Three Times Per Week Research Articles

POS-791 EVALUATION OF EFFECTIVENESS OF AN ALTERNATIVE PRESCRIPTION PATTERN OF CINACALCET FOR BETTER CONTROL OF PARATHYROID HORMONE LEVELS IN HEMODIALYSIS PATIENTS

Due to the high pill burden, non-adherence (NA) to medications is highly prevalent among hemodialysis patients. NA to Cinacalcet in particular, poses a significant challenge in controlling parathyroid hormone (PTH) levels. Perhaps an effective way to improve adherence to Cinacalcet is to reduce the frequency of administration. There is limited knowledge of the effectiveness of controlling PTH level with three times per week (TIW) Cinacalcet compared with conventional daily dosing. The objective of this longitudinal retrospective single-center observational study was to evaluate the effectiveness of three times a week (TIW) Cinacalcet dosing compared with conventional daily dosing (DD) in subsequent levels of Parathyroid Hormone (PTH) in hemodialysis patients. All adult hemodialysis patients on Cinacalcet for secondary hyperparathyroidism (sHPT) for more than six months were selected. Patients who did not have any adherence issues continued oral Cinacalcet daily (QID) while patients who were suspected to be NA to Cinacalcet or suffered from intolerance were given oral Cinacalcet three times a week (TIW) on dialysis days under direct observation of the dialysis nurse. The dose of Cinacalcet was determined by the physician to maintain PTH levels within 130 - 600 pg/ml as per KDIGO guidelines. PTH levels were monitored every other month and the dose was titrated accordingly. All these patients also received intravenous alfacalcidol and phosphate binders at the discretion of the physician to maintain adjusted calcium and phosphate levels within the KDIGO recommendations. The primary endpoint of the study was to assess whether TIW dosing was more effective than QID dosing in terms of maintaining PTH levels within the KDIGO recommended range. Data regarding patients’ acceptability, tolerability, hypocalcemia, and required weekly cumulative Cinacalcet dose were also collected. Patients were followed up for 12 months. There were 40 patients in the QID group and 52 in the TIW group. All participants in the TIW group reported acceptability and improved tolerability and hence better adherence to the dosing regimen. Some in the TIW model even reported perceived improvement in their commitment to adherence. In terms of effectiveness, the TIW group showed better monthly PTH trends compared to the QID group as illustrated by the graph below. This appeared to be sustained over the 12 months follow up period. Concomitantly, the required cumulative dose of Cinacalcet per week was also much less in the TIW group (270 mg/week) compared to the QID group (420 mg/week) suggesting a significant healthcare cost saving in long run. While there were cases of hypocalcemia observed in the QID group no such events were noticed in the TIW group. Taken together, the results of our study confirm that patients on the TID model of prescription were able to achieve and sustain the PTH levels consistent with KDIGO recommendation with much lower cumulative Cinacalcet dose with consequent lower healthcare costs. Nevertheless, we do agree that this alternative model of prescription (TIW) needs to be further validated in a prospective study before drawing stronger conclusions.

Notch pathway inhibition with LY3039478 in adenoid cystic carcinoma (ACC).

6024 Background: ACCs have high levels of Notch-1 receptor expression and activation. LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of LY in patients (pts) with ACC. Methods: Ongoing, multi-part, phase I trial enrolled pts with advanced or metastatic ACC, measurable disease, ECOG ≤1, and baseline tumor tissue. Eligible pts received LY 50 mg three times per week (TIW), on a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumor responses were assessed using RECIST 1.1. Primary objectives are to confirm the recommended phase II dose of LY and document antitumor activity. Secondary objectives are safety and toxicity, PK and progression-free survival (PFS). Exploratory objectives include assessment for PET metabolic responses. Results: 22 pts have been enrolled and received LY 50mg TIW (13 men, 9 women; median age 60, range 41-82). All pts had metastatic disease; median treatment duration was 3 cycles (range 1-10) with 6 pts continuing on treatment. One pt had an unconfirmed partial response. Disease control rate (DCR) was 16/22 (73%), of which 4 pts had stable disease ≥ 6 months. In the overall group (n = 22) median PFS (mPFS) was 5.3 months (95% CI: 2.4, NE). mPFS was 7.7 (95% CI: 4.0, NE) for pts in second line (n = 7), while mPFS was 2.4 (95% CI: 1.1, NE) for pts in third line or more (n = 9). In pts without prior systemic therapy (n = 6) mPFS could not be estimated since 4 of those patients were censored. In preliminary analysis, 14 pts were assessed by PET, with 2 (14%) achieving partial metabolic response. Most frequent related adverse events (all grades) occurring in ≥20% of pts included diarrhea (55%), fatigue (45%), vomiting (36%), decreased appetite (27%), dry mouth (27%), and dry skin (23%). Grade 3/4 related treatment-emergent adverse events observed in more than one pt were diarrhea (n = 3) and squamous cell carcinoma of skin (n = 2). PK was assessed in 17 pts, with peak concentrations occurring approximately 2 hours post-dose. Biomarker and histologic analyses of pre and post treatment biopsies will be presented. Conclusions: LY showed activity (73% DCR) in ACC with a manageable safety profile. Clinical trial information: NCT01695005.

Glatiramer acetate 40 mg/ml: A review of the results of GALA and GLACIER clinical studies

Multiple sclerosis (MS) is a demyelinating disease of the CNS, which affects mainly young able-bodied people; in this connection the problem of MS treatment assumes particular relevance. The paper reviews the main GALA (Glatiramer Acetate Low-frequency Administration) and GLACIER (Glatiramer Acetate low frequenCy safety and patient ExpeRience) clinical studies of subcutaneous glatiramer acetate (GA) 40 mg/ml three times per week (TIW). The results of the Phase III GALA multicenter randomized placebo-controlled parallel-group study of GA 40 mg injections administered less frequently (TIW) were published in 2013. The study involved 142 centers from 17 countries, including 17 Russian centers. The GALA study proved the efficacy, safety, and good tolerability of GA 40 mg TIW in patients with relapsing-remitting MS (RRMS). The safety profile of GA 40 mg was completely consistent with the well-known profile of GA 20 mg. The new GLACIER study was initiated to evaluate the efficiency and tolerability of treatment with GA 40 mg TIW versus GA 20 mg every day. This study confirmed that the tolerability profile of therapy with GA 40 mg TIW was better than that of GA 20 mg every day in patients with RRMS. GA 40 mg/ml TIW was approved for use in the USA, the United Kingdom, and a number of European countries for the treatment of patients with RRMS. In the Russian Federation, GA 40 mg was approved for use in September 2015.

Time savings of weekly versus three-times-per-week administration of erythropoiesis stimulating agents in United States dialysis patients

Objective:Previous research suggests that erythropoiesis stimulating agent (ESA) administration in dialysis is a time-consuming task and switching to less frequently dosed ESAs may offer operational efficiencies. Our objective was to describe and measure the time spent on tasks in the ESA administration process in US dialysis centers, and to estimate potential efficiency gains of using weekly (QW) administration vs three-times-per-week (TIW) administration.Methods:We conducted a time and motion study of staff time required to prepare, administer and document ESA doses. Dialysis centers using intravenous administration of TIW epoetin alfa (EPO) or QW darbepoetin alfa (DPO) were selected in pairs (one EPO, one DPO) from the same organization to help control for differences in ESA protocols and staffing patterns across organizations. ESA-related tasks were timed by trained observers. Time savings of TIW vs QW administration were estimated. Staff were interviewed about alternate activities that could be accomplished if time were saved in the ESA process.Results:A total of 200 administrations were observed (81 DPO, 119 EPO). A mean of 2.26 (95% CI: 2.1–2.5) minutes per dose were required for ESA administration. ESA process time per administration did not vary significantly between EPO and DPO (p = 0.83). Estimated potential monthly staff time savings for an average facility of 70 patients totaled 23 hours, due to fewer ESA administrations using QW DPO. Patient education and fulfillment of care plans were identified as opportunities for improved care processes that could be implemented if staff time was freed up from the ESA process.Limitations:Results should not be generalized to other countries, ESAs and/or dosing frequencies.Conclusions:Switching from TIW EPO to QW DPO can result in time savings due to fewer administrations and provide opportunities to redirect nurse time towards activities aimed at improving patient care.

Abstract 1677: Preclinical activity of Vintafolide/MK-8109 monotherapy and in combination with standard of care therapy in triple-negative breast cancer models

Abstract Vintafolide (also known as EC145 or MK-8109), is a small molecule drug conjugate for the treatment of cancers expressing high affinity folate receptor (FR). Vintafolide consists of the anti-mitotic vinca alkaloid desacetylvinblastine monohydrazide (DAVLBH) chemically linked to folic acid. Binding of vintafolide to FR located on the cell surface delivers the chemotherapy payload directly to the tumor cell. Clinical investigations of vintafolide are underway in ovarian and lung cancer, indications with a high prevalence of FR expression. Triple negative breast cancer (TNBC) may represent an additional indication for vintafolide due to the prevalence of FR expression (∼30%), sensitivity to vinca alkaloids, and unmet medical need. Vintafolide and/or DAVLBH were evaluated in preclinical models of TNBC as monotherapies and in combination with taxanes (paclitaxel or docetaxel). Taxanes represent a commonly used standard of care therapy for TNBC. A panel of TNBC cell lines was generally sensitive to DAVLBH, with IC50s ranging from 4-67 nM. In the majority of cell lines tested, DAVLBH in combination with paclitaxel provided combination benefit and induced more cell death than either single agent. Vintafolide and DAVLBH were further evaluated in vivo in the FR-high MDA-MB-231 and FR-low CAL51 TNBC xenograft models. Vintafolide was dosed at its MTD of 9.6 mg/kg three times per week (TIW), and at 1.5 mg/kg TIW. DAVLBH was dosed at its MTD of 0.77 mg/kg TIW. Mice were dosed for 3 weeks followed by a 6 week follow-up. Both vintafolide doses resulted in marked MDA-MB-231 tumor regressions of 56-78% at the end of therapy (Day 21) and 75% cures (6 of 8 mice) over the 6 week follow-up period. In the CAL51 model, vintafolide produced 8% and 76% tumor growth inhibition (TGI), respectively, at the 1.5 and 9.6 mg/kg doses, and no cures. DAVLBH was less efficacious compared to vintafolide, giving 96% TGI in the MDA-MB-231 model and 46% TGI in the CAL51 model. In mechanism of action studies in the MDA-MB-231 xenograft model, a dose of vintafolide that gave tumor regressions/cures was associated with increased phospho-histone H3 staining, indicative of a mitotic block of tumor cells, and consistent with the mechanism of action of vinca alkaloids. In combination therapy experiments in vivo, docetaxel (20 mg/kg weekly) monotherapy achieved near tumor stasis (98% TGI) of MDA-MB-231 tumors over 3 weeks of therapy, but all tumors re-grew upon cessation of treatment. Since vintafolide monotherapy at 1.5 mg/kg TIW gave significant regressions and cures, a combination benefit with docetaxel could not be determined. However, DAVLBH and docetaxel combination therapy delayed tumor re-growth over single agents upon follow-up, suggesting benefit of a vinca alkaloid / taxane combination. Taken together, these preclinical data support further investigation of vintafolide monotherapy and in combination with taxane therapy in TNBC. Citation Format: Brian B. Haines, Jennifer O'Neil, Marlene C. Hinton, Christopher Ware, Tammie C. Yeh, Tianxiao Sun, Kristen L. Picard, Theresa Zhang, Emmett V. Schmidt, Isabelle Dussault. Preclinical activity of Vintafolide/MK-8109 monotherapy and in combination with standard of care therapy in triple-negative breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1677. doi:10.1158/1538-7445.AM2014-1677

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.

A Randomized Controlled Study of Weekly and Biweekly Dosing of Epoetin Alfa in CKD Patients With Anemia

In clinical practice, physicians often use once-weekly (QW) and biweekly (Q2W) dosing of epoetin alfa to treat anemia in patients with chronic kidney disease (CKD). Although the literature supports this practice, previous studies were limited by short treatment duration, lack of randomization, or absence of the approved three times per week (TIW) dosing arm. This randomized trial evaluated extended dosing regimens of epoetin alfa, comparing QW and Q2W to TIW dosing in anemic CKD subjects. The primary objective was to show that treatment with epoetin alfa at QW and Q2W intervals was not inferior to TIW dosing. 375 subjects with stage 3 to 4 CKD were randomized equally to the three groups and treated for 44 wk; to explore the impact of changing from TIW to QW administration on hemoglobin (Hb) control and adverse events, subjects on TIW switched to QW after 22 wk. The Hb was measured weekly, and the dose of epoetin alfa was adjusted to achieve and maintain an Hb level of 11.0 to 11.9 g/dl. Both the QW and Q2W regimens met the primary efficacy endpoint. More subjects in the TIW group than in the QW and Q2W groups exceeded the Hb ceiling. Adverse events were similar across treatment groups and consistent with the morbidities of CKD patients. Administration of epoetin alfa at QW and Q2W intervals are potential alternatives to TIW dosing for the treatment of anemia in stage 3 to 4 CKD subjects.

A Comparison of Dosing Regimens of Paricalcitol Capsule for the Treatment of Secondary Hyperparathyroidism in CKD Stages 3 and 4

Background: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. Methods: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. Results: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive ≧30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca × P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. Conclusions: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive ≧30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca × P product as compared with placebo or intermittent dosing.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996–2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see Table 4). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration ⩽105 g/L, but none compared the effect of different baseline Hb levels on the response to treatment. Similarly, several studies defined the target Hb concentration as 120–130 g/L following treatment with erythropoietic proteins, but none specifically addressed the correlation between target Hb level and clinical benefit in a randomised fashion. Level I evidence shows that red blood cell (RBC) transfusion requirements are significantly reduced with erythropoietic protein therapy in patients with chemotherapy-induced anaemia or when used to prevent cancer anaemia (approximately 20% reduction compared with controls). We found indirect Level I and III evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase (absolute increases in response rate ranged from 8% to 18%). However, none of these studies examined the effect on response rates of a longer treatment period at the lower dose, or performed a randomised comparison of a dose increase versus an unchanged dose. There is Level I evidence to show that quality-of-life (QOL) is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease, particularly in patients achieving a Hb response to erythropoietic protein therapy. There are insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week (TIW) is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. There is Level III evidence that initial doses of erythropoietic proteins considered to be higher than current standard practice produce higher haematological responses in patients with chemotherapy-induced anaemia or anaemia of chronic disease. Level I evidence demonstrates that several baseline patient parameters (e.g., low endogenous erythropoietin [EPO] concentration, age <60 years, Hb concentration ⩾90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment. Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

Neurotrophin-3 improves functional constipation

Objective Neurotrophin-3 (NT-3) is a neurotrophic factor involved in the growth, development, and function of the nervous system. In preliminary studies, s.c. recombinant methionyl-human NT-3 enhanced transit throughout the GI tract and increased stool frequency in normal and constipated subjects. Our aim was to assess 1) the dose-related effects of NT-3 on bowel function, colon transit, and symptoms of chronic constipation, and 2) its safety. Methods This was a double-blind, randomized, placebo-controlled phase II study. A total of 107 patients with a diagnosis of functional constipation (Rome II criteria) were randomized to receive 4 wk of double blind, s.c. injections of either placebo, 3 mg, or 9 mg NT-3 once per week (qW) or three times per week (TTW); or 9 mg NT-3 TTW for 1 wk, then qW. The primary endpoint was the change in number of spontaneous, complete bowel movements per week. Colon transit was assessed before and at end of treatment. Results Compared with placebo, patients who received 9 mg NT-3 TTW showed significant increases in frequency of spontaneous, complete bowel movements and total bowel movements, as well as dose-related softening of stool and improved ease of passage. The number of days per week without a bowel movement also decreased, colon transit improved, as did constipation-related symptoms. Weekly dosing was ineffective. Transient injection-site reactions, seen in one third of patients receiving NT-3 TTW, were the most frequent adverse event. Conclusions NT-3, administered TTW, increased stool frequency, enhanced colon transit, and improved symptoms of chronic constipation. NT-3 seems to be a novel, safe, and effective agent for the treatment of functional constipation.