Cause Of Treatment Discontinuation Research Articles

Patients with BRAF-Mutant Advanced/Metastatic Melanoma: Original Research on the Treatment Reality in Germany and Austria in the Era of Choice.

Cutaneous melanoma isone of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stageIV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics. Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stageIV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein1 and anti-cytotoxic Tlymphocyte-associated protein4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events. Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Medication persistence on biological therapies prescribed for the treatment of chronic inflammatory arthropathies: a real-world data study

ObjectivesMedication persistence, defined as the duration of time from its initiation to its discontinuation, is a surrogate for treatment effectiveness. The aim of the study was to evaluate persistence and...

Decitabine As First Line Treatment in Acute Myeloid Leukemia of the Elderly: Real-Life Experience from a Single Center

Background: Acute myeloid leukemia, a disease common in the elderly, remains a therapeutic challenge for the hematologist. Patients are compromised and have comorbidities that make the treatment-related toxicities, difficult to manage; the net effect is treatment discontinuation. Therefore, hypomethylating agents present a reasonable and manageable therapeutic approach; our study provides information on the real-world data of such an approach in a cohort of patients. Patients and methods: A total of 44 patients were enrolled in the present study. They were referred to our hospital between January 2016 and March 2018. These patients were suffering from AML and they received decitabine as first line treatment (if they were not eligible for intensive chemotherapy) or as salvage treatment. The primary objective was to evaluate the efficacy and safety of decitabine in real life setting. The drug was administered at a dose of 20 mg/m2 body surface area by intravenous infusion over 1 hour, repeated daily for 5 consecutive days. Results: All patients received treatment with decitabine. The median age at diagnosis was 71.8 years ranging from 48 to 83 years old. The mean decitabine cycles were 2.6. Out of the 44 patients only 25% received ≥ 4 cycles of the drug while 20 patients received only 1 decitabine course. The Overall Response Rate (ORR=CR+PR) was 13.7%. CR was achieved in 1/44 patient (2.3 %). PR was achieved in 5/44 patients (11.4%) while SD was observed in 8/44 patients (18.2%). For the patient achieved CR, the duration of response was 9 months, while the median duration of response in the group of patients with PR and SD was 7 months and 4.5 months respectively. All patients experienced adverse events with hematological toxicity being the most common, following by infections. Thrombocytopenia was the most common among hematological toxicity (82.5%), while anemia and neutropenia were recorded in 45% and 55% of the cases respectively. The main cause of treatment discontinuation was the progression of the disease. The mean survival time was 6.8 months. Results from univariate Cox regression analysis for survival showed a significant association with comorbidities and number of cycles of decitabine. When multiple Cox regression analysis in a stepwise method was conducted it was found that patients with comorbidities had 2.5x greater hazard as compared to those without comorbidities. Additionally, patients treated with more than one cycles of decitabine had 71% lower hazard as compared to those treated with only one cycle. Conclusion: These data from a single center experience provide information about the efficacy and safety profile of decitabine in real life setting. Although the number of the patients is low, however our analysis confirms the acceptable use of decitabine in AML as first line or as salvage treatment especially in compromised patients. Decitabine is a well-tolerated drug with adverse events consistent with the safety profile of the drug and it appears as a reasonable treatment for patients with comorbidities such as the elderly or for the heavily treated. Disclosures No relevant conflicts of interest to declare.

430P - Tolerability of PCV in low grade glioma: A real world experience

BackgroundIn the phase III RTOG 9802 trial, median overall survival (OS) increased from 7.8 years with radiotherapy alone to 13.3 years (P = .002) with adjuvant procarbazine, lomustine, and vincristine (PCV) following surgery for low grade glioma. Although the PCV regimen improved survival, there were significant toxicities. We hypothesised more frequent toxicities would be observed in clinical practice. We aimed to identify and quantify toxicities in the real world setting in a National Neuro-Oncology centre. MethodsPatients with low grade glioma who received PCV following radiotherapy from Nov 2014 to Nov 2018 were identified from Institutional databases. Data on toxicities, dose reductions, dose delays and treatment discontinuation were collected from paper and electronic patient records. ResultsA total of 41 patients with low grade glioma were identified. Patients were predominantly male (n=28) and the median age at diagnosis was 41. Of these, 28/41 patients had a diagnosis of oligodendroglioma and 13/41 had astrocytoma. The majority of patients had tumours with favourable molecular features such as IDH mutations (n=38) and 1p19q co deletions (n=23). Only 4 patients completed 6 cycles of chemotherapy without any dose modification or delay. 16 patients completed PCV with dose reductions and dose delays at various levels. The dose intensity was as follows: procarbazine: 69%, lomustine: 71% and vincristine: 68%. Neutropaenia and thrombocytopaenia (table) were the major causes of treatment discontinuation (14/21 patients). Three patients had disease progression during chemotherapy and two patient’s treatment was discontinued due to abnormal LFTs. Three patients opted not to continue chemo due to intolerability in context of grade 3 to 4 fatigue and GI symptoms. At median follow up of 17 months, 9/41 patients have had disease progression.Table: 430PTable: 430POur Study %RTOG 9802%Patient Completed PCV4856Median Number of Cycles Completed33.5ThrombocytopeniaG2 (50-75)719G3 (25-50)1718G4 (<25)20NeutropeniaG2(1-1.5)879G3(0.5-0.1)3135G4(<0.5)78 ConclusionsFrequent toxicities are observed with PCV in clinical practice. Our data suggest it might be preferable to adjust doses from the start of chemotherapy to improve tolerability. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Continuous subcutaneous apomorphine infusion in Parkinson's disease: causes of discontinuation and subsequent treatment strategies.

Continuous subcutaneous apomorphine infusion (CSAI) is a well-recognized therapeutic option for the management of motor fluctuations in Parkinson's disease (PD), although clinical experience suggests that most patients discontinue CSAI after a variable amount of time due to several causes and circumstances. The objective of the present study was to evaluate the reasons of CSAI discontinuation and to investigate which treatment was adopted afterwards. Two independent raters retrospectively reviewed the electronic medical record of 114 patients treated with CSAI for at least 6months. The records were reviewed regarding efficacy, safety, and evolution of CSAI treatment. Most of PD patients on CSAI had a significant improvement in their clinical condition. Lack of improvement of dyskinesia was the most frequent causes of treatment discontinuation. The second reason for CSAI discontinuation was cognitive deterioration. At CSAI discontinuation, younger patients were more likely to undergo deep brain stimulation (DBS), while older patients and patients with cognitive impairment were more likely switched to oral therapy alone (OTA). CSAI is an effective treatment that unfortunately must be discontinued in a great number of patients with advanced PD. As older age is the main limiting factor for accessing second-level therapies at CSAI discontinuation, CSAI treatment should not be postponed to older age. CSAI might be considered a good first-line and fast strategy in patients undergoing rapid deterioration of their quality of life while waiting for DBS or levodopa/carbidopa intestinal gel therapy.

Expert consensus on the persistence of biological treatments in moderate-to-severe psoriasis.

Treatment persistence is becoming a useful measure to evaluate long-term effectiveness and safety of biological therapies in real-world settings. The main objective of this study was to explore the scientific opinion of a panel of dermatologists and hospital pharmacists to reach a consensus about the impact, causes, and best strategies and interventions that might be associated with improved drug persistence in patients with psoriasis in Spain. This research was conducted using a modified Delphi method organized in two rounds and involving a panel of 90 dermatologists and 34 hospital pharmacists. A questionnaire of 70 items was developed. The items proposed to reach a consensus included topics such as definitions and measures in the treatment of psoriasis, analysis of treatment persistence, factors that may influence treatment persistence, impact of treatment persistence and economic cost of treatment. Dermatologists reached a consensus on 77.1% of the items proposed, and hospital pharmacists reached a consensus on 71.4%. Both groups agreed that it is important to use standardized measures in the evaluation of treatment maintenance over time. Dermatologists agreed that treatment survival, persistence and retention are synonymous, but hospital pharmacists considered only treatment persistence as a valid term. In addition, panelists agreed that drug persistence is an indicator of success in the treatment of psoriasis that may be influenced by a drug's effectiveness and safety profile, as well as by patient satisfaction. They agreed that the different causes of treatment discontinuation should be considered in Kaplan-Meier analysis of treatment persistence. Moreover, treatment persistence was agreed to decrease the cost of therapy. This Delphi consensus highlights the different perspectives of dermatologists and hospital pharmacists regarding the interpretation of treatment persistence, and the challenge of harmonizing the results obtained.

Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial on the Use of Uncaria tomentosa (Cat's Claw) for Aromatase Inhibitor-Induced Arthralgia: A Pilot Study

Introduction: Aromatase inhibitors (AI) are widely used in adjuvant breast cancer treatment, and diffuse articular pain secondary to AI use is the most common cause of treatment discontinuation. Uncaria tomentosa (cat’s claw) has antiinflammatory activity and is used to treat arthrosis and arthritis. Patients and Methods: This prospective, single-center, double-blind, randomized, placebo-controlled phase II study analyzed 70 patients with breast cancer undergoing AI therapy with complaints of arthralgia. The patients received 100 mg of the dry extract of Uncaria tomentosa three times daily for 4 weeks. At the beginning and end of the study, patients answered the Brief Pain Inventory (BPI), Disability Arm, Shoulder, and Hand (DASH), Lequesne, SF-36 Quality of Life questionnaires, completed a visual analog scale (VAS) for pain, and underwent laboratory testing. Results: U. tomentosa was not more effective than the placebo. No evidence of grade 3 or 4 toxicity was found. In addition, no significant differences were seen in laboratory results or inflammatory markers between the two study groups. Conclusion: Dry extract of U. tomentosa was safe but ineffective in reducing AI-induced arthralgia compared with the placebo. Furthermore, the plant extract had no detectable anti-inflammatory activity.

Newer Antiepileptic Drugs Discontinuation due to Adverse Effects: An Observational Study.

Aims:Antiepileptic drugs are the main therapy for epilepsy. However, the incidence of adverse effects (AEs) results in treatment discontinuation. The aim of this study is evaluating the factors involved in discontinuation of antiepileptic drugs.Settings and Design:We studied 2797 epileptic patients who consumed levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), zonisamide (ZNS), rufinamide, and lacosamide to evaluate the discontinuation because of AEs.Statistical Analysis Used:Data were analyzed using descriptive statistics and Chi-square test.Results:This study showed the rate of discontinuation due to adverse reactions as follows: TPM (7.10%), OXC (4.5%), ZNS (1.8%), and LEV (1.6%) (Chi-square analysis, P < 0.0001). Our study also showed that 1.35% of the patients did not continue the therapy because of subjective experiences of the AEs. Furthermore, neurologic complications in TPM, skin rashes in OXC, and patients' subjective experiences in LEV prescription were the main reasons for nonadherence due to a AEs.Conclusions:AEs in newer antiepileptic drugs are extremely prevalent. Our observation revealed that skin rashes and paresthesia were the most probable causes of treatment discontinuation because of AEs.

Switching endocrine therapy in breast cancer as a strategy for musculoskeletal symptoms, tolerance, and adherence.

192 Background: Adverse effects of endocrine therapy (ET), especially musculoskeletal symptoms (MSS), represent the major cause of treatment discontinuation in breast cancer (BC) patients, resulting in increased risk of recurrence. Aromatase inhibitors (AI), the mainstay of ET, are associated with a high incidence of MSS such as arthralgia and myalgia. The hypothesis of whether switching ET subclass improves adherence and symptoms was tested. Methods: We conducted a retrospective single site chart review of female patients with nonmetastatic BC, who were seen at Cancer Clinic from January to June of 2017. All patients received AI as a first choice of adjuvant ET; those with disease recurrence while on ET were excluded. We collected data on baseline health, adherence and discontinuation rate, as well as whether switching to a different ET agent (another AI or tamoxifen) was attempted. The subsequent compliance and symptomatology after switching were assessed. Results: 483 eligible patients were identified and divided into 4 groups based upon adherence: 354 (73.3%) were found to be compliant with AI without interruption, 109 (22.5%) switched to a different ET and remained compliant (≥ 1 switch), 16 (3.3%) eventually discontinued ET despite attempting ≥ 1 switch, and 5 patients (1.0%) stopped treatment without a switch. On comparison of the different groups, patients who permanently discontinued ET were more likely to be elderly and have preexisting musculoskeletal condition. MSS was found to be the single most common cause for AI intolerance (105 patients, 81.4%). The median time to switch was 6.3 months (0.3-63.9). Among the compliant switchers, most needed only 1 switch (79) but there were patients who required 2 or 3 switches (23 and 6, respectively). Majority of patients switched from anastrozole to exemestane (84, 51.8%). Significant improvement in symptoms after the switch was reported by 73.3% of patients. Conclusions: Switching between different ET subclasses is an effective treatment strategy to alleviate side effects and enhance adherence to ET. A higher compliance rate of 95.8% was observed in our study compared to a national average estimated at &lt; 80%.

Clinical follow‐up of uveitis patients treated with TNF‐alpha inhibitors and causes of treatment discontinuation

Clinical follow‐up of uveitis patients treated with TNF‐alpha inhibitors and causes of treatment discontinuation

Association between Quality of Response and Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Association between Quality of Response and Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Hematologic toxicity of radium-223 in elderly patients with metastatic Castration Resistant Prostate Cancer: areal-life experience.

BackgroundTreatment with radium-223 has been shown to increase survival and to delay skeletal events related to bone metastases of patients with metastatic Castration Resistant Prostate Cancer (mCRPC). This treatment has also proved to be well tolerated, and hematological toxicity, in particular anemia, represents the most represented adverse event.Materials and methodsWe evaluated the hematologic toxicity of Ra-223 treatment in a real-life experience of 38 patients from two Italian cancer centers, with bone metastases from mCRPC. The main endpoint of the study was the evaluation of the efficacy and tolerability of treatment with radium-223, with greater reference to hematological toxicity (especially anemia) as the cause of interruption of treatment, specifically in the elderly patient.ResultsFrom August 2016 to October 2017, a total of 38 consecutive nonselected patients, 20 of them aged >75 years, with mCRPC symptomatic bone metastases, were enrolled for radium-223 at standard doses. Hematologic adverse events were recorded more frequently (72.4% with AE), and 36.8% had anemia. The most frequent cause of treatment discontinuation due to AEs was anemia [8/10 patients (80%)], followed by thrombocytopenia (2 patients) and neutropenia (1 patient). Hematologic AEs were more represented in elderly patients with greater disease burden and previously treated with docetaxel.ConclusionsAnemia is the most represented AE related to radium-223 treatment in elderly patients with greater disease burden and previously treated with docetaxel, besides representing the main reason for interruption of treatment. Correct patient selection, appropriate timing, and adequate supportive care are elements that could facilitate successful treatment with radium-223, preventing premature interruption of the same. The results of this experience support the opportunity to propose treatment with radium-223 mostly in patients in the earliest stages.

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events.

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612-622).

Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management.

Immunotherapy is one of the most recent systemic treatments to emerge for use in oncology, and is based on the blocking of inhibitory immune checkpoints to potentiate the immune response to cancer. The anti-cytotoxic T lymphocyte-associated antigen-4 antibody ipilimumab and anti-programmed cell death protein 1 antibodies, including nivolumab and pembrolizumab, are currently available and widely used, and other immune-inhibiting antibodies are now under intensive investigation. These antibodies have shown efficacy in a growing number of tumor types, following initial observations of their notable effects in melanoma treatment. Despite the efficacy of these antibodies, their novel mechanisms of action are also associated with a new class of side effects called immune-related adverse events (IRAEs). These side effects do not share a common pathophysiology with other anticancer treatments and, therefore, they often require specific therapies. When detected early and correctly treated, IRAEs are reversible; however, they can become severe and life-threatening if underestimated or inappropriately treated. This review aims to revisit the pathogenesis of IRAEs, with attention to gastrointestinal manifestations, since these are common and potentially dangerous complications of immunotherapy and represent a major cause of treatment discontinuation. Recommendations and guidelines for the management of IRAEs are also presented, in order to provide a clear and applicable algorithm for use by clinicians.

A retrospective feasibility study of biweekly, reduced-dose docetaxel in Asian patients with castrate-resistant, metastatic prostate cancer

BackgroundThe aim of this retrospective study was to evaluate the clinical outcomes of reduced dose, biweekly docetaxel chemotherapy for Korean patients with castrate-resistant prostate cancer (CRPC).MethodsWe retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were treated with a biweekly regimen (intravenous docetaxel 40 mg/m2 on day 1 plus prednisolone 5 mg twice daily) between 2012 and 2015 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve patients with CRPC received a 40 mg/m2 biweekly regimen (n = 24). The primary end point was a PSA response, defined as a greater than 50% decline in PSA level from baseline.ResultsThe baseline characteristics of the patients in the two treatment groups were similar. The most common cause of treatment discontinuation was disease progression, which was exhibited by 17 patients (71%) in the 3-weekly group and 20 (75%) in the biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively (p = 0.683). Time to treatment failure (TTTF, 4.5 vs 3.9 months) and time-to-progression (TTP, 5.0 vs 4.2 months) were not significantly different between the 3-weekly and biweekly groups.ConclusionsWithin the limitations of a retrospective study, the biweekly reduced dose docetaxel regimen was active and well-tolerated in Korean patients with metastatic CRPC.

Patient Retention in Antiretroviral Therapy Programs; A Retrospective Cohort Study in a Triangular HIV Clinic

Background: High rate of adherence to antiretroviral therapy (ART) is critical for the optimized outcome. The present study aimed to determine the rate of retention in ART programs and its’ associated factors in a triangular clinic. Materials and Methods: The present retrospective cohort study was conducted on people living with HIV receiving care in a triangular clinic affiliated with Iranian research center for HIV/AIDS, Tehran, Iran, from 2003 to 2008. Baseline variables, duration of ART, and cause of treatment discontinuation were gathered using patients’ profile and analyzed by SPSS 21 and STATA 11. Results: Three hundred and seventeen cases with the mean age of 37.69 ± 10.63 (2–76) years were included (83.9% male). Treatment discontinuation had happened in 142 (45.2%) cases. Cause of treatment discontinuation was death in 20 (13.7%) cases and personal preference in 126 (86.3%) individuals. 6, 12, 18, 24, 36, and 60 months retention rates were 81.1%, 58.4%, 48.3%, 35.6%, 22.9%, and 6.3%, respectively. The results of multivariate logistic regression analysis showed a significant association between treatment retention and female sex (OR: 4.10; 95% CI: 1.59–10.56, P=0.003), addiction/drug use (OR: 0.39; 95% CI: 0.21– 0.77, P=0.007), and lamivudine+ zidovudine+ indinavir treatment regimen (OR: 0.63; 95% CI: 0.46 -0.87, P= 0.005). Conclusion: Based on the findings, male sex, addiction/drug use, and type of treatment regimen were among the most important risk factors for ART attrition in HIV-infected patients. [GMJ.2017;6(2):110-117]

Abstract A29: Anti-CTLA-4 antibody scFv producing recombinant Bifidobacterium secretes CTLA-4 blocker specifically inside hypoxic tumor and suppresses tumor growth in syngeneic mice model

Abstract Success of immune checkpoint antibody drugs has provided broad perspective in cancer immunotherapy. Anti-PD-1 antibody and anti-CTLA-4 antibody showed notable efficacy and the combination complimentarily enhanced antitumor benefit. Nevertheless, either single-agent therapy or combination therapy is facing immune-related adverse events (irAEs), which is major cause of treatment discontinuation. Also, still large fraction of cancer patients doesn't respond to the antibody immunotherapy. Since non-specific systemic activation of normal immune system by the therapy is one of major reasons to cause the above problems, approaches to target the hypoxic condition of tumors may help increasing the drug's tumor-targeting specificity, which results in minimizing the irAEs and improving the response rate in patients. In an aim to improve anti-cancer drug delivery efficacy, we have been developing in situ Delivery and Production System (i-DPS) by modifying a non-pathogenic anaerobic bacterium, Bifidobacterium, which localizes and proliferates only in the hypoxic environment like solid tumors after intravenous administration, produces anticancer proteins, enzymes or other pharmacologically active molecules selectively at the tumor site. Here we present anti-human CTLA-4 antibody scFv producing i-DPS in cancer immunotherapy, which could be specifically delivered to and amplified only at the hypoxic sites of solid tumors. A series of in vitro assays has been performed to confirm the stable expression and secretion of anti-hCTLA-4 scFv by recombinant Bifidobacterium, the binding affinity of purified anti-hCTLA-4 scFv and the IC50 competing with hCTLA-4/hCD80 or hCD86 interaction as well. Anti-murine CTLA-4 scFv producing Bifidobacterium as surrogate systemically administered to the syngeneic mice model demonstrated significant tumor growth inhibition. Moreover, the combination therapy of anti-mCTLA-4 scFv producing Bifidobacterium and anti-murine PD-1 antibody was more effective than each of monotherapy. It is noteworthy that scFv was only detected in tumor tissue but not in blood proved by immunoprecipitation assay. Altogether, i-DPS for anti-CTLA-4 antibody provide a new promising immune-therapeutic modality to target hypoxic solid tumors and also provide a unique insight for antibody drug delivery in cancer immunotherapy. Citation Format: Koichiro Shioya, Shiro Kataoka, Li Wang, Tomio Matsumura, Hitomi Shimizu, Yasuyoshi Kanari, Yuji Seki, Yuko Shimatani, Minoru Fujimori, Shun'ichiro Taniguchi. Anti-CTLA-4 antibody scFv producing recombinant Bifidobacterium secretes CTLA-4 blocker specifically inside hypoxic tumor and suppresses tumor growth in syngeneic mice model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A29.

824P - Efficacy and safety of the combination of bevacizumab (BEV) and temsirolimus (TEM) in patients with metastatic renal cancer (mRCC) after first-line anti-VEGF treatment: A Hellenic Cooperative Oncology group (HeCOG) phase II trial

Anti vascular endothelial growth factor (aVEGF) agents represent the standard 1st-line therapy for mRCC. Monotherapy with agents blocking VEGF, mTOR or PD1/PD-L1 interaction are approved therapies. Since post progression blockade of VEGF may be of value, we studied the combination of BEV + TEM in mRCC patients relapsing after 1st-line treatment. A prospective, phase II, multicenter, trial evaluating the combination of BEV(10mg/kg, every 2 weeks) withTEM(25 mg weekly), until progression of the disease or unacceptable toxicity, was conducted in patients with mRCC who failed first-line aVEGF treatment. No previous therapy for relapsed disease was allowed. % of 6-month progression-free survival (PFS) was the primary end point. 39 patients were enrolled and 37 of them were evaluable for response. 1st-line therapy included: sunitinib (16), bevacizumab/interferon (12), pazopanib (10), sorafenib (1). The median age was 67 (40-80) years. Clear cell histology was present in 97% of patients, while 69% had PS 0. 51% of patients were progression-free at 6 months (95% CIs: 34-66) and 20% (95% CIs: 9-34) at 12 months. The median time to progression was 6.8 months (95%CI 5.5-9.2) and the overall survival 18.2 months (95%CI 12.9-27.2). Best responses were: complete-1 (2.7%), partial-9(24.3%), stable disease-20 (54.1%), progression-7(18.9%). Worst toxicities were of grade: 1 in 1 case (3%), 2 in 20 (51%), 3 in 15 (38%), 4 in 2 (5%), 5 in 1 (3%). The most common adverse evets (AEs) were metabolic (44%), gastrointestinal (11%) and myelotoxicity (9%). The most common grade 3 and 4 AEs were infection (10%), hypertension (5%), hypertriglyceridemia (5%) and mucositis (5%).Toxicity was the most frequent cause of treatment discontinuation (33%). The combination of BEV and TEMis active in mRCC patients relapsing after a VEGF 1st-line treatment. Our study confirms recent encouraging data of another anti-VEGF/anti-mTOR combination in this population. Nevertheless, toxicity was considerable leading to the discontinuation of therapy in 1/3 of patients.

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.

Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.

The Association Between Bleeding and the Incidence of Warfarin Discontinuation in Patients with Atrial Fibrillation.

SummaryAimWhile bleeding is a well‐known complication of warfarin use and is thought to be a contributory cause of treatment discontinuation, studies quantifying this association are limited. The objective of this study was to quantify the association between bleeding events and subsequent warfarin discontinuation in patients with nonvalvular atrial fibrillation (NVAF).MethodsA nested case–control analysis was conducted within a cohort of patients with NVAF newly treated with warfarin. All patients who discontinued warfarin (at least 60 days from last day of warfarin supply) during follow‐up were identified as cases and matched with up to 10 controls on age, sex, and duration of follow‐up. The index date was defined as the date of warfarin treatment discontinuation of the cases. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of warfarin treatment discontinuation associated with a bleeding event in the 60 days before the index date.ResultsThe cohort included 24,243 patients who initiated warfarin treatment, of whom 13,482 discontinued treatment during follow‐up (cases). Bleeding was associated with an increased risk of warfarin treatment discontinuation (3.55% vs. 0.85%; OR, 4.31; 95% CI, 3.87–4.81). When including only bleeds as the first listed diagnosis, the unadjusted OR was 4.64 (95% CI, 4.10–5.26), and the adjusted OR was 4.65 (95% CI, 4.10–5.27).ConclusionsBleeding was significantly associated with warfarin discontinuation, and thus, the selection of an effective treatment regimen associated with a lower bleeding rate could be a desirable treatment approach.