A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy

Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP), which stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO). NESP has been shown to be safe and efficacious in patients with chronic renal failure. NESP is biochemically distinct from rHuEPO, due to its increased sialic acid content. NESP has an approximately 3-fold greater half-life. rHuEPO has been shown to be safe and effective for the treatment of chemotherapy-induced anaemia. This study assessed the safety and efficacy of NESP administered once per week, under the supervision of a physician, to patients with solid tumours who were receiving multicycle chemotherapy for up to 12 weeks. Three dose cohorts are presented in this sequential, unblinded and dose-escalating study. Thirteen to 59 patients received NESP (0.5, 1.5 or 2.25 mcg kg−1wk−1) in each cohort. Patients were monitored for adverse events, including antibody formation to NESP and for effects on haemoglobin. NESP appeared to be well tolerated. Adverse events were similar across all cohorts and were consistent with the population being studied. No antibody formation was detected over the 16-week study period and follow-up. A dose–response relationship was evident for NESP and multiple measures of efficacy, including proportion of patients responding to NESP and the mean change in haemoglobin by week 4 and end of treatment for NESP 0.5, 1.5 and 2.25 mcg kg−1wk−1cohorts (mean change in haemoglobin at end of treatment was 1.24, 1.73 and 2.15 g dl−1respectively). Controlled studies of this agent at higher doses and less frequent schedules of administration are ongoing. © 2001 Cance Cancer Research Campaig

Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer

Anaemia is a common haematologic disorder in patients with cancer and has a multifactorial aetiology, including the effects of the malignancy itself and residual effects from previous therapy. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa), a protein with additional sialic acid compared with erythropoietin (EPO), stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO) but it is biochemically distinct. NESP, with its approximately 3-fold greater serum half-life, can maintain haemoglobin levels as effectively as rHuEPO in anaemic patients with chronic renal failure and do so with less frequent dosing. We investigated the ability of NESP to safely increase haemoglobin levels of anaemic patients with non-myeloid malignancies not receiving chemotherapy. NESP was administered under the supervision of a physician at doses of 0.5, 1.0, 2.25 or 4.5 mcg kg−1wk−1for a maximum of 12 weeks. This report includes 89 patients completing the study by November 2000. NESP was well tolerated, with no reported dose-limiting toxicities or treatment-related severe adverse events. Increasing doses of NESP corresponded with increased efficacy. The percentage (95% confidence interval) of patients responding ranged from 61% (42%, 77%) in the 1.0 mcg kg−1wk−1group to 83% (65%, 94%) in the 4.5 mcg kg−1wk−1group. © 2001 Cance Cancer Research Campaig

Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies

PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of \u3e/=1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of \u3e/=1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of \u3e/=1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA

Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy

BACKGROUND: C.E.R.A. (Continuous Erythropoietin Receptor Activator) is an innovative agent with unique erythropoietin receptor activity and prolonged half-life. This study evaluated C.E.R.A. once weekly (QW) or once every 3 weeks (Q3W) in patients with anemia and advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: In this Phase II, randomized, open-label, multicenter, dose-finding study, patients (n = 218) with Stage IIIB or IV NSCLC and hemoglobin (Hb) ≤ 11 g/dL were randomized to one of six treatment groups of C.E.R.A. administered subcutaneously for 12 weeks: 0.7, 1.4, or 2.1 μg/kg QW or 2.1, 4.2, or 6.3 μg/kg Q3W. Primary endpoint was average Hb level between baseline and end of initial treatment (defined as last Hb measurement before dose reduction or transfusion, or the value at week 13). Hematopoietic response (Hb increase ≥ 2 g/dL or achievement of Hb ≥ 12 g/dL with no blood transfusion in the previous 28 days determined in two consecutive measurements within a 10-day interval) was also measured. RESULTS: Dose-dependent Hb increases were observed, although the magnitude of increase was moderate. Hematopoietic response rate was also dose dependent, achieved by 51% and 62% of patients in the 4.2 and 6.3 μg/kg Q3W groups, and 63% of the 2.1 μg/kg QW group. In the Q3W group, the proportion of early responders (defined as ≥ 1 g/dL increase in Hb from baseline during the first 22 days) increased with increasing C.E.R.A. dose, reaching 41% with the highest dose. In the 6.3 μg/kg Q3W group, 15% of patients received blood transfusion. There was an inclination for higher mean Hb increases and lower transfusion use in the Q3W groups than in the QW groups. C.E.R.A. was generally well tolerated. CONCLUSION: C.E.R.A. administered QW or Q3W showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 μg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day

Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease

BACKGROUND: Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease. However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD). METHODS: This is a post-hoc analysis of a study which enrolled a population of adults aged 35–79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000. In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels. We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia. To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures. RESULTS: In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs. 49.2 (SD 9.1); p < 0.0001]. Among patients with COPD (n = 495) the PF scores (39.9 vs. 45.4) and the PCS (41.9 vs. 45.9) were significantly lower in individuals with anemia compared to those without. In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003). There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD. CONCLUSION: In patients with moderate to very severe COPD anemia may be associated with worse HRQL. However, co-morbidities may explain part or all of this association in these patients

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

BACKGROUND: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events

Use of complementary/alternative therapies by women with advanced-stage breast cancer

BACKGROUND: This study sought to describe the pattern of complementary/alternative medicine (CAM) use among a group of patients with advanced breast cancer, to examine the main reasons for their CAM use, to identify patient's information sources and their communication pattern with their physicians. METHODS: Face-to-face structured interviews of patients with advanced-stage breast cancer at a comprehensive oncology center. RESULTS: Seventy three percent of patients used CAM; relaxation/meditative techniques and herbal medicine were the most common. The most commonly cited primary reason for CAM use was to boost the immune system, the second, to treat cancer; however these reasons varied depending on specific CAM therapy. Friends or family members and mass media were common primary information source's about CAM. CONCLUSIONS: A high proportion of advanced-stage breast cancer patients used CAM. Discussion with doctors was high for ingested products. Mass media was a prominent source of patient information. Credible sources of CAM information for patients and physicians are needed

NF-KappaB expression correlates with apoptosis and angiogenesis in clear cell renal cell carcinoma tissues

<p>Abstract</p> <p>Background</p> <p>Clear cell renal cell carcinoma (ccRCC) is the most frequently encountered tumor in the adult kidney. Many factors are known to take part in the development and progression of this tumor. Nuclear factor kappa B (NF-κB) is a family of the genes that includes five members acting in events such as inflammation and apoptosis. In this study, the role of NF-κB (p50 subunit) in ccRCC and its relation to angiogenesis and apoptosis were investigated.</p> <p>Methods</p> <p>Formalin-fixed and paraffin embedded tissue blocks from 40 patients with ccRCC were studied. Expressions of NF-κB (p50), VEGF, EGFR, bc1-2 and p53 were detected immunohistochemically. The relationship of NF-κB with these markers and clinicopathological findings were evaluated.</p> <p>Results</p> <p>The expression of NF-κB was detected in 35 (85%), VEGF in 37 (92.5%), EGFR in 38 (95%), bc1-2 in 33 (82.5%) and p53 in 13 (32.5%) of 40 ccRCC patients. Statistical analyses revealed a significant relation between NF-κB expression and VEGF (p = 0.001), EGFR (p = 0.004), bc1-2 (p = 0.010) and p53 (p = 0.037). There was no significant correlation between NF-κB and such parameters as tumor grade, stage, age and sex.</p> <p>Conclusion</p> <p>The results of this study indicated that in ccRCC cases NF-κB was associated with markers of angiogenesis and apoptosis such as VEGF, EGFR, bc1-2 and p53. In addition, the results did not only suggest a close relationship between NF-κB and VEGF, EGFR, bc1-2 and p53 in ccRCC, but also indicate that NF-κB was a potential therapeutic target in the treatment of ccRCC resistant to chemotherapy.</p