MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Wolfgang Winkelmayer ◽  
James A Tumlin ◽  
Steven Fishbane ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Reticulocyte Count ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Cardiovascular Safety ◽  
Open Label ◽  
Phase 3 ◽  
Evaluation Period ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within <16 weeks with limited or no prior ESA exposure and >12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase >1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.

scholarly journals MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Mark Koury ◽  
Pablo E Pergola ◽  
Prabir Roy-Chaudhury ◽  
Youssef Farag ◽  
Dennis Vargo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Darbepoetin Alfa ◽  
Hypoxia Inducible Factor ◽  
The United States ◽  
Target Range ◽  
Phase 3 ◽  
Two Phase ◽  
Prolyl Hydroxylases ◽  
Safety Outcome

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be <10.0 g/dL, and for the ESA-treated NDD-CKD trial (NCT02680574), the range had to be from 8.0-11.0 g/dL in the United States (US) and from 9.0-12.0 g/dL non-US. In the ESA-untreated trial, patients received no ESA within 8 weeks before randomization; in the ESA-treated trial, patients were maintained on ESA therapy, with ≥1 dose received within 6 weeks prior to or during screening. The vadadustat starting dose was 300 mg/day for all patients, whereas the initial darbepoetin alfa dose depended on each patient’s prior dose or the product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) both during the primary (PEP; weeks 24-36) and secondary (SEP; weeks 40-52) evaluation periods. Herein, we present topline results from the PEP and SEP endpoints, in addition to more detailed erythrocyte parameters. Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase >1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

MO542MOLIDUSTAT FOR ANAEMIA IN JAPANESE PATIENTS UNDERGOING PERITONEAL DIALYSIS: A SINGLE ARM, OPEN-LABEL, PHASE 3 STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Tadao Akizawa ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Kentaro Taki ◽  
Yasuhiro Hayashi ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Japanese Patients ◽  
Target Range ◽  
Renal Anaemia ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Maintenance Haemodialysis ◽  
Rescue Treatment

Abstract Background and Aims Erythropoiesis-stimulating agents (ESA) are the standard of care for anaemia due to chronic kidney disease (renal anaemia). Molidustat, a novel hypoxia-inducible factor prolyl hydroxylase (HIF–PH) inhibitor for the treatment of renal anaemia, could offer an alternative to ESAs. Molidustat was evaluated in the “molidustat once daily improves renal anaemia by inducing erythropoietin (MIYABI) program”, comprising five phase 3 studies. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anaemia undergoing peritoneal dialysis (PD) and previously treated with ESAs or not. Method This was a 36-week, open-label, single-arm, phase 3 study in Japanese patients ≥20 years with renal anaemia undergoing PD and not expected to start maintenance haemodialysis. Molidustat was administered once daily at a starting dose of 75 mg. Doses were titrated every 4 weeks based on the patient’s haemoglobin (Hb) response to the previous dose during visits to maintain the Hb level within the target range of ≥ 11.0 g/dL to < 13.0 g/dL (Japanese guidelines). The primary efficacy outcome was the responder rate, defined as the proportion of patients who meet all of the following criteria: (1) mean Hb level during the evaluation period in the target range from week 30 to week 36; (2) ≥50% of Hb values within the target range during the evaluation period; (3) no rescue treatment before the end of the evaluation period. Other outcomes included mean Hb level during the evaluation period and its change from baseline, Hb level at each visit and the number of treatment-emergent adverse events (TEAEs). Results Overall, 51 patients received molidustat (49 ESA-treated; 2 ESA-untreated) and 36 (70.6%) completed treatment. Mean age was 63.3 years, mean body weight was 62.4 kg and 62.7% were male. Mean baseline Hb level was 11.19 g/dL and mean duration of peritoneal dialysis was 2.8 years. Over the study period, mean treatment duration was 200.8 days with a mean dosage of 93.8 mg/day. The responder rate (95% confidence interval [CI]) during the evaluation period was 54.9% (40.3, 68.9). The proportions of patients meeting criterion (1), (2) or (3) were 54.9%, 58.8% and 92.2%, respectively. The mean (95% CI) for mean Hb level during the evaluation period was 11.18 (10.83, 11.54) g/dL and the mean (95% CI) for the change in mean Hb level during the evaluation period from baseline was 0.00 (–0.41, 0.41) g/dL. Mean Hb level stayed in the target range from week 12–36. Of the 15 patients who did not complete treatment, 9 discontinued because of a TEAE, 4 initiated rescue treatment and 2 progressed to maintenance haemodialysis. Overall, 98.0% of patients experienced ≥1 TEAE during the study; most TEAEs were mild (49.0%) or moderate (37.3%) in intensity. The most common TEAEs were nasopharyngitis (35.3%), constipation and medical device site infection (11.8% each). No deaths were reported, and major adverse cardiovascular events occurred in 2.0% of patients. Conclusion In this phase 3, single-arm, open-label study, over 70% of patients completed the study and more than half of the patients met the responder criteria. Molidustat maintained Hb in the prespecified range (≥ 11.0 g/dL to < 13.0 g/dL) and was well-tolerated over the 36 weeks of treatment. Molidustat offers a potential alternative to ESAs in patients with renal anaemia undergoing PD.

Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD

2021 ◽  
pp. ASN.2020091311
Author(s):  
Masaomi Nangaku ◽  
Kazuoki Kondo ◽  
Yoshimasa Kokado ◽  
Kiichiro Ueta ◽  
Genki Kaneko ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Randomized Study ◽  
Hypoxia Inducible Factor ◽  
Safety Data ◽  
Japanese Patients ◽  
Open Label ◽  
Phase 3 ◽  
Cardiovascular Morbidity And Mortality ◽  
The Difference ◽  
Average Hemoglobin

BackgroundStandard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo.MethodsIn this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs.ResultsA total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0–13.0 g/dl), and the lower 95% confidence limit for the difference between groups (−0.50 g/dl) was above the predefined noninferiority margin (−0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation.ConclusionsIn Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.

scholarly journals A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

2021 ◽  
pp. 1-9
Author(s):  
Tadao Akizawa ◽  
Masaomi Nangaku ◽  
Takuhiro Yamaguchi ◽  
Ryosuke Koretomo ◽  
Kazuo Maeda ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Binding Capacity ◽  
Hypoxia Inducible Factor ◽  
Intravenous Iron ◽  
Target Range ◽  
Maintenance Hemodialysis ◽  
Phase 3 ◽  
Evaluation Period ◽  
The Mean

<b><i>Introduction:</i></b> Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis. <b><i>Methods:</i></b> Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to &#x3c;12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20–24 (noninferiority margin: −1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0–4. <b><i>Results:</i></b> The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was −0.12 g/dL (95% CI: −0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA. <b><i>Discussion/Conclusion:</i></b> Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

scholarly journals Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial

2021 ◽  
pp. 1-13
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
The Mean ◽  
Change In Mean

<b><i>Introduction:</i></b> Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the “Molidustat Once Daily Improves Renal Anemia by Inducing EPO” (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. <b><i>Methods:</i></b> This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3–5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and &#x3c;13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. <b><i>Results:</i></b> In total, 162 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was −0.38 (−0.67, −0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. <b><i>Discussion/Conclusion:</i></b> In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

scholarly journals Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study

2021 ◽  
pp. 1-10
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Erythropoiesis Stimulating Agents ◽  
Previously Treated ◽  
The Mean

<b><i>Introduction:</i></b> Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. <b><i>Methods:</i></b> This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3–5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0–13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. <b><i>Results:</i></b> In total, 164 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48–11.85] g/dL) and darbepoetin (11.53 [11.31–11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (−0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. <b><i>Discussion/Conclusion:</i></b> Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

A phase 3 open-label, randomized, multicenter study of Imprime PGG in combination with cetuximab in patients with KRAS wild type metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS787-TPS787
Author(s):  
Richard Dale Huhn ◽  
Jamie Lowe ◽  
Michele Grady ◽  
Corina Candiani Taitt ◽  
Michele Anne Gargano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
The United States ◽  
Wild Type ◽  
Open Label ◽  
Phase 3

TPS787 Background: Imprime PGG (Imprime) is a novel immune modulator (complex carbohydrate biologic), which harnesses innate immune cells to enhance killing of antibody-targeted tumor cells. In a phase 2 single-arm clinical trial in mCRC, the combination of Imprime with cetuximab resulted in 24% ORR, 62% disease control rate (DCR), and median time to progression (TTP) of 12 wks (Tamayo ME, Ann Onc 2010), representing approximate 100% increases vs historical control (Cunningham, NEJM 2004). ORR was 45%, DCR, 82% and TTP, 24 wks in pts with KRAS WT tumors (post hoc analysis). Single-agent cetuximab has been shown to improve objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients (pts) with epidermal growth factor receptor (EGFR) expressing, KRAS wild-type (WT) metastatic colorectal cancer (mCRC) who failed oxaliplatin- and irinotecan-based therapy or are intolerant to irinotecan. The mechanism of action of cetuximab is thought to rely on competitive blockade of endogenous ligand binding and downstream signaling, internalization and down regulation of EGFR, as well as antibody-dependent cellular cytotoxicity (ADCC) (Erbitux SmPC). The current trial, sponsored by Biothera (registered with ClinicalTrials.gov NCT01309126) is to confirm these findings in phase 3. Methods: Eligible pts will have had prior oxaliplatin- and irinotecan-based therapy or be intolerant to irinotecan, and will meet key inclusion criteria including measurable disease and ECOG performance status of 0 or 1. In a 2:1 randomization, stratified by geographic region, prior chemotherapy and site, approximately 795 pts will receive weekly open-label Imprime plus cetuximab or cetuximab alone. The primary endpoint of the study is OS and primary analysis will occur when ~709 deaths have occurred. Secondary endpoints include PFS, ORR (based on RECIST 1.1), quality of life, safety and pharmacokinetics. Exploratory endpoints include biomarker analyses. Pt screening and enrollment is underway in the United States and Europe. Clinical trial information: NCT01309126.

Efficacy of Darbepoetin Alfa in the Treatment of Chemotherapy-Induced Anemia in Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3296-3296
Author(s):  
Stephanie A. Gregory ◽  
Douglas W. Blayney ◽  
Saroj Vadhan-Raj ◽  
Dianne K. Tomita ◽  
Greg Rossi ◽  
...  
Keyword(s):  
Data Analysis ◽  
Darbepoetin Alfa ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Target Range ◽  
Dose Titration ◽  
Open Label ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Patient Reported

Abstract Introduction: Chemotherapy-induced anemia is common in patients (pts) undergoing chemotherapy for Non Hodgkin’s Lymphoma (NHL). Darbepoetin alfa (DA) has been shown to increase hemoglobin (Hb), decrease transfusions, and reduce fatigue. NCCN evidence-based guidelines for using erythropoietic agents recommend a target Hb of 11-12g/dL for efficacy and safety. We report here an analysis of the efficacy of DA in achieving and maintaining Hb within the target range in anemic NHL pts undergoing chemotherapy. Methods: This analysis presents the results of 2 sequentially conducted, multicenter, open-label studies with pts treated with either DA 3 mcg/kg Q2W (Study 1, SOAR) or DA 200 mcg Q2W (Study 2, SURPASS). Dose withholding rules for Study 1 required DA to be withheld when Hb >14g/dL for women and >15g/dL for men while in Study 2 DA was withheld for any pt with a Hb >13g/dL. This subset analysis involved pts diagnosed with NHL. Eligibility was similar with the 2 studies: ≥18 years, anemic (Hb <11g/dL), with non-myeloid malignancies, and receiving chemotherapy. Hematologic endpoints included Hb at end of study (EOS), percent of pts achieving target Hb (11–12g/dL) and mean Hb after reaching target. Endpoints were analyzed by the last value carried forward (LVCF) approach where missing Hb values are imputed and without imputation (available data analysis) and analyzed at week 17 unless otherwise noted. Pt reported outcomes were assessed with the FACT-F scale collected at EOS using available data analysis. Results: This analysis involved 279 pts with NHL (Study 1: n=114; Study 2: n=165). Baseline disease and demographics were similar between the 2 studies. In both studies, DA Q2W was effective in increasing Hb levels into the NCCN recommended target range (Hb >11g/dL) and improving patient reported fatigue. Dose titration rules between the studies seemed to have a different impact in the ability to maintain Hb within the range of 11–12g/dL as recommended by NCCN guidelines. When dose withholding at 13g/dL was used, the average maintenance Hb (ie, the average Hb after achieving target range) was approximately 12g/dL (Study 2) compared with 12.5g/dL if a higher withholding threshold was employed (Study 1). In Study 1, 31% of pts who achieved the target Hb range actually maintained a mean Hb above 13g/dL compared with 11% in Study 2. Interestingly, despite an approximate 1g/dL difference in final Hb achieved, higher average maintenance Hb and higher overall dose, no difference in FACT-F scores for NHL patients was observed between the 2 studies. Conclusions: Patients with NHL and anemia due to chemotherapy can be effectively treated with less frequent injections by dosing with DA 200 mcg Q2W. Summary of Endpoints Study 1 Study 2 N 114 165 Baseline Hb, g/dL (SD) 10.2 (1.1) 10.0 (0.8) Mean Hb (week 17); LVCF imputation, g/dL (SD) 12.4 (2.2) 11.3 (1.7) Mean Hb (week 17); without imputation, g/dL (SD) 13.1 (1.8) 11.9 (1.5) Pts achieving Hb target, % (n) 77% (85) 82% (131) Mean maintenance Hb after achieving target, g/dL (SD) 12.6 (1.1) 11.9 (0.9) Mean change (95% CL) in FACT-F at EOS 6.2 (3.7, 8.7) 6.1 (2.7, 9.4) Mean (SD) Q2W dose, mcg 249.4 (74.6) 184.3 (73.3)

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