Bayer HealthCare Pharmaceuticals Research Articles

Sequential Brentuximab Vedotin (Bv) before and after Adriamycin, Vinblastine, and Dacarbazine (Bv-AVD) for Older Patients with Untreated Classical Hodgkin Lymphoma (cHL): Final Results from a Multicenter Phase II Study

Background: Standard therapeutic regimens for older HL patients (pts) may confer significantly increased toxicity and inferior survival compared with younger pts. Reported complete remission (CR) rates for older pts are 45-76% with 2-year (yr) progression-free survival (PFS) rates of 50-71% (eg, Evens et al. Blood 2012). With a goal of improving outcomes for older cHL pts, this multicenter phase 2 study tested Bv given sequentially before and after standard AVD chemotherapy. Methods: Older pts (aged ≥60 yrs) with stage IIB-IV, untreated cHL were eligible. Pts received 2 9lead-in9 doses of single-agent Bv 1.8 mg/kg (q 3 weeks) followed by 6 cycles of standard AVD. Supportive antibiotics were encouraged & granulocyte growth factor was allowed. Responding pts proceeded to consolidation (Cx) therapy with 4 Bv cycles. Study design was a Simon 2-stage; the primary endpoint was CR rate after AVD (ie, prior to Bv Cx) using revised Cheson with FDG-PET; pts must have received 2 cycles of AVD to be evaluable for response. The study was considered promising if >70% of evaluable pts demonstrated CR. Univariate & multivariate analyses (MVA) were performed using Cox proportional hazard regression for associations between lab and clinical factors (including co-morbidities assessed by the Cumulative Illness Rating Scale (CIRS)) with survival. Results: 48 pts enrolled to the study (8/2012-8/2016) with 41 being evaluable for response. Characteristics for all pts included: median age 69 yrs (60-88); 30M:18F; median ECOG PS of 1 (21% PS=2); 82% stage III/IV disease (bone marrow involved 23%); and IPS 3-7 in 60%. No pts had loss of activities of daily living (ADL) at baseline, while 12% had loss of instrumental ADLs. Median CIRS co-morbidity score at baseline was 6 (0-20). 6 pts received 1 pt were neutropenia (60%); infection (15%), febrile neutropenia (8%); transaminitis (6%); renal insufficiency (6%); urinary infection (6%); pneumonia (6%); hyponatremia (6%); fatigue (6%); febrile neutropenia (6%); diarrhea (4%); pancreatitis (4%), & peripheral neuropathy (PN) (4%). 33% of all pts experienced grade 2 PN (6% motor/27% sensory); the majority were reversible. Treatment related mortality on study was 2% (n=1 pancreatitis). Reasons for study discontinuation were: completed treatment (52%); toxicity/AEs (33%); withdrew consent/refused additional treatment (9%); & progressive disease or death (6%). Finally, for pt prognostication, increasing age (continuous) (P=0.005), female (P=0.05) & increased CIRS (continuous) (P=0.006) were associated with inferior PFS on univariate analysis; on MVA, only increasing age remained significant (HR 1.19 per yr >60, 95%CI 1.02-1.37, P=0.02). Conclusions: Bv-AVD incorporating Bv sequentially before and after chemotherapy represents among the best-reported outcomes to date for untreated older cHL pts. Efforts to maintain these robust remission and survival rates, but with less toxicity, should be a focus of ongoing investigation. This should include response-adapted design and integration of other novel agents (eg, checkpoint inhibitors), especially for pts with advanced ages and/or multiple co-morbidities. Disclosures Evens: Novartis: Consultancy; Affimed: Consultancy; Merck: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Millennium: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; • Spectrum Pharmaceuticals: Consultancy. Advani: Spectrum: Consultancy; Gilead: Consultancy; Agensys: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Kura: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Nanostring: Consultancy; FortySeven: Research Funding; Janssen: Research Funding; Cell Medica: Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy; Sutro: Consultancy; Juno Therapeutics: Consultancy; Pharmacyclics: Research Funding; Infinity: Research Funding; Genentech: Research Funding. Fanale: ONYX: Research Funding; CELGENE: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; AMGEN: Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity9s Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; ADC THERAPEUTICS: Research Funding. Winter: Merck: Research Funding; Glaxo-Smith-Kline: Research Funding. Gordon: Janssen: Other: Data Monitoring Committee. Hamlin: Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support; Incyte: Other: research support; Gilead: Consultancy, Honoraria; Novartis: Other: research support; Seattle Geneitcs: Other: research support.

Metformin for endometrial hyperplasia.

Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain.To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar, OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015.We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type.Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health-related quality of life, and adverse effects during treatment.We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision.We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low-quality evidence). We found no data for recurrence of endometrial hyperplasia or health-related quality of life. Both studies (n = 59) provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others.Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37, one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea.At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate - versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.

365O - Phase 1 safety and clinical activity of BLU-554 in advanced hepatocellular carcinoma (HCC)

Background: Treatment for advanced HCC remains limited and outcomes are poor. However, emerging data implicate FGF19 as a key HCC driver and suggest its receptor, FGFR4 as a novel therapeutic target. A phase 1 study (NCT02508467) was initiated to assess the safety and clinical activity of BLU-554, a potent, highly-selective oral FGFR4 inhibitor. Methods: Adult patients (pts) with advanced HCC and well-preserved liver function received BLU-554 once daily on a 4-week cycle following a 3 + 3 escalation/MTD expansion design. Adverse events (AEs) per CTCAE, PK, PD and pathway activation (tumor FGF19 IHC) were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 4/20/17 cutoff, 61 pts have been treated with BLU-554 including 25 in dose escalation (140-900 mg) and 36 in the ongoing dose expansion. 48 (79%) pts had metastatic disease, 54 (89%) had failed ≥1 prior systemic therapy (48 (79%) sorafenib; 11 (18%) nivolumab) and 29 (48%) had pathway activation (IHC+). Based on safety profile, PK, PD, and anti-tumor activity, 600 mg was the MTD and RP2D. Radiographic tumor reduction and objective response per RECIST 1.1 were observed in IHC+ pts in dose escalation and dose expansion. Of 19 IHC+ pts with ≥ 1 radiographic assessment, 11 (58%) pts had tumor reduction: 6 with SD, 4 with PR and 1 with CR (ORR 26%). 6 (32%) IHC+ pts had duration of treatment ≥ 6 months. In contrast, only 4 (15%) of 27 IHC negative pts had tumor reduction (all SD) and only 1 (4%) had duration of treatment ≥ 6 months. Most AEs (regardless of causality) were Grade (Gr) 1-2, including diarrhea (66%), nausea (43%), vomiting (39%), ALT increase (33%), fatigue, AST increase (29% each), abdominal pain (23%), anemia, and decreased appetite (20% each). AST (13%) and ALT (10%) increase, were the only BLU-554-related Gr 3-4 AEs occurring in ≥ 10% of pts. 2 pts experienced DLT (1 Gr 3 abdominal pain; 1 Gr 3 fatigue lasting > 7 days) at 900 mg. 36 (59%) pts have discontinued treatment: 26 disease progression; 5 AE; 3 investigator’s decision; 2 withdrew consent. Conclusions: BLU-554 is well tolerated at the recommended dose of 600 mg and demonstrates important clinical activity in FGF19 IHC+ advanced HCC pts who have failed prior systemic therapy. Clinical trial identification: NCT02508467 Legal entity responsible for the study: Blueprint Medicines Corporation Funding: Blueprint Medicines Corporation Disclosure: D. Sarker: Honoraria: Pfizer, Novartis, Bayer, Ipsen. Advisory board: Blueprint, Baxalta. S.P. Choo: Advisory board +/- honoraria: Norvatis; Celgene; Sirtex, Bristol-Myers Squibb; New Beta-Innovation Oncology; Bio-Cancer Treatment; Research grant: Bristol-Myers Squibb, Sirtex. T. Meyer: Advisory board for Merck, Bristol-Myers Squibb, Bayer and Eisai. Grants from Bayer and BTG. J-H. Yoon: Research grants from Bayer HealthCare Pharmaceuticals, Daewoong Pharmaceuticals, and Bukwang Pharmaceuticals. J-W. Park: Honoraria Support from: Bayer, Merck. Advisory Board of: Bristol-Myers Squibb, Merck. Consulting of: Bristol-Myers Squibb, ONO, Bayer. S. Faivre: Consulting of Bayer, BMS, Lilly, Merck Serono, Novartis. Y-K. Kang: Advisory Board of Blueprint, Novartis, Roche, Merck, Ono, Bristol-Myers Squibb, LSK Biopharma, Daehwa, Taiho. All other authors have declared no conflicts of interest.

432PD - Prognostic impact of RNA expression profile (EP) in the phase III DECISION trial for patients with advanced radioactive-iodine refractory differentiated thyroid cancer (DTC)

Background: Sorafenib has demonstrated a significant impact in progression free survival (PFS) in patients with advanced DTC in the DECISION trial. BRAF and RAS mutation status (MS) have not shown prognostic significance on PFS and overall survival (OS) in multivariate model. The aim of this study was to correlate different RNA expression profiles with PFS and OS in a multivariate model. Methods: We previously identified 3 expression profiles, BRAF, RAS and non-BRAF/RAS-like based on RNA-seq analysis (77 million paired-end reads for each sample on HiSeq2000) of 125 tumour samples of patients included in the DECISION trial. RNAseq reads were mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. We used multivariate Cox proportional models to study the association between clinical variables (sex, age, thyroid cancer histology, Eastern Cooperative Oncology Group performance status), arm of treatment and biomarkers (EP and MS) with PFS and OS. Results: The clinical variables in each expression profiles are shown in Table. Multivariable analysis indicated that only sorafenib treatment (HR: 0.39, 95% CI 0.23-0.66, p < 0.001), age (HR: 0.97, 95% IC 0.94-0.99, p = 0,002) and BRAF-like EP (HR = 0.41, 95% IC 0.17-0.99, p = 0.046) were independent prognostic factors for PFS. No significant prognostic factors we identified for OS. However, in papillary histology (PTC), only the BRAF-like EP was associated with outcome (HR = 0.32, 95% IC 0.118-0.876, p = 0.026).Table432PD Clinical variables in each expression profilesBRAF like (n = 56)RAS like (n = 28)non-BRAF/RAS-like (n = 41)TreatmentSorafenib37(66.1%)9 (32%)22 (53.7%)Placebo19 (33.9%)19 (68%)19 (46.3%)SexFemale26 (46.4%)19 (68%)15 (36.6%)Male30 (53.6%)9 (32%)26 (63.4%)ECOG036 (64%)15 (53.6%)29 (70.7%)1-220 (36%)13 (46.4%)12 (29.3%)Tumor histologyPapillary53 (94.6%)14 (50%)6 (14.6%)Follicular2 (3.6%)7 (25%)24(58.5%Poorly differentiated1 (1.8%)7 (25%)10 (24.4%)BRAF statusMutated31 (55.4%)2 (7%)0 (0%)Wild type25 (44.6%)26 (93%)41 (100%)RAS statusMutated5 (8.9%)14 (50%)1 (2.4%)Wild type51 (91.1%)14 (50%)40 (97.6%) Open table in a new tab Conclusions: RNA-seq analysis identifies 3 different expression profiles in DTC: BRAF-like, RAS-like and non-BRAF/RAS-like. BRAF-like EP includes almost all BRAF mutant tumors but also a 45% of tumors with no mutation in BRAF gene. In the multivariate analysis, BRAF-like EP has shown a better prognostic factor for PFS in DTC and for OS in PTC. Legal entity responsible for the study: Vall d’Hebron Institute of Oncology Funding: Bayer HealthCare Pharmaceuticals, Inc. Disclosure: C. Peña: Bayer employee. All other authors have declared no conflicts of interest.

610TiP - A randomized Phase 2 study comparing different dosing approaches of induction treatment (first cycle) of regorafenib in metastatic colorectal cancer (mCRC) patients

Background: Regorafenib is a multikinase inhibitor with broad anti-angiogenic, anti-stroma and anti-proliferative effects that improved overall survival in patients with mCRC after failure of all approved drugs in the CORRECT phase 3 trial. The different tolerability profile of regorafenib compared with other agents normally used for the treatment of colorectal cancer, caused frequent dose-reductions and interruptions, thereby jeopardizing dose-intensity and limiting incorporation of the drug as standard of care. The CORRECT trial showed that the highest rate and intensity of treatment-related adverse events occurs during the first two cycles. The standard approved dose of regorafenib (160 mg daily three weeks on/one week off) was determined in a phase 1 study and this dose was moved directly into the phase 3 trial. The immediate sub-MTD dose level of 120mg daily 3 weeks on/1 week off did not show any DLT among 7 patients treated in the phase I. In addition, an intermittent dose approach consisting of regorafenib 160 mg daily on a 1 week on/1 week off schedule was tested in combination with chemotherapy in the CORDIAL trial and showed a favorable safety profile. Trial design: This randomized phase 2 study will evaluate the tolerability regorafenib using different dose-escalation approaches in patients with treatment refractory mCRC. Patients will be randomized 1:1:1 to receive regorafenib at the standard approved dose (arm A), or at 120 mg daily 3 weeks on/one week off during the first cycle (arm B), or 160 mg daily one week on/one week off during the first cycle (arm C). In arms B and C, the dose will be escalated to the standard dose from cycle two onwards if no limiting toxicity appears. The primary objective is to compare the safety profile of the different treatment arms. Secondary aims include assessment of the percentage of total administered dose over the planned dose, dose intensity during the treatment period and during first two cycles, disease control rate, progression-free survival, time to treatment failure, and overall survival. The trial is in progress; 160 of 295 planned patients have been recruited at the end of March 2017 (first patient 15 July 2016). Clinical trial identification: NCT02835924 Legal entity responsible for the study: Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) in collaboration with UNICANCER GI Funding: Bayer HealthCare Pharmaceuticals Inc Company Disclosure: J.M. Viéitez: Consultant or advisory relationship: Amgen, Roche. Honoraria: Servier, Shire. Research funding: Amgen, Roche, Merck Serono. A. Falcone: Consultant or advisory relationship, research funding and honoraria: Amgen, Bayer, Roche, Merck, Servier, Sanofi. F. Ciardiello: Advisory Boards (compensate): Bayer, Roche, Merck, Amgen, Lilly. Research funds: Bayer, Roche. J. Bennouna: Consultant or advisory relationship and honoraria: Roche, BMS, Boehringer-Ingelheim, Astra-Zeneca. J. Tabernero: Consultant or advisory relationship and honoraria: Roche, BMS, Boehringer-Ingelheim, Astra-Zeneca. E. Aranda Aguilar: Advisory role: Amgen, Bayer, Celgene, Merk, Roche, Sanofi. All other authors have declared no conflicts of interest.

Riociguat in PAH and CTEPH: Strategies for Patient Management

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subtypes of pulmonary hypertension—a rare, life-threatening condition defined by chronically elevated pulmonary artery pressure. Treatment goals include improving patient functioning, symptom management, and delaying disease progression. Traditional therapies have focused on affected physiologic pathways, with endothelin-receptor antagonists and/or phosphodiesterase-5 inhibitors as first-line agents and prostacyclins for more severe disease. Riociguat, a therapeutic agent that stimulates soluble guanylate cyclase via nitric-oxide pathways, was approved in 2013 for treatment of PAH and CTEPH. Riociguat significantly improved exercise capacity, hemodynamic parameters, and other functional endpoints in phase 3 trials. Safety and efficacy were maintained in long-term extension studies. Adverse events (AEs) were generally mild to moderate and self-limiting and did not require treatment discontinuation. To optimize adherence, frequent patient monitoring and management of AEs are recommended. Management strategies include patient education, treatment/prevention of adverse events, and individualized dose adjustment. Funding: Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.

Abstract OT1-04-04: A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases

Abstract Background: Bone-metastatic breast cancer (MBC) treatment is limited. In a phase 2a study of bone-dominant MBC patients, radium-223, a first-in-class α emitter with targeted cytotoxic effect on bone metastases (mets), reduced bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat. 2014). Trial design: This study evaluates efficacy and safety of radium-223 versus placebo (pbo), each + endocrine treatment (ET), in patients with HER2- estrogen receptor+ (ER+)bone-dominant MBC (NCT02258464). Patients receive (1:1) radium-223 50 kBq/kg IV or pbo q 4 wk (6 cycles) + ET + denosumab or bisphosphonates + best supportive care. Stratification is by geographic region (EU/N America vs Asia), number of prior ET lines (1 vs ≥ 2) for MBC, and number of prior skeletal-related events (SREs) (1 vs 2). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ bone-dominant MBC and ≥ 2 bone mets or with soft tissue and/or visceral mets, and 1-2 prior SREs (external beam radiotherapy, pathologic bone fracture, spinal cord compression, orthopedic surgery); they have received ≥ 1 line of ET for MBC and are considered appropriate for further ET. Patients must have evaluable disease (RECIST 1.1), be taking bisphosphonates or denosumab for ≥ 1 month before study treatment, have an ECOG score 0-1, and have adequate hematologic, renal, and liver function. Patients must not have had visceral or brain mets or leptomeningeal disease, or need chemotherapy for MBC, and must not be suitable for everolimus for MBC. Patients are not eligible if they had prior radium-223 treatment or have untreated spinal cord compression. Specific aims: The primary end point is SSE-free survival (SSE-FS). Secondary end points are radiologic progression-free survival; overall survival; times to opioid use, pain progression, and cytotoxic chemotherapy; pain improvement rate; and safety. Patients are assessed for efficacy and safety and are followed to SSE, radiologic progression, death, or withdrawal. Statistical methods: Assuming 1-sided α 0.1, power 90%, ∼ 119 SSE-FS events are needed for analysis. Time-to-event analysis will use a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each treatment group. Safety analyses will be descriptive. Present and target accrual: Target accrual is ∼ 227. Currently, 40 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Coleman RE, Fried G, Petrenciuc O, Sawhney A, Li R, Rugo HS. A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-04.

Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases

Abstract Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451). Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment. Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination. Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive. Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-05.

A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States.

Sponsorship for this review and article processing charges were funded by Bayer HealthCare Pharmaceuticals. Divers and Platt are employees of Bayer HealthCare Pharmaceuticals. Wang is an employee of Bayer HealthCare Pharmaceuticals and owns stock in the company. Lin and Lingohr-Smith are employees of Novosys Health, which received research funds from Bayer HealthCare Pharmaceuticals in connection with conducting this review and developing this manuscript. Mathai is a consultant to Bayer HealthCare Pharmaceuticals and also reports consulting fees from Actelion and Gilead. Study concept and design were contributed by Divers, Platt, Lin, and Mathai. Lin and Lingohr-Smith collected the data, and data interpretation was performed by Divers, Platt, Wang, and Matthai. The manuscript was written primarily by Lingohr-Smith, with assistance from the other authors, and revised by Divers, Platt, Wang, and Mathai.

Late-Breaking Clinical Trial and Clinical Science Special Reports Abstracts From the American Heart Association's Scientific Sessions 2016; Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2016.

Late-Breaking Clinical Trial and Clinical Science Special Reports Abstracts From the American Heart Association's Scientific Sessions 2016; Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2016.

An Ongoing Open-Label Phase 1/2 Study of INCB050465, a Selective PI3Kδ Inhibitor, in Patients with Previously Treated B-Cell Malignancies

Background: Signaling of PI3Kd has been implicated in proliferation, migration, and function of B cells. PI3Kd inhibitors have demonstrated clinical activity in a number of lymphoid tumor types. INCB050465 is a novel, potent, and highly specific inhibitor of PI3Kd (≥19,000-fold more selective for the d vs other isoforms) with no hepatotoxicity in preclinical evaluation at clinically relevant exposures. Here we report the emerging safety, pharmacokinetics, and efficacy results of INCB050465 monotherapy in B-cell malignancies.Methods: This phase 1/2 study (NCT02018861) enrolled patients aged ≥18 years with relapsed/refractory B-cell malignancies. After an initial single-patient cohort of oral INCB050465 5 mg once daily, a 3+3 dose escalation was conducted with doses ranging from 10 to 45 mg once daily; the dose-limiting toxicity observation period was 21 days. The 20 mg and 30 mg once daily doses were selected for monotherapy expansion. Efficacy was assessed every 9 weeks by Lugano Classification or International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria.Results: As of the data cutoff (May 20, 2016), 39 patients had been enrolled and treated with INCB050465 monotherapy. The median age was 63 and 62% were men. Subtypes included diffuse large B-cell lymphoma (n=13); Hodgkin lymphoma (HL; n=8); follicular lymphoma (FL; n=6); CLL (n=5); marginal zone lymphoma (MZL; n=4); and mantle cell lymphoma (n=3). At baseline, the median number of prior systemic regimens was 3, and the median time since diagnosis was 4.9 years. INCB050465 demonstrated low oral clearance and linear pharmacokinetics, with a terminal half-life that supports once-daily dosing. The steady-state Cavg was 15-fold greater than the whole blood IC90 at the 30-mg dose. Pharmacodynamic analysis indicated maximal inhibition of the target throughout the dosing interval at all doses tested. Patients received INCB050465 for a median duration of 82 days (range: 4+ to 382+ days); no DLTs were observed. Treatment was discontinued in 16 patients due to disease progression (n=12), adverse events (AEs; n=3), or loss to follow-up (n=1). Dose interruption occurred in 6 patients (15%) and dose reduction in 1 (3%). The most common nonhematologic AEs were nausea (33%), pyrexia (21%), and cough (18%), all of which were grade 1 or 2. All observed alanine aminotransferase (15%) and aspartate aminotransferase elevations (15%) were grade 1. Nine patients (23%) experienced 16 grade ≥3 nonhematologic AEs, 3 of which were considered treatment-related by the investigator. New or worsening grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 8%, 10%, and 15% of patients, respectively. There was 1 instance (3%) each of colitis (grade 3) and pneumonitis (grade 2). Thirteen patients (33%) experienced a serious AE (SAE); SAEs occurring in more than 1 patient included diarrhea, exfoliative dermatitis, and hypotension (n=2 each). Among efficacy-evaluable patients (n=35), the objective response rate (ORR) was 57% and varied by disease subtype (Table 1). The ORRs for non-Hodgkin lymphoma (NHL) and HL were 66% (19/29) and 17% (1/6), respectively. Objective responses were observed in both transformed and non-transformed DLBCL, and both germinal center B-cell (GCB) and non-GCB subtypes. Objective responses were observed for all 10 patients with FL or MZL. Ninety percent of objective responses were observed at the first response assessment, and responses occurred at all but the 5-mg dose.Conclusion: The linear pharmacokinetics and absence of DLTs allow INCB050465 to achieve higher levels of target inhibition at the recommended phase 2 dose (30 mg once daily) than have been reported for other PI3Kd inhibitors. INCB050465 monotherapy was well tolerated at all doses tested with no significant transaminase elevations or early-onset diarrhea, and no cases of Pneumocystis jirovecii pneumonia. Objective responses, including complete responses, were observed in both aggressive and indolent NHL. Enrollment is ongoing at the 30 mg once daily dose level. [Display omitted] DisclosuresGutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage; Incyte Corporation: Consultancy; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging. Edenfield:Astellas/Medivation: Speakers Bureau; Novartis: Speakers Bureau; Greenville Health System Cancer Institute: Employment. Dawkins:Incyte Corporation: Employment, Other: Stocks. DeMarini:Incyte Corporation: Employment, Other: Stocks. Zhou:Incyte Corporation: Employment, Other: Stocks. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Newton:Incyte Corporation: Employment, Other: Stocks. Chen:Incyte Corporation: Employment, Other: Stocks. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM).Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS).Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table).Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone.Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS [Display omitted] DisclosuresAnsell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

Targeted Inhibition of Activated Protein C Anticoagulant Activity By Monoclonal Antibody HAPC1573 for Treatment of Hemophilia

In patients with hemophilia, hereditary defects in coagulation factors result in unstable clots and recurrent bleeding. Although the current standard of care focuses on replacement factor therapy, we propose that inhibition of the anticoagulant pathways may offer novel therapeutic opportunities. Activated protein C (APC) is one of the major anticoagulants, which works by degrading factors Va and VIIIa to maintain hemostatic balance. APC also exhibits cytoprotective effects, which include antiapoptotic effects, endothelial barrier protection, and anti-inflammatory effects. Antibodies are ideally suited to inhibit the anticoagulant activity of APC while preserving its cytoprotective activity.We have developed an anti-APC monoclonal antibody (mAb), HAPC1573 (murine immunoglubulin G1/kappa), using hybridoma technology, that specifically binds to human APC (hAPC) at 3 to 7 nM binding affinity (Kd) but not to its zymogen, protein C (PC) as determined by surface plasmon resonance (SPR) using a Biacore T200 instrument (GE Healthcare, Pittsburgh, PA). To investigate the binding epitope of mAb HAPC1573, APC was inhibited with Phe-Pro-Arg-chloromethylketone (PPACK). PPACK is an irreversible inhibitor of APC and forms a covalent bond with the catalytic triad Ser195 (chymotrypsin numbering).HAPC1573 bound comparably to PPACK-hAPC and untreated hAPC coated on an enzyme-linked immunosorbent assay (ELISA) plate, suggesting that the binding epitope of HAPC1573 is located outside the active site of APC. These ELISA results were also confirmed by SPR analyses. HAPC1573 inhibited the cleavage of a small peptide substrate Spectrozyme PCa (Sekisui Diagnostics, Lexington, MA) by hAPC up to 40%. The antibody protected factors Va and VIIIa from APC-mediated inactivation in a dose-dependent manner. HAPC1573 significantly reduced activated partial thromboplastin time of hemophilic plasma and enhanced thrombin generation (assessed by thrombin generation assay) in the presence of thrombomodulin. HAPC1573 inhibited the anticoagulant activity of APC without affecting its cytoprotective functions, as measured by histone-mediated cytotoxicity assays on human umbilical vein endothelial cells (up to 300 nM HAPC1573). Given its cross-reactivity with monkey APC, the antibody was evaluated in Cynomolgus monkeys for therapeutic efficacy and safety. Intravenous administration of the antibody at 3 and 10 mg/kg significantly shortened bleeding time after injury and restored hemostasis in a dose-dependent manner in an anti-FVIII antibody-induced hemophilia monkey model (Figure). Administration of a sheep-anti-FVIII antibody (Haematologic Technologies, Inc., Essex Junction, VT) reduced plasma FVIIIa activity to below the lower limit of quantification (LLOQ; Figure [left panel]) and led to a significantly longer bleeding time in normal monkeys (Figure; right panel), recapitulating the hemophilia A phenotype. This prolonged bleeding time was partially reduced by 270 µg/kg of recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Plainsboro, NJ) used as a positive control for these studies. There was a statistically significant dose-dependent reduction in bleeding time by HAPC1573 with the 10-mg/kg dose restoring the bleeding time back to normal.This study provides in vivo proof of concept of using anti-APC antibody for hemophilia. HAPC1573 represents an anti-APC antibody with therapeutic utility for patients with hemophilia with inhibitors. [Display omitted] DisclosuresZhao:Bayer Pharmaceuticals: Employment. Yegneswaran:Bayer Healthcare Pharmaceuticals: Employment. Sim:Bayer: Employment. Patel:Bayer Pharmaceuticals: Employment. Schneider:Bayer HealthCare LLC: Employment, Patents & Royalties. McLean:Bayer: Employment, Equity Ownership. Zhu:Bayer Healthcare: Employment. Jiang:Bayer Pharmaceuticals: Employment. Gu:Bayer Pharmaceuticals: Employment. Ivens:Bayer Pharmaceuticals: Employment. Xu:Shanghai RAAS Blood Products Co.Lt: Employment, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties: Patent. Bringmann:Bayer Corporation, Parmaceuticals Division: Employment. Kauser:Bayer: Employment.

Value of Transfusion Independence in Severe Aplastic Anemia from Patients' Perspectives - a Discrete Choice Experiment

Background:Aplastic anemia is a rare, serious blood disorder due to bone marrow failure to produce blood cells. Blood transfusions are commonly used to control bleeding and relieve anemia symptoms. In severe patients, transfusions may be required more than once per week. Discrete choice experiments (DCE) can help to understand the trade-offs patients are willing to make to become less reliant on blood transfusion and symptoms associated with the condition and its treatment.Objective: To elicit patient preferences for attributes associated with treatment of severe aplastic anemia (SAA), including transfusion independence.Methods:An online DCE survey was conducted with adults diagnosed with SAA who had insufficient response to immunosuppressive therapy (IST) and experienced transfusion dependence for ≥3 months in the past 2 years. Patients were recruited though announcements in the newsletter of the Aplastic Anemia and Myelodysplastic Syndromes International Foundation and referrals from clinical sites in the U.S. and France. The survey collected information on patient characteristics, treatment, and their views on the impact of achieving transfusion independence on their life. The DCE component asked patients to choose between pairs of hypothetical treatments characterized by a common set of attributes. The attributes were selected based on focus groups conducted with patients and providers: frequency of transfusions (0, 4, and 8 per month), fatigue which interferes with daily activities like work and school (none, moderate, severe), risk of infection (low [ANC>1,000cells/mm3], moderate [500-1,000], high [<500]), and risk of serious bleeding (low [platelet count>50,000], moderate [10,000-50,000], high [<10,000]). A conditional logit model with effects coding was used to estimate part-worth utilities for different attribute levels and assess the relative importance of each attribute. Utility scores associated with different levels of transfusion frequency were also estimated.Results:30 patients meeting study criteria completed the survey. Most patients were age ≥40 years (73%), female (70%), and from the U.S. (87%). 50% of patients were diagnosed with SAA within 2 years before the survey; 33% had undergone hematopoietic stem cell transplant; and 37% had received iron chelation therapy. When asked about improvement in quality of life with a new therapy, patients most often noted the following as important: less frequent transfusions, less fatigue, and better emotional well-being (each endorsed by 97% of patients). Patients most often agreed that achieving transfusion independence would result in less burden in terms of time and costs, greater quality of life and life enjoyment, less fatigue, and greater control despite their health condition (each noted by 87% of patients) as well as less need to arrange life around medical appointments (83%). Based on the findings from the DCE, risk of bleeding was the most important factor in patient treatment preferences (0.30 relative importance), followed by risk of infection (0.28), fatigue (0.23), and frequency of transfusions (0.20), based on the range of tested attributed levels. Having more transfusions was associated with lower utility, in particular for increase in frequency of transfusions from 4 to 8 per month (Fig. 1). The mean utility scores estimated by only varying the frequency of transfusion were 0.58 with 0 transfusions per month, 0.57 with 4 transfusions per month, and 0.35 with 8 transfusions per month (Fig. 2).Conclusion:Among patients with SAA with insufficient response to IST, the estimated utility was higher with fewer transfusions. While attributes such as risk of bleeding, risk of infection, and fatigue were more important for patient treatment preferences, frequency of transfusions was also important for treatment preferences. Over 80% of patients agreed that achieving transfusion independence would result in less burden on time, less need to arrange life around medical appointments, improved quality of life, less fatigue, and feeling in control despite their health condition. [Display omitted] [Display omitted] DisclosuresPickard:Analysis Group, Novartis: Consultancy. Ivanova:Novartis: Research Funding; GSK: Research Funding; Teva: Research Funding; Lilly: Research Funding. Huynh:Novartis Pharmaceuticals Corporation, GSK: Research Funding. Totev:Novartis Pharmaceuticals Corporation, AbbVie Inc., Bayer Healthcare Pharmaceuticals LLC, Biogen Idec Inc., Boehringer Ingelheim, Bristol-Myers Squibb Company, GlaxoSmithKline, Janssen Scientific Affairs LLC, Shire Pharmaceuticals Inc.: Research Funding. Graham:Novartis Pharmaceuticals Corporation: Research Funding. Mühlbacher:Analysis Group, Novartis: Consultancy. Roy:Novartis: Employment. Duh:Abbvie: Consultancy; Allergan: Consultancy; Novartis: Research Funding; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding.

Oral Contraception and Female Sexual Dysfunction in Reproductive Women

Abstract Introduction Oral contraception (OC) remains one of the most commonly used forms of family planning. It allows couples to continue sexual activity without the worry of unintended pregnancy. However, one possible side effect of OC use is female sexual dysfunction (FSD), of which many patients and even physicians are unaware. This would be counter to the original intent of an OC and thus could affect a couple's relationship. Aim To examine the prevailing evidence on the effect of OCs on FSD in women of reproductive age. Methods A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant studies was conducted in February 2016. Relevant studies pertaining to OCs and FSD in women of reproductive age were examined. Main Outcome Measures A comprehensive review of the current literature on FSD as measured by the Female Sexual Function Index. Results Most studies indicated that women who use OC pills have decreased sexual desire and libido. OCs also can cause dyspareunia owing to increased risk of vestibulitis and vaginal dryness. This risk is increased if OCs are used in adolescents and the duration of OC use is at least 2 years. Newer OCs containing drospirenone 3 mg plus ethinylestradiol (EE) 30 μg (drospirenone 3 mg + EE 30 μg; Yasmin; Bayer Healthcare Pharmaceuticals, Inc, Berkeley, CA, USA), non-antiandrogenic progestin gestodene 75 μg plus EE 20 μg (gestodene 75 μg + EE 20 μg; Meliane; Bayer Healthcare Pharmaceuticals, Inc), and estradiol valerate plus dienogest (Qlaira; Bayer AG, Leverkusen, Germany) or EE plus levonorgestrel (Jolessa; Teva Specialty Pharmaceuticals, Petah Tikva, Israel; and Seasonale; Duramed Pharmaceuticals, Augusta, GA, USA) do not seem to cause OC-related FSD symptoms. Conclusion This review suggests that OCs can cause FSD in reproductive women. Domains that include female sexual interest and arousal and genito-pelvic pain are affected. Newer OCs such as drospirenone 3 mg plus EE 30 μg (Yasmin) and gestodene 75 μg plus EE 20 μg (Meliane) could be better alternatives because FSD symptoms are less likely to occur.

Tackling Health System Delays for Cancer Patients in LMICs: An Innovative Multicomponent Programmatic Intervention in Botswana

Abstract 67 Background: Health system delays are a major contributor to poor outcomes among cancer patients in low- and middle-income countries (LMICs). In Botswana, while median time from cancer-related symptom onset to first presentation at local health facility is 29 days, median time to initiation of cancer treatment is 401 days. Challenges to timely diagnosis and care include clinicians' lack of knowledge, limited diagnostic capacity, poor coordination between facilities, and socioeconomic barriers of patients that impede follow-up. We sought to develop an intervention to improve access to prompt cancer care. Methods: Participating facilities are all public health facilities (21 health posts, 14 clinics, 2 hospitals) in Botswana's Kweneng-East district as well as the national referral hospital. The five components of intervention are a) training of clinicians at primary facilities on evaluation of patients with suspected cancer, b) implementation of a standardized referral algorithm for cancer suspects, c) introduction of care-coordinator role to support patient and clinician navigation of the health system, d) use of SMS-based platform to support follow-up, e) provision of transport support for vulnerable patients. The primary endpoints are stage at cancer diagnosis and time from initial presentation to initiation of cancer treatment. Evaluation of the intervention's impact will include comparing endpoints following intervention with those at baseline and those among patients residing outside the Kweneng-East district. Results: Implementation of the above multi-component intervention will be presented, including a standardized algorithm to guide the evaluation, triage and referral of patients, an intensive one-day didactic training program that adapts curricula employed in the region, and the impact of training on knowledge. Conclusion: In conducting this study, we hope to identify effective program-based measures to reduce delays and improve cancer outcomes in Botswana. These measures may be scaled to other districts, and may be applicable to similar settings in the region. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Neo M. Tapela No relationship to disclose Malebogo Pusoentsi No relationship to disclose Kerapetse Botebele No relationship to disclose Michael Peluso No relationship to disclose Isaac Nkele No relationship to disclose Jason Efstathiou Honoraria: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Consulting or Advisory Role: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Tomer Barak No relationship to disclose Scott Dryden-Peterson No relationship to disclose

Demographic Characteristics and Preliminary Outcomes in a Cohort of HIV-Positive Patients With Kaposi's Sarcoma in a High ART Coverage Setting: A Report from Botswana

Abstract 50 Objective: Despite antiretroviral treatment coverage exceeding 90% by government estimates, Kaposi sarcoma (KS) remains the most prevalent malignancy in Botswana. Incidence has decreased minimally over the last decade. We sought to explore reasons for persistent high incidence and describe KS outcomes. Methods: Since 2010, consenting patients presenting to one of three oncology centers for KS treatment were enrolled prospectively and followed quarterly. Baseline HIV testing performed and records abstracted through April 2015. Results: 207 KS patients enrolled, 60% (125) with clinical diagnosis, 34% (71) with pathologic diagnosis, and 11 (6%) with radiologic/other diagnosis. Median age at diagnosis was 37 years (IQR: 11.9) and 63% (133) male. At presentation, 65% (134) had cutaneous and 24% (49) had disseminated disease. Revised ACTG staging was 8% (17) stage I, 54% (112) stage II, 35% (73) stage III. Nearly all, 98% (199), were HIV-infected with median nadir CD4 190 cells/μL (IQR: 208). Among HIV-infected patients, 68% (109) were not on ART at time of KS diagnosis and 26% (42) were diagnosed within first six months of ART. Of those not yet on ART, 72% (47) of men and 28% (18) of women had CD4 &lt;250 cells/μL, p=.0004. Few cases, 6 (10%), developed in patients on ART for &gt;6 months. Patients not on ART were referred to start. 71% (146) received chemotherapy and 7% (15) required radiation. After median follow-up 19 months, 21% (43) patients had died. Estimated 3-year OS was 76% (95% CI: 69-82%). Gender, ART duration, disease extent, and stage did not significantly predict survival. Conclusions: With high population ART coverage, KS development among individuals with CD4&lt;250 cells/μL accounts for majority of cases referred for oncologic treatment. ART delay, particularly among men, also contributed to persistent KS burden. Overall survival with KS in Botswana is similar to US and Europe. Initiation of ART at higher CD4 thresholds is needed to control the KS epidemic. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Shekinah N. Elmore No relationship to disclose Elizabeth S. Bigger No relationship to disclose Mukendi K.A. Kayembe No relationship to disclose Zola Musimar No relationship to disclose Gita Suneja No relationship to disclose Jason A. Efstathiou Honoraria: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Consulting or Advisory Role: Medivation/Astellas, Bayer Healthcare Pharmaceuticals Scott Dryden-Peterson Patents, Royalties, Other Intellectual Property: UpToDate

Sequential Therapies and the Cost-Effectiveness of Treating Metastatic Colon Cancer Patients.

Technological advances in colon cancer treatment have significantly increased survival outcomes among metastatic patients. With different chemotherapy and biologic regimens administered in first, second, and subsequent lines of treatments, costs and survival outcomes vary considerably. However, there is little evidence on how the type of regime administered in the first line of treatment affects the costs and survival outcomes of the second line of treatment. To examine how the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients varies by the type of regimen administered in the first line of treatment. The Surveillance, Epidemiology and End Results (SEER) cancer registry was used, which is linked with the Medicare claims database, to study elderly metastatic patients diagnosed between 2003 and 2009. Average survivals are estimated using the robust nonparametric Kaplan-Meier method. Selection bias was adjusted for using inverse probability weighting and censoring using robust nonparametric methods of estimating the average of total health care costs. Mean incremental survival was 6.7 months for patients who received second-line treatment (95% CI = 5.7-7.7) compared with those receiving only first-line treatment. However, the mean incremental survival varied between 4 months (95% CI = 0.0-7.3) and 9 months (95% CI = 6.5-11.0) depending on whether fluorouracil with or without leucovorin, irinotecan, oxaliplatin, or other agents were administered in first-line treatment. The mean incremental cost associated with receipt of second-line treatment was $60,231 (95% CI = 52,461-64,198) but ranged between $55,368 (95% CI = 48,294-61,290) and $71,211 (95% CI = 43,168-99,667), depending on the type of regimen administered in the first-line treatment. Combining survival benefits and costs, the incremental cost-effectiveness ratios per life-year gained associated with the receipt of second-line treatment were $97,368 (95% CI = 80,415-117,965); $110,621 (95% CI = 89,560-133,961); $130,689 (95% CI = 101,459-171,918); and $247,951 (95% CI = 112,629808,976) when irinotican, fluorouracil/leucovorin, oxaliplatin, and "other" combinations were, respectively, administered in first-line treatment. In addition, the results varied depending on which statistical method was used. When therapies are administered in a sequential manner, the cost-effectiveness of the second line of therapy depends on what was administered in the first line of therapy. Bayer Healthcare Pharmaceuticals provided funding for this project. Onukwugha has received research funding from Bayer and Amgen and has a consultant/advisory relationship with Jansen Analytics at Johnson & Johnson. Seal was formerly an employee of Bayer and holds stock in Bayer. Mullins has research funding sponsored by Bayer and Pfizer and has a consultant/advisory relationship with Bayer, Amgen, BMS, Genentech, GSK, Novartis, NovoNordisk, and Pfizer. Woldemichael and Nader report no conflicts of interest. All authors contributed to the concept and design of this study. Onukwugha, Seal, and Mullins collected the data, with assistance from Woldemichael and Hanna, while Woldemichael interpreted the data, assisted by the other authors. The manuscript was written primarily by Woldemichael, with assistance from the other authors, and revised by Seal, Hanna, and Mullins, with assistance from Woldemichael and Onukwugha.

Acute side effects of three commonly used gadolinium contrast agents in the paediatric population.

To determine the incidence of acute side effects of three commonly used gadolinium contrast agents in the paediatric population. A retrospective review of medical records was performed to determine the incidence of acute adverse side effects of i.v. gadolinium contrast agents [MultiHance(®) (Bracco Diagnostics Inc., Princeton, NJ), Magnevist(®) (Bayer Healthcare Pharmaceuticals, Wayne, NJ) or Gadavist(®) (Bayer HealthCare Pharmaceuticals)] in paediatric patients. 40 of the 2393 patients who received gadolinium contrast agents experienced acute side effects, representing an incidence of 1.7%. The majority of the acute side effects (in 30 patients) were nausea and vomiting. The incidence was significantly higher in non-sedated patients (2.37% vs 0.7%; p = 0.0018). Furthermore, without sedation, the incidence of both nausea and vomiting was significantly higher in children receiving MultiHance, with a 4.48% incidence of nausea when compared with Magnevist (0.33%, p < 0.0001) and Gadavist (0.28%, p < 0.0001) and a 2.36% incidence of vomiting compared with those for Magnevist (0.50%, p = 0.0054) and Gadavist (0.28%, p = 0.014), whereas no difference was observed between Magnevist and Gadavist within the power of the study. In addition, there was no apparent difference between any of the three contrast agents for the incidence of allergy or other acute side effects detected, given the sample size. The gadolinium contrast agents MultiHance, Magnevist and Gadavist have a low incidence of acute side effects in the paediatric population, a rate that is further reduced in moderately sedated patients. MultiHance demonstrated significantly increased incidence of gastrointestinal symptoms compared with Magnevist and Gadavist. The incidence of acute side effects of three commonly used gadolinium contrast agents was determined in the paediatric population, which can have clinical implications.

Technique for the Laparoscopic Removal of Essure Microinserts

Study ObjectiveTo describe our technique for the laparoscopic removal of Essure microinserts (Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ). DesignStep-by-step explanation of the procedure using video (Canadian Task Force classification III). SettingHysteroscopic sterilization using tubal microinsert devices has generally been reported to be well tolerated in terms of procedure-related pain. Persistent pelvic pain requiring microinsert removal has been described in a few case reports and series and was estimated at 0.16% of cases (7 cases [49/4,274]) in a large retrospective study. Removal is usually performed at the patient's request and/or because of persistent pelvic pain unresponsive to other treatments with no other etiologies found. In general, the pain starts at the initial insertion and persists thereafter. Both laparoscopic and hysteroscopic removal approaches have been described in the few cases reported. InterventionsIn this video, we describe our technique for the surgical management of pelvic pain resulting from Essure microinserts. We performed laparoscopic removal of bilateral Essure microinserts in a 30-year-old G3P3 (Gravida 3 Para 3) with bilateral Essure devices placed 2 years before the procedure; hysterosalpingogram confirmed appropriate placement. The patient was suffering from bilateral sharp pelvic pain since insertion that was related to positional change and movements but unrelated to periods along with menorrhagia. A pelvic ultrasound showed a small intramural uterine leiomyoma. She failed a trial of treatment of her symptoms with a levonorgestrel intrauterine device. The patient requested removal of her Essure microinserts and endometrial ablation. She underwent laparoscopic bilateral Essure microinsert removal and bilateral salpingectomy along with hysteroscopic removal of the levonorgestrel intrauterine device and endometrial ablation. Her surgery was uneventful, and she was discharged the day of the surgery. Her symptoms resolved completely after the procedure. ConclusionLaparoscopic removal of Essure microinserts in the context of persistent pelvic pain after insertion is a feasible and effective procedure and allows the avoidance of performing a hysterectomy when the patient declines this procedure. Sound knowledge of the Essure components and meticulous surgical technique are paramount for successful results.