Support to early clinical decisions in drug development and personalised medicine with checkpoint inhibitors using dynamic biomarker-overall survival models.

Longitudinal models of biomarkers such as tumour size dynamics capture treatment efficacy and predict treatment outcome (overall survival) of a variety of anticancer therapies, including chemotherapies, targeted therapies, immunotherapies and their combinations. These pharmacological endpoints like tumour dynamic (tumour growth inhibition) metrics have been proposed as alternative endpoints to complement the classical RECIST endpoints (objective response rate, progression-free survival) to support early decisions both at the study level in drug development as well as at the patients level in personalised therapy with checkpoint inhibitors. This perspective paper presents recent developments and future directions to enable wider and robust use of model-based decision frameworks based on pharmacological endpoints.

A multistate model for early decision-making in oncology.

The development of oncology drugs progresses through multiple phases, where after each phase, a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single-arm studies based on a set of rules to define whether the tumor improves ("responds"), remains stable, or progresses (response evaluation criteria in solid tumors [RECIST]). These decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS). With the emergence of new therapies, for which the link between RECIST tumor response and long-term endpoints is either not accessible yet, or the link is weaker than with classical chemotherapies, tumor response-based rules may not be optimal. In this paper, we explore the use of a multistate model for decision-making based on single-arm early phase trials. The multistate model allows to account for more information than the simple RECIST response status, namely, the time to get to response, the duration of response, the PFS time, and time to death. We propose to base the decision on efficacy on the OS hazard ratio (HR) comparing historical control to data from the experimental treatment, with the latter predicted from a multistate model based on early phase data with limited survival follow-up. Using two case studies, we illustrate feasibility of the estimation of such an OS HR. We argue that, in the presence of limited follow-up and small sample size, and making realistic assumptions within the multistate model, the OS prediction is acceptable and may lead to better early decisions within the development of a drug.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.

One of the main aims of early phase clinical trials is to identify a safe dose with an indication of therapeutic benefit to administer to subjects in further studies. Ideally therefore, dose-limiting events (DLEs) and responses indicative of efficacy should be considered in the dose-escalation procedure. Several methods have been suggested for incorporating both DLEs and efficacy responses in early phase dose-escalation trials. In this paper, we describe and evaluate a Bayesian adaptive approach based on one binary response (occurrence of a DLE) and one continuous response (a measure of potential efficacy) per subject. A logistic regression and a linear log-log relationship are used respectively to model the binary DLEs and the continuous efficacy responses. A gain function concerning both the DLEs and efficacy responses is used to determine the dose to administer to the next cohort of subjects. Stopping rules are proposed to enable efficient decision making. Simulation results shows that our approach performs better than taking account of DLE responses alone. To assess the robustness of the approach, scenarios where the efficacy responses of subjects are generated from an Emax model, but modelled by the linear log-log model are also considered. This evaluation shows that the simpler log-log model leads to robust recommendations even under this model showing that it is a useful approximation to the difficulty in estimating Emax model. Additionally, we find comparable performance to alternative approaches using efficacy and safety for dose-finding.

Bayesian adaptive designs in single ascending dose trials in healthy volunteers.

AIM: Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach. METHODS: A trial simulation approach was used and seven different scenarios of dose-response were tested. RESULTS: The new approach provided less biased estimates of maximum tolerated dose (MTD). In all scenarios, the number of subjects needed to define a MTD was lower with the new approach than with the traditional approach. With respect to duration of the trials, the two approaches were comparable. In all scenarios, the number of subjects exposed to a dose greater than the actual MTD was lower with the new approach than with the traditional approach. CONCLUSIONS: The new approach with Bayesian adaptive design shows a very good performance in the estimation of MTD and in reducing the total number of healthy subjects. It also reduces the number of subjects exposed to doses greater than the actual MTD.

A Composite Decision Rule of CD8+ T-cell Density in Tumor Biopsies Predicts Efficacy in Early-stage, Immunotherapy Trials.

PURPOSE: To examine whether CD8+ T-cell numbers in paired tumor biopsies in early-stage clinical trials can be used as an early indicator of clinical benefit for cancer immunotherapies. EXPERIMENTAL DESIGN: Paraffin sections of tumor biopsies were stained immunohistochemically for CD8+ T cells, which were digitally enumerated. The tumor biopsies were from cancer patients in early-phase trials testing novel immunotherapeutic agents. Paired biopsies taken before the start of treatment and on-treatment were compared. A total of 155 patients were used as the training set and an additional 221 patients were used as the validation set. RESULTS: Using the Cox proportional hazard model, a ≥0.9- increase in fold change (FC) on a ln scale in CD8+ T cells (corresponding to a 2.5-fold increase on the linear scale), from baseline, demonstrated a greater association with prolonged progression-free survival and allowed improved differentiation between groups above and below the threshold. Similarly, a ≥6.2 threshold in geometric mean of the on-treatment density (OTD) of T cells, which approximately corresponds to 500 cells/mm2, correlated with longer PFS. The combination of both criteria (FC and OTD) provided the best discrimination between clinically nonactive and active compounds. CONCLUSIONS: We propose that a composite score of CD8+ T-cell density in paired biopsies taken before and on-treatment may be a new biomarker to inform on clinical outcomes in early immunotherapy clinical trials.

C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis.

BACKGROUND: No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients. METHODS: Patients were randomized (1:1) to receive either 1.2 µg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation. RESULTS: The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups. CONCLUSION: C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients.

Issues in the assessment of non-inferiority: perspectives drawn from case studies.

Superiority claims for improved efficacy are the backbone of clinical development of new therapies. However, not every new therapy in development allows for such a claim. Some therapies per se do not try to improve efficacy further but concentrate on important aspects in safety or convenience. Such improvements can be equally important to patients, and development strategies should be available for such compounds. A three-arm design with placebo, active control and experimental treatment may be viewed as the golden standard for such compounds; however, it may be difficult if not impossible to add a placebo arm in certain diseases. In such situations, non-inferiority designs are the only development option left. This paper will highlight some of the key issues with such designs in practice and will report experience from two studies from different therapeutic areas intended for regulatory submission.

Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design.

In phase 1 dose escalation studies, dose limiting toxicities (DLTs) are defined as adverse events of concern occurring during a predefined time window after first dosing of patients. Standard dose escalation designs, such as the continual reassessment method (CRM), only utilize this binary DLT information. Thus, late-onset DLTs are usually not accounted for when CRM guiding the dose escalation and finally defining the maximum tolerated dose (MTD) of the drug, which brings safety concerns for patients. Previously, several extensions of CRMs, such as the time-to-event CRM (TITE-CRM), fractional CRM (fCRM) and the data augmented CRM (DA-CRM), have been proposed to handle this issue without prolonging trial duration. However, among the model-based designs, none of the designs have explicitly controlled the risk of overdosing as in the escalation with overdose control (EWOC) design. Here we propose a novel dose escalation with overdose control design using a two-parameter logistic regression model for the probability of DLT depending on the dose and a piecewise exponential model for the time to DLT distribution, which we call rolling-CRM design. A comprehensive simulation study has been conducted to compare the performance of the rolling-CRM design with other dose escalation designs. Of note, the trial duration is significantly shorter compared to traditional CRM designs. The proposed design also retains overdose control characteristics, but might require a larger sample size compared to traditional CRM designs.

Multistate model for pharmacometric analyses of overall survival in HER2-negative breast cancer patients treated with docetaxel.

The aim of this study was to develop a multistate model for overall survival (OS) analysis, based on parametric hazard functions and combined with an investigation of predictors derived from a longitudinal tumor size model on the transition hazards. Different states - stable disease, tumor response, progression, second-line treatment, and death following docetaxel treatment initiation (stable state) in patients with HER2-negative breast cancer (n = 183) were used in model building. Past changes in tumor size prospectively predicts the probability of state changes. The hazard of death after progression was lower for subjects who had longer treatment response (i.e., longer time-to-progression). Young age increased the probability of receiving second-line treatment. The developed multistate model adequately described the transitions between different states and jointly the overall event and survival data. The multistate model allows for simultaneous estimation of transition rates along with their tumor model derived metrics. The metrics were evaluated in a prospective manner so not to cause immortal time bias. Investigation of predictors and characterization of the time to develop response, the duration of response, the progression-free survival, and the OS can be performed in a single multistate modeling exercise. This modeling approach can be applied to other cancer types and therapies to provide a better understanding of efficacy of drug and characterizing different states, thereby facilitating early clinical interventions to improve anticancer therapy.

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial.

BACKGROUND: Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. METHODS: Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11-13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50-53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. RESULTS: Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. CONCLUSIONS: Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Mitomycin C in patients with gynecological malignancies.

Mitomycin C (MMC) is an effective cytostatic agent used in the treatment of patients with gynecological malignancies and breast carcinoma. This review presents and discusses the current treatment options with MMC in patients with breast, cervical, and vulvar carcinomas, as well as rarer gynecological malignancies. New combinations and developments are also presented and their potential clinical relevance is examined. Consequently, also for the next years a MMC-containing chemotherapy continues to be a relevant part of an individualized therapy despite numerous innovative new drugs, especially for the salvage therapy of metastatic breast cancer and the simultaneous radiochemotherapy of other gynecological malignancies.

Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients.

BACKGROUND: Hepcidin is thought to be the central regulator of iron metabolism. Iron deficiency is associated with low hepcidin concentrations, and anemia in patients with cancer is associated with high concentrations of hepcidin. STUDY OBJECTIVES: Our main objective was to assess the potential role of hepcidin for predicting response to epoetin therapy in anemic cancer patients. We also aimed to identify a cutoff value for hepcidin as a potential predictive marker for response to epoetin therapy. METHODS: Using data from 525 anemic cancer patients enrolled in 5 studies, we assessed serum hepcidin concentrations in 408 of these patients at baseline and analyzed pooled data from the 408 patients. The analysis population was separated into 2 categories using a threshold hepcidin concentration of 13 nmol/L: low hepcidin (< 13 nmol/L) and high hepcidin (> or = 13 nmol/L). RESULTS: A significantly higher percentage of responders (defined as hemoglobin increase > or = 10 g/L or > or = 20 g/L from baseline) was observed in the low hepcidin group compared with the high hepcidin group (P = 0.04 for > or = 10 g/L increase and P = 0.009 for > or = 20 g/L from baseline). There was also a statistically significant difference between the 2 groups for hematopoietic response (hemoglobin rise at least once > or = 20 g/L from baseline or at least once > or = 120 g/L) to epoetin therapy (P = 0.0004). CONCLUSIONS: The results of this analysis suggest a potential role of hepcidin serum concentrations in predicting the response to epoetin therapy.

Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA).

BACKGROUND: Conventional treatment with epoetin to manage anaemia in chronic kidney disease needs frequent administrations, changes of dose, and close monitoring of haemoglobin concentrations. We aimed to compare the effectiveness of methoxy polyethylene glycol-epoetin beta, given intravenously at 2-week or 4-week intervals, with epoetin treatment one to three times per week for haemoglobin control in haemodialysis patients. METHODS: We screened 1115 adult patients from 96 centres who had stable chronic renal anaemia and were on dialysis treatment and intravenous maintenance epoetin. We did an open-label, parallel-group, non-inferiority trial to compare two dosing intervals of methoxy polyethylene glycol-epoetin beta with standard epoetin treatment. We established baseline haemoglobin concentration and eligibility over a 4-week run-in period. 223 patients were randomly assigned to receive methoxy polyethylene glycol-epoetin beta every 2 weeks, and 224 to receive it every 4 weeks. The initial dose was based on the average epoetin dose given during the week before the switch. The primary endpoint was change in haemoglobin concentration between baseline and the assessment period. We analysed patients both by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00077610. FINDINGS: We excluded 133 of the 673 randomised patients from the per-protocol analysis because they had inadequate iron status or fewer than five haemoglobin measurements during the assessment period or needed red blood cell transfusions. The mean change from baseline haemoglobin for patients who had switched to intravenous methoxy polyethylene glycol-epoetin beta every 2 weeks (-0.71 g/L, 95% CI -2.20 to 0.77) or every 4 weeks (-0.25 g/L, -1.79 to 1.29) was non-inferior to the mean change for patients who continued treatment with epoetin (-0.75 g/L, -2.26 to 0.75) (p<0.0001 for both comparisons). Of the 666 patients who received at least one dose of study drug, the incidence of adverse events or serious adverse events did not differ between groups (p=0.30 and p=0.40, respectively). INTERPRETATION: This long-acting erythropoiesis-stimulating agent is as safe as conventional epoetin treatment, and can maintain anaemia management in haemodialysis patients when given intravenously at 4-week dosing intervals.

C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks.

BACKGROUND/AIMS: This Phase III study examined the efficacy and safety of C.E.R.A., a continuous erythropoietin receptor activator, given once every 2 weeks (Q2W) via subcutaneous or intravenous injection using pre-filled syringes, for maintaining hemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis who converted directly from epoetin therapy. METHODS: Patients (n = 336) were randomized 1:1 to continue epoetin at their current dose, route and administration interval (once to three times weekly (QW-TIW)), or receive C.E.R.A. Q2W by the same route as previous epoetin treatment for 36 weeks. Dosage was adjusted to maintain patients' Hb within +/-1.0 g/dl of baseline value and within 10.0-13.5 g/dl. Primary endpoint was mean change in Hb between baseline and the evaluation period (weeks 29-36). RESULTS: Mean change in Hb for C.E.R.A. and epoetin was 0.088 and -0.030 g/dl, respectively (endpoint Hb 11.93 and 11.86 g/dl, respectively). Analysis showed that C.E.R.A. was as effective as epoetin in maintaining Hb (p < 0.0001), and was well tolerated. The administration route had no impact on primary endpoint. CONCLUSION: Q2W C.E.R.A. administered using pre-filled syringes effectively maintains stable control of Hb in patients on dialysis who convert directly from epoetin QW-TIW.

Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study.

BACKGROUND: Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life ( approximately 130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis. METHODS: STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within +/- 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29-36). RESULTS: Most patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (-0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated. CONCLUSIONS: Stable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA.

Mitomycin C in the treatment of gastrointestinal tumours: recent data and perspectives.

Mitomycin C (MMC) is among the most effective anticancer drugs used for the treatment of a broad variety of tumours. This review summarises results of MMC-based chemotherapy in gastrointestinal tumours with special focus on current treatment options in gastric, pancreatic, biliary tract, colorectal, and anal cancer. In addition, these new developments are critically discussed with special attention to their potential clinical relevance.

Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy.

Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non-small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1.1 included allowance for best overall response after progressive disease (PD) and changes in PD definitions per new lesions (NLs) and nontarget lesions. imRECIST progression-free survival (PFS) did not count initial PD as an event if the subsequent scan showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1. Results The best overall response was 1% to 2% greater, the disease control rate was 8% to 13% greater, and the median PFS was 0.5 to 1.5 months longer per imRECIST versus RECIST v1.1. Extension of imRECIST PFS versus RECIST v1.1 PFS was associated with longer or similar OS. Patterns of progression analysis revealed that patients who developed NLs without target lesion (TL) progression had a similar or shorter OS compared with patients with RECIST v1.1 TL progression. Patients infrequently experienced a spike pattern (TLs increase, then decrease) but had longer OS than patients without TL reversion. Conclusion Evaluation of PFS and patterns of response and progression revealed that allowance for TL reversion from PD per imRECIST may better identify patients with OS benefit. Progression defined by the isolated appearance of NLs, however, is not associated with longer OS. These results may inform additional modifications to radiographic criteria (including imRECIST) to better reflect efficacy with CIT agents.

Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial.

BACKGROUND: C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients. STUDY DESIGN: Open-label, multicenter, randomized, parallel-group, phase 3 study. SETTING & PARTICIPANTS: Dialysis patients (age >or= 18 years). INTERVENTION: Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly. OUTCOMES & MEASUREMENTS: The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population. RESULTS: Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated. LIMITATIONS: Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin. CONCLUSIONS: Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

Efficacy and tolerability of intravenous continuous erythropoietin receptor activator: a 19-week, phase II, multicenter, randomized, open-label, dose-finding study with a 12-month extension phase in patients with chronic renal disease.

BACKGROUND: A continuous erythropoietin receptor activator (C.E.R.A.) is currently in development for the treatment of anemia in patients with chronic renal disease (CRD) receiving or not receiving dialysis treatment. OBJECTIVES: The objectives of this study were to determine the optimal dose and administration schedule for IV C.E.R.A. in patients with CRD previously treated with IV epoetin alfa TIW, and to assess its tolerability profile in these patients. In addition, a 12-month extension phase was used to assess the long-term efficacy and tolerability of C.E.R.A. METHODS: This randomized, open-label, dose-finding study was conducted at 14 study centers across the United States. Male and female patients aged >/=18 years with CRD and CRD-related anemia and receiving treatment with IV epoetin alfa were enrolled. After a 2-week run-in period in which all patients continued to receive their previous epoetin treatment TIW, patients were switched to C.E.R.A. at 1 of 3 doses, determined by multiplying the previous weekly epoetin dose by 1 of 3 ratios (0.25 pg/150 IU, 0.4 pg/150 IU, or 0.6 pg/150 IU). Within each dose group, patients were randomized to 1 of 2 frequency subgroups: QW or Q2W Dose adjustments were not permitted during the first 6 weeks; the total dose during this period was the same for a particular dose group across the frequency subgroups. The primary efficacy parameter was change in hemoglobin (Hb) standardized to a 6-week period between baseline and the point when the patient had a dose change or blood transfusion, thus providing an estimate of Hb change based on starting dose. Following completion of a 19-week core period, patients could enter the 12-month extension period, aiming to maintain Hb concentrations between 11 and 12 g/dL. Adverse events (AEs) were recorded in the patients' case-report forms by the investigators throughout the study. RESULTS: A total of 91 patients entered the core period (mean age, 58 years; 66% male); 10 patients withdrew prematurely during this period (4 owing to AEs and 6 for other reasons). Fifty-three patients continued into the extension period; 22 patients withdrew during this period (6 because of AEs, and 16 for other reasons). There was a significant dose-response effect (P < 0.001) and a significant effect of schedule (P < 0.002) for the primary efficacy end point. Stable Hb concentrations were maintained throughout the study (11-12 g/dL, with a narrow 95% CI). No significant difference between schedules was observed during the extension period, and few dose changes were required (mean, 4 and 2 per patient per year in the QW and Q2W groups, respectively). Nineteen and 22 patients experienced serious AEs during the core and extension periods, respectively, but only 1 event was considered related to study treatment. The most frequent AEs were headache and vomiting during the core study period and dizziness, fatigue, chest pain, and pyrexia during the extension period. CONCLUSIONS: In this study, N C.E.R.A. provided effective maintenance of Hb concentrations in patients receiving dialysis treatment who were switched directly from N epoetin alfa TIW to N C.E.R.A. QW or Q2W C.E.R.A. was generally well tolerated.