequency data. Annual medical costs in the first year varied by the treatment group, averaging $1798 in those assigned to metformin alone (M), $2971 to combination drug therapy with metformin + rosiglitazone (M + R), and $2092 to metformin + an intensive lifestyle and behavior change program (M + L). Differences were primarily due to costs related to combination drug therapy. Adult caregiver support costs were higher for participants in the lifestyle program, which was delivered in weekly sessions in the first 6 months. Expenses for purchases to enhance diet and exercise change did not vary by treatment assignment. In year 2, medication costs increased in M and M + L due to the initiation of insulin in subjects who failed to maintain glycemic control on the assigned treatment. Data are reported for use by researchers and those providing healthcare to this vulnerable patient population.

PMID: 31119838 [PubMed - indexed for MEDLINE]

Switching immunoglobulin products, what are the implications? Result of 2018 census of immunology centres.

Clin Med (Lond). 2019 05;19(3):201-204

Authors: Bethune C, Herriot R

Abstract
The use of regular infusions of immunoglobulin is well established as a treatment for patients with antibody deficiency and for patients requiring immunomodulation. Although efficacy is believed to be equivalent for the different immunoglobulin products, it is generally regarded as best practice not to switch from one product to another unless there is a clinical reason to change. Changes in commissioning guidance and issues with the supply of some immunoglobulin products to the UK resulted in a requirement for a significant number of patients to switch between immunoglobulin products in 2017-2018. Data from the 2018 UK Primary Immunodeficiency census has been used to evaluate the clinical results of switching. Results from 30 immunology centres reported a total of 802 immunoglobulin product switches. Twelve reactions were recorded, none of which required admission to hospital, one patient was treated with oral corticosteroids, the others required either no treatment or treatment with oral antihistamines. This review of immunoglobulin product switch reactions gives a clearer indication regarding the safety of product switching than has previously been published.

PMID: 31092511 [PubMed - indexed for MEDLINE]

Rational deprescribing in the elderly.

Ann Clin Psychiatry. 2019 05;31(2):144-152

Authors: Williams S, Miller G, Khoury R, Grossberg GT

Abstract
BACKGROUND: Polypharmacy, defined as being prescribed 5 or more medications, has been shown to be associated with a decline in mental and physical functioning in elderly patients. Despite this, elderly patients are currently being prescribed a median of 7 medications, which often causes more harm than benefit, and emphasizes the importance of deprescribing.
METHODS: Five classes of potentially inappropriate medications for the elderly population, especially for the aging brain, are discussed, including anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors. Recommendations regarding these medications were collected from the 2015 Beer's Criteria, the Screening Tool of Older Person's Prescriptions (STOPP) criteria, the Screening Tool to Alert doctors to the Right Treatment (START) criteria, and the Fit fOR The Aged (FORTA) list. The PubMed database was also searched for the most recent evidence regarding prescription patterns, adverse effects, and recommendations regarding discontinuation of these medications in older adults.
RESULTS: Anticholinergics, benzodiazepines, antipsychotics, and opioids were all found to have significant adverse effects in the elderly population. All of the discussed medication classes have been shown to be successfully deprescribable.
CONCLUSIONS: Polypharmacy increases the risk of adverse drug reactions and hospitalizations in geriatric patients. Rational deprescribing of anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors in selected patients may be a good first step to reducing this risk.

PMID: 31046036 [PubMed - indexed for MEDLINE]

DrugCentral 2018: an update.

Nucleic Acids Res. 2019 01 08;47(D1):D963-D970

Authors: Ursu O, Holmes J, Bologa CG, Yang JJ, Mathias SL, Stathias V, Nguyen DT, Schürer S, Oprea T

Abstract
DrugCentral is a drug information resource (http://drugcentral.org) open to the public since 2016 and previously described in the 2017 Nucleic Acids Research Database issue. Since the 2016 release, 103 new approved drugs were updated. The following new data sources have been included: Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), FDA Orange Book information, L1000 gene perturbation profile distance/similarity matrices and estimated protonation constants. New and existing entries have been updated with the latest information from scientific literature, drug labels and external databases. The web interface has been updated to display and query new data. The full database dump and data files are available for download from the DrugCentral website.

PMID: 30371892 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/05/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/05/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/05/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Rheumatology Common Toxicity Criteria (RCTC): An Update Reflecting Real-World Use.

Drug Saf. 2019 12;42(12):1499-1506

Authors: Stach CM, Sloan VS, Woodworth TG, Kilgallen B, Furst DE

Abstract
INTRODUCTION: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatology Common Toxicity Criteria (RCTC) version 2.0 was published in 2007 by the OMERACT Drug Safety Working Group, building on limited experience with RCTC version 1.0, to facilitate standardization of assessment (grading) and reporting of adverse events (AEs) commonly seen in rheumatic disease clinical trials (Woodworth et al. in J Rheumatol 34:1401-1414, 2007).
OBJECTIVES: The objectives of this study were to (1) report the real-world performance of RCTC 2.0; (2) report immediately correctable errors in RCTC 2.0, and provide a revised RCTC 2.1; and (3) begin to identify the need for a comprehensive revision of RCTC 2.0.
METHODS: Safety data outputs for several large rheumatic/autoimmune disease clinical trials in which RCTC 2.0 was used were evaluated for accuracy of reporting and the ability to assess differences among treatments. We examined RCTC 2.0 tables for errors, as well as for omission of terms for AEs that commonly occur in more recent rheumatology clinical trials. We also considered recommendations from recent US Food and Drug Administration (FDA) and international initiatives such CDISC (Clinical Data Interchange Standards Consortium) to improve the consistency of safety data collection and interpretability of safety data analyses.
RESULTS: RCTC 2.0 enabled comparisons of safety data across treatment groups, including grading. However, we discovered inaccuracies in laboratory results grading and omission of AE terms now recognized to occur in rheumatic disease clinical trials.
CONCLUSION: The RCTC 2.0 performed as intended, although some inaccuracies and omissions were found. We provide a corrected version, RCTC 2.1, and also recommend further revision of the RCTC within OMERACT guidances to include AEs that have been reported in rheumatology clinical trials since RCTC 2.0 was published. Ideally, a revised RCTC 3.0 would not only facilitate standardized assessment and reporting of AEs, but would also expand and encourage accurate comparison of the safety profiles of treatments for rheumatic/autoimmune diseases.

PMID: 31696432 [PubMed - indexed for MEDLINE]

Data-Driven Identification of Adverse Event Reporting Patterns for Japan in VigiBase, the WHO Global Database of Individual Case Safety Reports.

Drug Saf. 2019 12;42(12):1487-1498

Authors: Wakao R, Taavola H, Sandberg L, Iwasa E, Soejima S, Chandler R, Norén GN

Abstract
INTRODUCTION: Adverse event reporting patterns vary between countries, reflecting differences in reporting culture, clinical practice and underlying patient populations. Japan collects about 60,000 domestic adverse event reports yearly and shares serious reports with the World Health Organization (WHO) Programme for International Drug Monitoring in VigiBase, the WHO global database of individual case safety reports. Understanding these reports in the global context can be helpful for regulators worldwide and can aid hypothesis-generation for Japanese-specific vulnerabilities to adverse drug reactions.
OBJECTIVE: The objective of this study was to explore differences in the reporting of adverse events between Japan and other countries.
METHODS: vigiPoint is a method for data-driven exploration in pharmacovigilance. It outlines data subsets, pinpoints key features and facilitates expert review, using odds ratios subjected to statistical shrinkage to distinguish one data subset from another. Here, we compared 260,000 Japanese reports in E2B format classified as serious and received in VigiBase between 2013 and 2018 with 2.5 million reports from the rest of the world (of which 51% are from the USA). Reporting patterns for which the 99% credibility interval of the shrunk log-odds ratios were above 0.5 or below - 0.5 were flagged as key features. The shrinkage was set to the vigiPoint default corresponding to 1% of the size of the Japanese data subset. As a sensitivity analysis, additional vigiPoint comparisons were performed between Japan and, in turn, Africa, the Americas, the Americas except the USA and Canada, Asia and Europe.
RESULTS: There were higher reporting rates in Japan from physicians (83% vs. 39%) and pharmacists (17% vs. 10%). It was also more common to see reports with more than five drugs per report (22% vs. 14%) and with a single adverse event (72% vs. 45%). More than half of the Japanese reports had a vigiGrade completeness score above 0.8 compared with about one in five from the rest of the world. There were more reports than expected for patients aged 70-89 years and fewer reports for adults aged 20-59 years. Adverse events reported more often in Japan included interstitial lung disease, abnormal hepatic function, decreased platelet count, decreased neutrophil count and drug eruption. Adverse events reported less often included death, fatigue, dyspnoea, pain and headache. Drugs reported more often in Japan included prednisolone, methotrexate and peginterferon alfa-2b. Drugs reported less often included rosiglitazone and adalimumab as well as blood substitutes and perfusion solutions. The findings were generally robust to the sensitivity analysis except for the less often reported drugs, many of which were rarely reported in most countries, except in the USA.
CONCLUSION: Analysis of Japanese adverse event reporting patterns in a global context has revealed key features that may reflect possible pharmaco-ethnic vulnerabilities in the Japanese, as well as differences in adverse event reporting and clinical practice. This knowledge is essential in the global collaboration of signal detection afforded by the WHO Programme for International Drug Monitoring.

PMID: 31559542 [PubMed - indexed for MEDLINE]

A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial).

Cancer Chemother Pharmacol. 2019 10;84(4):909-917

Authors: Clarke JM, Blobe GC, Strickler JH, Uronis HE, Zafar SY, Morse M, Dropkin E, Howard L, O'Neill M, Rushing CN, Niedzwiecki D, Watson H, Bolch E, Arrowood C, Liu Y, Nixon AB, Hurwitz HI

Abstract
PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer.
METHODS: The first stage of this study was a standard "3 + 3" open-label dose-escalation scheme. Cohorts of 3-6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis.
RESULTS: Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level - 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level - 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events.
CONCLUSIONS: The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer.

PMID: 31444620 [PubMed - indexed for MEDLINE]

Clinical difference between discontinuation and retreatment with nivolumab after immune-related adverse events in patients with lung cancer.

Cancer Chemother Pharmacol. 2019 10;84(4):873-880

Authors: Mouri A, Kaira K, Yamaguchi O, Shiono A, Miura Y, Hashimoto K, Nishihara F, Murayama Y, Kobayashi K, Kagamu H

Abstract
BACKGROUND: After the cessation of immune checkpoint inhibitor (ICI) therapy due to an immune-related adverse event (irAE), it remains unclear whether retreatment with ICI is more effective than its discontinuation. To explore the clinical significance of its retreatment, patients with non-small cell lung cancer (NSCLC) who had treatment interruption of nivolumab due to irAEs were identified and the clinical differences between discontinuation and retreatment with nivolumab were retrospectively reviewed.
METHODS: 49 (26%) of 187 patients treated with nivolumab experienced the cessation of treatment due to a serious irAE. Retreatment was chosen in 21 patients (retreatment cohort), while 28 patients discontinued treatment (discontinuation cohort).
RESULTS: The most common irAEs requiring treatment cessation in 49 patients included pneumonitis (59.2%), adrenal insufficiency (8.2%), liver dysfunction (8.2%) renal dysfunction (8.2%), colitis (6.1%), hypothyroidism (4.1%), and rash (2.0%). The frequency of grade 3 or 4 initial irAEs did not differ between the retreatment and discontinuation cohorts; however, the incidence of renal dysfunction and colitis was higher in the retreatment cohort than in the discontinuation cohort. Retreatment with nivolumab displayed an overall response rate of 15%, without a significant increase in irAEs. The median overall survival and progression-free survival did not differ significantly between the retreatment and discontinuation cohorts, irrespective of the efficacy of prior nivolumab.
CONCLUSIONS: Retreatment exhibited a slightly higher efficacy without a significant increase in irAEs; however, the clinical significance of retreatment and discontinuation was similar in NSCLC patients that led to treatment interruption due to any irAE after initial nivolumab.

PMID: 31444618 [PubMed - indexed for MEDLINE]

Development and preliminary validation of an instrument to enable laypersons to assess suspected side effects from medicines.

Pharmacoepidemiol Drug Saf. 2019 07;28(7):1023-1031

Authors: O'Donovan B, Rodgers RM, Cox AR, Krska J

Abstract
PURPOSE: Research into causality assessment tools enabling patients to assess suspected adverse drug reactions (ADRs) is limited. Supporting patients with tools could improve their confidence in discussions with health professionals and encourage reporting of suspected ADRs to regulators. This study describes development and preliminary validation of an instrument: Side Effect Patient ASsessment Tool (SE-PAST).
METHODS: SE-PAST was developed from survey and interview data involving patients experiencing suspected ADRs. It included 10 statements enabling causality assessment, covering timing, additional information sources, and experiences, with four options: yes/no/don't know/not applicable. Scoring and weighting resulted in four categories of causal association: highly probable, probable, possible, unlikely. Validation involved obtaining feedback from 31 individuals experiencing an ADR. Further validation involved online distribution through patient support groups and comparison of reported symptoms to known ADRs.
RESULTS: Validators found SE-PAST easy to read (31), to understand (27), and to complete (29). A total of 294 respondents completed SE-PAST online, with 98% completing eight or more causality assessment statements. Symptoms were categorised as highly probable (46; 16%), probable (80; 62%), possible (44; 15%), and unlikely (21; 7%). A total of 221 respondents identified one suspected medicine, with 95% of these reporting at least one symptom known to be an ADR. Of 227 providing feedback, 139 (61%) found SE-PAST useful, 160 (71%) felt motivated to discuss their experience with a health professional, and 136 (60%) were encouraged to report to the regulator.
CONCLUSION: SE-PAST was easily completed and understood by people experiencing suspected ADRs and could be useful in encouraging patient reporting to health professionals and agencies.

PMID: 31197912 [PubMed - indexed for MEDLINE]

Determination of good pharmacovigilance reporting practices in Quebec hospital pharmacies using a modified Delphi method.

Pharmacoepidemiol Drug Saf. 2019 07;28(7):985-992

Authors: Rault P, Mégrourèche É, Labarre JS, Pettersen-Coulombe F, Lebel D, Bussières JF

Abstract
PURPOSE: Many published guidelines are available for health care providers describing the best way to manage patient's adverse drug reactions (ADRs). However, there is a lack of guidance on the best way to promote and manage ADR reporting within hospitals. The goal of this study was to develop good pharmacovigilance reporting practices (GPRPs).
METHODS: This descriptive study used a modified Delphi method. The research team developed 41 statements, according to a modified Specific Measurable Attainable Realistic Timely (SMART) method and grouped them in six categories: organization (n = 12 statements), pharmacovigilance committee (n = 4), database (n = 5), training (n = 5), tools (n = 3), and quality (n = 12). The Delphi consultation (two online rounds, conducted in 2018) involved directors of pharmacy in Quebec hospitals.
RESULTS: Of 30 directors of pharmacy invited to participate in the first round, 27 (90%) did so. Following this round, the wording of five statements was modified according to pre-established rules. Twenty-five (93%) of the original 27 participants responded during the second round. Of the initial 41 statements, 37 were selected (average score ≥ 7); the other four were eliminated. Of the 37 statements selected, 22 had a "must do" formulation, 12 had a "should do" formulation, and three had a "may do" formulation.
CONCLUSION: Using a modified Delphi method, we established a set of GPRPs for hospital pharmacy based on 37 statements. To our knowledge, these are the first GPRPs published in the hospital pharmacy literature.

PMID: 31179606 [PubMed - indexed for MEDLINE]

Safety profile of traditional Chinese herbal injection: An analysis of a spontaneous reporting system in China.

Pharmacoepidemiol Drug Saf. 2019 07;28(7):1002-1013

Authors: Li H, Deng J, Deng L, Ren X, Xia J

Abstract
PURPOSE: Although a series of serious adverse events have continually raised concerns about the potential toxicity of traditional Chinese medicine injections (TCM injections), studies on this subject are still sparse. We conducted a descriptive analysis of a spontaneous reporting system in China to describe the safety profile of TCM injections.
METHODS: The safety profile of TCM injections is described by descriptive analysis of 559 066 adverse reports collected from Guangdong Provincial Center for adverse drug reaction (ADR) Monitoring in China during 2003 to 2017.
RESULTS: The percentage of new or serious ADRs of TCM injections is much higher than average percentage of China's spontaneous reporting system (SRS) as a whole (48.70% vs <25%). Compared with conventional injections, TCM injections have a slightly lower percentage of serious ADRs (6.02% vs 6.72%) and much higher percentage of unknown (new) ADRs (46.74% vs 24.13%). The gender and age distribution for TCM injections are similar to conventional injections. The reporting rates of ADRs increased with age. Anaphylactic shock and anaphylactoid reaction are high-risk ADRs for TCM injections and, anaphylactic shock is ranked number 1 in causing deaths (50.00%).
CONCLUSIONS: There are some differences and similarities on the safety profile between TCM injections and conventional injections. TCM injections have higher risk of adverse effects than any other dosage forms of TCM medications and higher percentage of new or serious adverse effects than conventional injections. A lot of work need to be done to clarify the huge amount of potential unknown adverse effects related to TCM injections.

PMID: 31131950 [PubMed - indexed for MEDLINE]

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