Common Reason For Discontinuation Research Articles

A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy.

7530Background: Although KI therapies are generally well-tolerated, intolerance is the most common reason for discontinuation, thus representing an unmet medical need. Umbralisib (TGR-1202), a next...

Long-term follow-up of clozapine prescribing.

Clozapine is uniquely effective for treatment-resistant schizophrenia, and so treatment continuation is essential. We aimed to identify factors associated with an increased likelihood of clozapine discontinuation in a cohort of patients in South East London. We gathered demographic and treatment information such as duration of illness and antipsychotic treatment history. t-tests, chi-square tests and binary logistic regression were used to compare patients who continued and discontinued clozapine during the study and to identify predictor variables for discontinuation. Out of the study population of 133 patients, 48 discontinued clozapine at least once during the study period. The majority of these (75%) stopped treatment within the first 4 years of clozapine therapy. Age, ethnicity, diagnosis and antipsychotic treatment history were not predictive of the risk of clozapine discontinuation. However, male patients were more likely to stop taking clozapine (χ2 = 6.81, p = 0.009). The odds of discontinuing clozapine were 2.15 times higher for male patients. The most common reason for discontinuation was patient refusal of treatment. We found that patients who discontinue clozapine are more likely to be male, but no other demographic variable was found to predict treatment cessation. Discontinuation usually occurred due to patient refusal of treatment.

F232. A PHASE 3 STUDY TO DETERMINE THE ANTIPSYCHOTIC EFFICACY AND SAFETY OF ALKS 3831 IN ADULT PATIENTS WITH ACUTE EXACERBATION OF SCHIZOPHRENIA

BackgroundALKS 3831, currently under development for the treatment of schizophrenia, is composed of a flexible dose of olanzapine (OLZ) and a fixed dose of 10 mg of samidorphan. In a Phase 2 study, ALKS 3831 mitigated OLZ-associated weight gain and exhibited antipsychotic efficacy similar to OLZ alone. This Phase 3 study assessed antipsychotic efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.MethodsThis was an international (USA, Ukraine, Serbia, and Bulgaria), 4-week, randomised, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomised 1:1:1 to receive either ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2 weeks of the study and could be treated as inpatients or outpatients for the remaining 2 weeks. Patients were excluded if they received OLZ within 6 months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression–Severity (CGI-S), and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).ResultsOf 401 patients randomised and dosed to ALKS 3831, OLZ, and PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831 and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body-mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean ± standard deviation scores were 101.7 ± 11.9 for PANSS total score and 5.1 ± 0.7 for CGI-S score. The mean OLZ dose was 18.4 mg/day in both active treatment arms. Least squares (LS) mean difference ± standard error (SE) versus PBO from baseline to Week 4 in PANSS total score was –6.4 ± 1.8 (P<.001) for the ALKS 3831 group and –5.3 ± 1.8 (P=.004) for the OLZ group. LS mean difference ± SE vs PBO from baseline to Week 4 in CGI-S score was −0.38 ± 0.12 (P=.002) for the ALKS 3831 group and −0.44 ± 0.12 (P<.001) for the OLZ group. The percentage of patients with an improvement in PANSS response (≥30% improvement from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5%) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.DiscussionALKS 3831 demonstrated greater antipsychotic efficacy than PBO, as measured by the PANSS and CGI-S scale, and was similar to the active control, OLZ. The safety profile of ALKS 3831 was similar to OLZ.

Safety, Effectiveness, and Treatment Persistence of Golimumab in Elderly Patients with Rheumatoid Arthritis in Real-World Clinical Practice in Japan.

Golimumab has been proven as an effective treatment for rheumatoid arthritis in clinical trials. However, there is a scarcity of data regarding its use in elderly patients in a real-world setting. This study aims to evaluate the safety, effectiveness, and treatment persistence of golimumab in elderly Japanese patients (≥75years) with rheumatoid arthritis. This study was a post hoc analysis of post-marketing surveillance data on 5137 Japanese patients with active rheumatoid arthritis who received golimumab for 24weeks. The study population was divided into two age groups (younger: <75years and elderly: ≥75years), and the safety, effectiveness, and treatment persistence of golimumab were assessed. Also, the reasons for discontinuing golimumab treatment were analyzed by multi-logistic regression. During golimumab treatment over 24weeks, younger and elderly groups exhibited comparable improvement of disease activity as measured by EULAR response criteria with similar overall rates of adverse events. However, the survival curve of golimumab for elderly patients was significantly different from that for younger patients due largely to the discontinuation at 4weeks. The most common reason for discontinuation in elderly patients was patient choice, while it was disease progression in younger patients. Analysis of elderly patients who discontinued treatment by their own decision identified EULAR good response as a factor associated with continuation of golimumab treatment whereas no predictive factor associated with discontinuation was identified. The safety and effectiveness of golimumab treatment in elderly Japanese patients aged 75years or older were comparable to those in younger patients in real-world clinical practice. Analysis of the survival curves suggested that continuous use of golimumab might further improve clinical benefit of golimumab in elderly patients, underpinning the importance of effective communication between physicians and elderly patients based on the treat-to-target strategy. Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Role of Pharmacists in Completion of Adjuvant Cisplatin-Vinorelbine Chemotherapy in Japanese Patients with Non-small Cell Lung Cancer

Adjuvant cisplatin-vinorelbine chemotherapy has been shown to be effective in patients with completely resected non-small cell lung cancer (NSCLC) in several Phase III trials, but not yet in the Japanese population. Pharmacists are expected to assist patients with completion of adjuvant chemotherapy. The aim of this retrospective study was to evaluate the compliance with and safety of adjuvant cisplatin-vinorelbine chemotherapy in Japanese patients and to evaluate the contribution of pharmacists to completion of treatment. Thirty-four patients with NSCLC who received adjuvant cisplatin-vinorelbine chemotherapy at Kyorin University Hospital between January 2006 and June 2015 were reviewed. The treatment schedule comprised cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Four 3-week cycles were planned. A pharmacist provided guidance to all patients and monitored them for adverse effects thereafter. The pharmacist intervened with advice to doctors as necessary. The 4 cycles were administered in 67.6% of cases. There were no treatment-related deaths. The main grade 3 or 4 toxicities were neutropenia (76.5%) and anorexia (38.2%). The most common reason for discontinuation and dose reduction was anorexia. There were 56 instances of pharmacist intervention. In total, 96.4% of the pharmacist interventions were implemented by doctors, which included administration of an antiemetic on 15 occasions and hot fomentation for prevention of vasculitis on 7 occasions. Adjuvant cisplatin-vinorelbine chemotherapy was tolerated by most patients but was discontinued because of adverse events in some. Pharmacist intervention aids completion of planned chemotherapy and management of treatment-related adverse events.

Abstract P5-21-28: Phase Ib study of ribociclib + letrozole in Asian non-Japanese patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESASIA

Abstract Background: First-line ribociclib (RIB; a selective cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival vs placebo + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). The Phase Ib MONALEESASIA dose-escalation/-expansion study (NCT02333370) is investigating RIB + LET in Asian pts with HR+, HER2– ABC; here we report results in Asian non-Japanese pts. Methods: Asian, non-Japanese postmenopausal women with HR+, HER2– ABC, with no prior systemic treatment for ABC, received RIB (starting dose 400 mg/day; 3-weeks-on/1-week-off; option to escalate or de-escalate) + LET (2.5 mg/day; continuous) until disease progression or discontinuation for other reasons. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control. The primary objective of the dose-escalation part was to estimate the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D), based on the BLRM, safety data, and pharmacokinetic analyses; secondary/exploratory objectives included safety and tolerability, and antitumor activity. Results: At data cut-off (January 16, 2017), 26 pts were enrolled; 13 in the dose escalation (RIB 400 mg: n=6; RIB 600 mg: n=7) and 13 in the 600 mg dose expansion. Treatment was ongoing in 18 pts (69%; 400 mg: n=3; 600 mg: n=15); the most common reason for discontinuation was disease progression (400 mg: n=3; 600 mg: n=4). One dose-limiting toxicity occurred at 600 mg (Grade 3 increased alanine transaminase [ALT]). The MTD/RP2D was declared as 600 mg/day RIB (3-weeks-on/1-week-off) + 2.5 mg/day LET (continuous). The most common all-grade, all-cause adverse events (AEs; ≥35% in either cohort; 400 mg vs 600 mg) were neutropenia (n=1 [17%] vs n=8 [40%]), increased ALT (n=1 [17%] vs n=7 [35%]), decreased neutrophil count (n=3 [50%] vs n=7 [35%]), and alopecia (n=3 [50%] vs n=2 [10%]). All-cause Grade 3/4 AEs occurred in 4 pts (67%) at 400 mg and 18 pts (90%) at 600 mg; the most common (≥25% in either cohort; 400 mg vs 600 mg) were decreased neutrophil count (n=3 [50%] vs n=7 [35%]) and neutropenia (n=1 [17%] vs n=6 [30%]). At least one RIB dose reduction due to AEs occurred in 2 pts at 400 mg and 10 pts at 600 mg. At least one RIB dose interruption due to AEs occurred in 4 pts at 400 mg and 13 pts at 600 mg. Post-baseline QTcF &amp;gt;480 ms occurred in 0 pts at 400 mg and 4 pts (20%) at 600 mg. No pt had a post-baseline QTcF &amp;gt;500 ms. The overall response rate was 50% (n=3) at 400 mg and 35% (n=7) at 600 mg (all partial responses). Stable disease was reported in 1 pt (17%) at 400 mg and 8 pts (40%) at 600 mg. Conclusions: RIB + LET demonstrated a manageable safety profile with preliminary signs of antitumor activity in Asian non-Japanese pts with HR+, HER2– ABC; the safety profile was broadly consistent with that seen in non-Asian pts. The MTD/RP2D was declared as 600 mg/day RIB (3-weeks-on/1-week-off) + 2.5 mg/day LET (continuous). Further safety and efficacy data for RIB + LET will be reported in this pt population after the dose expansion is completed. Citation Format: Yap YS, Ito Y, Suarez-Vizcarra J, Liu X, Han Y, Germa C, Chiu J. Phase Ib study of ribociclib + letrozole in Asian non-Japanese patients with hormone receptor-positive, HER2-negative advanced breast cancer: MONALEESASIA [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-28.

Women\u2019s contraceptive discontinuation and switching behavior in urban Senegal, 2010\u20132015

BackgroundWith the focus of global and national family planning initiatives on reaching “additional user” targets, it is increasingly important for programs to assess contraceptive method discontinuation and switching. This analysis calculated the discontinuation rate and method-specific discontinuation rates, examined reasons given for contraceptive discontinuation, and assessed characteristics associated with subsequent contraceptive switching and abandonment among women living in urban areas of Senegal.MethodsData came from the Measurement, Learning & Evaluation project’s 2015 survey of 6927 women of reproductive age living in six urban sites (Dakar, Pikine, Guédiawaye, Mbao, Kaolack and Mbour). Information on contraceptive use and discontinuation for the five years preceding the survey were recorded in a monthly calendar. Single decrement life tables were used to calculate discontinuation rates. Descriptive analyses were used to assess reasons for discontinuation and method switching after discontinuation. A multinomial logistic regression was used to estimate the likelihood of being a non-user in-need of contraception, a non-user not in-need of contraception, or a method switcher in the month after discontinuation, by sociodemographic and other characteristics.ResultsThe 12-month discontinuation rate for all methods was 34.7%. Implants had the lowest one-year discontinuation rates (6.3%) followed by the intrauterine device (IUD) (18.4%) while higher rates were seen for daily pills (38%), injectables (32.7%), and condoms (62.9%). The most common reasons for discontinuation were reduced need (45.6%), method problems (30.1%), and becoming pregnant while using (10.0%). Only 17% of discontinuations were followed by use of another method; most often daily pills (5.2%) or injectables (4.2%). In the multivariate analysis, women with any formal education (primary, secondary or higher) were more than 50% more likely to switch methods than remain in need of contraception after discontinuation than women with no education or Koranic-only education (RRR = 1.59, p-value = 0.004; RRR = 1.55, p-value = 0.031). The likelihood of switching compared to being “in need” was also significantly higher for women who were married and who discontinued traditional methods.ConclusionsTo support increased contraceptive method use, women with no education and unmarried women are priorities for counseling and information about side effects and method switching at the time of method adoption.

Why I Quit Pre-Exposure Prophylaxis (PrEP)? A Mixed-Method Study Exploring Reasons for PrEP Discontinuation and Potential Re-initiation Among Gay and Bisexual Men.

Literature concerning pre-exposure prophylaxis (PrEP) among gay and bisexual identifying men (GBM) has explored facilitators and barriers to uptake and adherence. Far less reported are the reasons why GBM discontinue PrEP use. A national sample of 1071 GBM completed surveys about PrEP use and discontinuation. Participants who were still taking PrEP the 24-month follow up were compared to those that had stopped. Eighteen percent (n=31) of GBM who reported ever using PrEP discontinued use. Younger (AOR=0.96; 95% CI 0.92-1.00), and unemployed (AOR=4.58; 95% CI 1.43-14.70) GBM were more likely to discontinue PrEP than their counterparts. Those that discontinued provided details on why via a free response question. The most common reasons for discontinuation were lower perceived HIV risk (50%) and cost/insurance (30%). Reasons for potential re-initiation included higher-risk sexual activities and changes to structural related barriers. More research is needed to inform interventions on how GBM can continue taking PrEP during changes to employment that effect insurance coverage and cost.

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Effectiveness of paliperidone long-acting injection in clinical practice.

The efficacy of the long-acting injectable formulation of the antipsychotic paliperidone (paliperidone palmitate) has been investigated in randomized controlled trials. Due to the nature of study designs, these may not be representative of usual clinical practice. The aim of this study was to assess the clinical effectiveness of the long-acting injectable antipsychotic paliperidone palmitate using treatment continuation at 1 year as an outcome. Patients were initiated on paliperidone palmitate prior to December 2014 in a single health board in Wales (UK). Demographic factors that may have influenced outcome, including diagnosis, age at initiation, sex, inpatient or outpatient status on initiation, were analysed to assess whether they influenced patient outcome. For patients completing 1 year of treatment, inpatient stay in the 12 months prior to and following paliperidone palmitate initiation was compared. Data were available for 64 patients; 41 had a diagnosis of schizophrenia and 7 had previously received clozapine. Continuation rates at 6 and 12 months were 69% and 63% respectively. Treatment continuation was not associated with demographic factors. For continuers, mean inpatient stay pre- and post-initiation was 83.2 ± 105.3 and 73.5 ± 103.3 days respectively (p = 0.61). The most common reason for discontinuation was lack of effect (n = 9). The proportion of patients remaining on treatment was comparable to that reported in other naturalistic studies. Prescribing for indications outside the product licence was relatively common, but did not appear to influence outcome, although the number of patients in each group was small. Treatment continuation at 6 months appeared to be a predictor of longer-term outcome.

Second-Line Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia (CP CML) Resistant or Intolerant to Prior Imatinib: An 8-Year Update

Bosutinib is an orally active, dual SRC/ABL tyrosine kinase inhibitor (TKI) approved for treating adult patients with chronic phase, accelerated phase (AP), or blast phase (BP) Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. In an open-label, phase 1/2 study (NCT00261846), second-line bosutinib demonstrated durable hematologic and cytogenetic responses and good tolerability in patients with Ph+ CP CML who were imatinib resistant (IM-R) or imatinib intolerant (IM-I) (Cortes, Am J Hematol, 2016). Here we report a 96-month update of this study and its ongoing extension study (NCT01903733).Adult patients with Ph+ CP CML who were resistant or intolerant to first-line imatinib were included in this analysis. 195 IM-R and 89 IM-I patients received bosutinib starting at 500 mg/d. Median age (range) was 53 yr (18-91 yr), time from CML diagnosis was 3.7 yr (0.1-15.1 yr), treatment duration was 25.6 mo (0.2-133 mo), and follow-up duration was 53.7 mo (0.5-133 mo). Bosutinib dose was increased to 600 mg/d in 13% of patients. For the last enrolled IM-R and IM-I patients, time from first dose of bosutinib to data cutoff was 96.5 mo and 94.2 mo, respectively. At 8 yr, 26% of patients were still receiving bosutinib.Major cytogenetic response (MCyR) was achieved by 60% of patients in both groups (Table). Median duration of MCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining MCyR at 8 yr was 60% (IM-R) and 75% (IM-I). Complete cytogenetic response (CCyR) was achieved by 49% (IM-R) and 51% (IM-I) of patients. Median duration CCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining CCyR at 8 yr was 57% (IM-R) and 69% (IM-I) of patients. On-treatment transformation to accelerated phase or blast phase occurred in 7% (IM-R) and 2% (IM-I) of patients with no new events since the 5-yr follow-up. The cumulative incidence of on-treatment progression or death at 8 yr was 28% (IM-R) and 11% (IM-I), respectively (Table). Overall survival at 8 yr on study was 75% for the IM-R group and 87% for the IM-I group.Dose delays due to adverse events (AEs) occurred in 133 (68%) and 76 (85%) of IM-R and IM-I patients, resulting in median cumulative treatment delays of 25 d and 27 d, respectively. Dose reductions due to AEs occurred in 93 (48%) and 54 (61%) of IM-R and IM-I patients, respectively. Median cumulative duration of dose reduction was 357 d and 267 d, and median time to dose reduction was 49 d and 54 d in the IM-R and IM-I cohorts, respectively. By 8 yr, treatment was discontinued in 141 (72%) and 69 (78%) of IM-R and IM-I patients, respectively. The most common reasons for discontinuation were disease progression (23%) and AEs (16%) in the IM-R cohort, and AEs (42%) and patient request (13%) in the IM-I cohort. In the IM-R cohort, the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (4%), increased ALT (2%), and diarrhea (2%). In the IM-I cohort the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (11%), neutropenia (5%), increased ALT (3%), and rash (3%). Among the 40 patients (21%) in the IM-R cohort who died on study, the most frequent reasons for death were disease progression (12%) and AEs unrelated to study drug (7%). For the 11 patients (12%) in the IM-I cohort who died on study, the most frequent reasons were disease progression (7%) and unknown (3%). No patients died due to an AE related to study drug and 13 patients (5%) died within 30 days of last dose. Five subjects died since the 5-yr follow-up; 3 within 30 days of last dose.These long-term (8-yr) data are consistent with previous findings associating second-line bosutinib therapy with similar rates of durable major cytogenetic responses in the majority of patients with imatinib-resistant and imatinib-intolerant CP CML. Most AEs could be managed through temporary treatment interruptions and dose reductions. [Display omitted] DisclosuresBrümmendorf:Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Pagnano:Roche: Speakers Bureau; Amgen: Consultancy; Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy. Aguiar:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study

Nivolumab Treatment Beyond Investigator-Assessed Progression: Outcomes in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma from the Phase 2 Checkmate 205 Study

Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.

Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF.

A randomized double-blind, placebo-controlled, cross-over trial (Vestparoxy) of the treatment of vestibular paroxysmia with oxcarbazepine

ObjectiveVestibular paroxysmia (VP) is characterized by short, often oligosymptomatic attacks of vertigo which occur spontaneously or are sometimes provoked by turning the head. Despite the description of the disease almost 40 years ago (first termed “disabling positional vertigo”), no controlled treatment trial has been published to date. The Vestparoxy trial was designed as a randomized, placebo-controlled, double-blind cross-over trial to examine the therapeutic effect of oxcarbazepine (OXA) in patients with definite or probable VP.MethodsPatients were recruited from August 2005 to December 2011 in the outpatient Dizziness Unit of the Department of Neurology of the Munich University Hospital, and randomized to receive OXA (first week: 300 mg once per day, second week: 300 mg b.i.d., third week: 300 mg t.i.d. until the end of the third month), followed by placebo or vice versa with a 1-month wash-out period in between. The primary endpoint was the number of days with one or more attacks. Secondary endpoints were the number of attacks during the observed days, and the median (for each day) duration of attacks. All these endpoints were assessed using standardized diaries collected at the end of each treatment phase.ResultsForty-three patients were randomized, 18 patients provided usable data (2525 patient days) for at least one treatment phase and were included in the main (intention-to-treat) analysis. The most common reasons for discontinuation documented were adverse events. The risk of experiencing a day with at least one attack was 0.41 under OXA, and 0.62 under placebo treatment, yielding a relative risk of 0.67 (95% CI 0.47–0.95, p = 0.025). The number of attacks during the observed days ratio was 0.53 (95% CI 0.42–0.68, p < 0.001) under OXA compared to placebo. Median attack duration was 4 s (Q25: 2 s, Q75: 120 s) under OXA, and 3 s (Q25: 2 s, Q75: 60 s) under placebo treatment. When days with no attacks, i.e., duration = 0, were included in the analysis, these figures changed to 0 (Q25: 0, Q75: 3 s), and 2 (Q25: 0, Q75: 6 s). No serious adverse events or new safety findings were identified during the trial.ConclusionsThe Vestparoxy trial showed a significant reduction of VP attacks under OXA compared to placebo treatment, confirming the known and revealing no new side effects.

Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05).

BackgroundTherapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy.MethodsImmunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks.ResultsTwenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months’ median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic.ConclusionThe addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05]Clinical Trial RegistrationNCT00335140, clinicaltrials.gov

Vismodegib persistence and discontinuation patterns in Greek patients from a real world setting.

Hedghehog pathway inhibitors have been successfully used for patients with locally advanced basal cell carcinomas. However, these treatments have been associated with various adverse events that may limit patient compliance. In this study, an association of patient and disease characteristics with drug compliance in a real clinical setting was made. 18 patients were included in the study. The average patient age was 78.39 years. The time that patients remained to treatment was, on average, 8.73 months. 72.2% of patients experienced at least one adverse event. At study cut-off, 11 out of 18 patients had discontinued treatment. The most common reason for discontinuation was reported "fatigue" from the treatment due to the type of AEs experienced (37.4%) and patient's choice after complete response achievement (30.8%). Factors that were associated with treatment discontinuation was: number of previous treatments, severity of AEs and patient age.

The Use of Saxagliptin in People with Type 2 Diabetes in France: The Diapazon Epidemiological Study.

IntroductionSaxagliptin is a potent, reversible inhibitor of dipeptidyl peptidase-4 that is indicated for the treatment of type 2 diabetes. The DIAPAZON study was a multicenter observational study intended to document the effectiveness, safety and patterns of saxagliptin use in France, including the saxagliptin retention rate, over 2 years of follow-up.MethodsA geographically representative sample of 304 French physicians (general practitioners and specialist endocrinologists or diabetologists) recruited 1131 adults with type 2 diabetes into an ambispective cohort; 1033 fulfilled the inclusion criteria. All had started saxagliptin during the previous 6 months or at study inclusion, and follow-up was for 24 ± 3 months after starting saxagliptin.ResultsThe mean age of the study population when starting saxagliptin was 61 years, and the mean HbA1c level was 8.0%; 79% had an HbA1c level ≥7%. Prior to starting saxagliptin treatment, most participants (91%) were receiving treatment with oral glucose-lowering drugs alone. The most commonly prescribed regimen at starting saxagliptin (53% of participants) was a combination of saxagliptin and metformin. The overall saxagliptin retention rate at 2 years was 79%, as estimated by the Kaplan-Meier method. The most common reasons for discontinuation were inadequate glycemic control (52%) and intolerance (22%). During the course of the study, the mean HbA1c level decreased to 7.0%, and the percentage of people with HbA1c <7% increased from 21% to 49%. The mean change in body weight was −1.8 kg. A total of 294 hypoglycemic episodes were reported in 70 participants (6.8%) during the follow-up period. Of these, 143 episodes in 41 participants (4.0%) occurred when saxagliptin was used in combination with agents associated with hypoglycemia, such as insulin, sulfonylureas or glinides.ConclusionSaxagliptin is efficacious and well tolerated in a real-world practice setting, with almost 80% of participants remaining on treatment after 2 years.FundingAstraZeneca, France.

Incidence of and Predictors for Early Discontinuation of Biological Therapies in Veteran Patients with Inflammatory Bowel Disease.

Biological therapies are effective for inducing and maintaining remission in inflammatory bowel disease (IBD), but patients often require changes in biological agents over the course of their illness. We sought to evaluate the rate of and reasons for discontinuing biological agents and to identify risk factors for their discontinuation. We performed a retrospective cohort study across 4 VA hospital systems (Dallas, TX; Houston, TX; Ann Arbor, MI; Richmond, VA). Patients with IBD who were started on biological therapy between 1998 and 2015 were identified, and their medical records were reviewed to confirm the diagnosis of IBD and to collect study data. Of 1969 patients with IBD; 256 were treated with 346 courses of therapy. By 6 months after initiation of therapy, 82 (24%) had stopped the biological agent. Among patients starting their first biological agent, 21.5% had stopped by 6 months. Patients taking a concomitant thiopurine and those with ileocolonic disease or a nonpenetrating, nonstricturing phenotype were less likely to discontinue biological therapy, whereas those taking 5-ASA concomitantly were more likely to discontinue biological therapy. The most common reasons for discontinuation were primary nonresponse (40%) and adverse drug reactions (29%). In conclusion, in a large multicenter VA cohort, we found that 24% of patients who are prescribed a biological stop their treatment early, most commonly for primary nonresponse or for an adverse drug reaction. Consideration should be given to treating patients with a concomitant thiopurine if at all possible, as this reduces the likelihood of early discontinuation.

Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy.

To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8months (interquartile range [IQR] 5-15). Median starting dose was 48.1mg/kg per day (IQR 29.8-52.3) with a median target of 100mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1months (n=89, IQR 5.0-22.9) overall, and 13.3months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p=0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

KI intolerance study: A phase 2 study to assess the safety and efficacy of TGR-1202 in pts with chronic lymphocytic leukemia (CLL) who are intolerant to prior BTK or PI3K-delta inhibitor therapy.

TPS7569 Background: Although kinase inhibitor (KI) therapies, such as ibrutinib, are generally well tolerated, intolerance is the most common reason for discontinuation (d/c) in practice (~50%, Mato et al, Blood 2016). Additionally KI interruptions (≥ 8 days) can shorten OS (Barr et al, ASCO 2015). Fortunately, data suggest that KIs have non-overlapping toxicity profiles. Therefore, pts who d/c KI due to intolerance, with ongoing CLL response, represent an unmet need. TGR-1202 is a next generation, highly-specific PI3K-delta inhibitor with nanomolar inhibitory potency. TGR-1202 is well-tolerated with a d/c rate due to AEs of 8% as demonstrated in an integrated safety analysis of 165 treated pts (Burris et al, ASCO 2016). Methods: A phase 2 investigator initiated study is being conducted to assess the safety and activity of TGR-1202 in CLL pts who are KI intolerant. KI Intolerance is defined as ≥ 1 Gr 3 or ≥ 2 Gr 2 non-heme toxicities, ≥ 1 Gr 3 neutropenia with infection or fever, and/or ≥ 1 Gr 4 heme toxicity leading to KI (BTK and/or PI3K inhibitor) d/c (Table). Toxicities must resolve to ≤ Gr 1 prior to TGR-1202 dosing. Prior KI must be d/c for ≥ 14 days without progression (PD). All eligible pts are treated with TGR-1202 (800mg oral daily) until PD, toxicity or study conclusion. Primary study endpoint is PFS. Secondary endpoints include ORR, duration of response, time to treatment failure and TGR-1202 safety profile. Peripheral blood samples are collected prior to TGR-1202, after 28 days and at PD for correlative analyses to identify markers associated with KI intolerance. The trial commenced 10/1/2016. 55 eligible pts will be enrolled in approximately 12 months with 24 months follow-up. As of 1/2017, 10 study sites are enrolling pts with 10 more to be activated. To date, 10 pts have been enrolled and treated with TGR-1202. Clinical trial information: NCT02742090. [Table: see text]