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Background The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence/duration while maintaining quality of life (QoL) and improving outcomes. Patients and Methods US community sites are enrolling non-transplant-eligible newly diagnosed multiple myeloma (MM) patients with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive ixazomib-Rd (up to 39 cycles or until progression/toxicity). Patients use mobile/wearable digital devices to collect actigraphy (activity/sleep) data and electronically complete QoL/treatment satisfaction/medication adherence questionnaires. Primary endpoint: progression-free survival (PFS); key secondary endpoints include response rates and therapy duration. Results At data cutoff, 84 patients had been treated (median age 73 years; 44% ≥ 75 years; 49% male; 15% black/African American; 10% Hispanic/Latino); 62% of patients remain on therapy. Mean duration of total PI therapy was 10.1 months and of ixazomib-Rd was 7.3 months. With 8 months median follow-up, 12-month PFS rate was 86% (95% confidence interval, 73–93) from both the start of bortezomib-based treatment and the start of ixazomib-Rd. Overall response rate was 62% (complete response [CR], 4%; very good partial response [VGPR], 25%; partial response [PR], 33%) after bortezomib-based induction and 70% (CR, 26%; VGPR, 29%; PR, 15%) after iCT. The ixazomib-Rd safety profile was consistent with previous clinical trial data. QoL/treatment satisfaction were maintained. Conclusion US MM-6 patients are representative of the real-world US MM population; iCT may permit prolonged PI-based therapy with promising efficacy, without impacting patients’ QoL/treatment satisfaction., Graphical abstract, While long-term proteasome inhibitor therapy improves outcomes in multiple myeloma, many patients cannot tolerate long-term treatment or may require/prefer to continue treatment outside the hospital/clinic. US MM-6 evaluates in-class transition from parenteral bortezomib- to oral ixazomib-based therapy in routine clinical practice. Preliminary results indicate feasibility, prolonged duration of therapy, and promising efficacy and treatment adherence/satisfaction.

Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.

e19332 Background: US MM-6 is investigating iCT from parenteral V-based induction to all-oral I-lenalidomide-dexamethasone (IRd) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence/duration while maintaining quality of life (QoL) & further improving outcomes in the diverse US community population. Methods: 21 US community sites, including VA hospitals, are enrolling non-transplant-eligible newly diagnosed MM pts with ≥stable disease after 3 cycles of V-based therapy to receive IRd. Pts use mobile & digital devices to collect actigraphy (activity/sleep) data, complete QoL & treatment satisfaction questionnaires, & self-report medication adherence. Primary endpoint: progression-free survival (PFS); key secondary endpoints include: response rates & duration of therapy. Results: As of Nov 18, 2019, 84 pts had been treated (median age 73 [range 49–90] yrs; 44% ≥75 yrs; 49% male; 15% black/African American; 10% Hispanic/Latino; 35% International Staging System stage III disease; 42% lytic bone disease). Comorbidities included hypertension (57%), anemia (44%), fatigue (43%), & peripheral neuropathy (13%). 85% of pts were receiving VRd at the time of iCT. 62% of pts are still on therapy & enrollment is ongoing. After initiating iCT, ≥complete response (CR) rate increased from 4% to 26% (Table). At 8 mos median follow-up, 6 pts had progressed & there were 2 on-study deaths. The 12-mo PFS rate was 86% (95% CI, 73–93) from the start of V-based regimen & from the start of IRd. During IRd treatment, 92% of pts had treatment-emergent adverse events (TEAEs) (48% grade [G] ≥3). G3 TEAEs (≥5% of pts) were diarrhea (7%), pneumonia (6%), syncope (6%), & anemia (5%). TEAEs led to study drug discontinuation in 7% of pts; 36% had serious TEAEs. I/R/d dose was adjusted due to AEs in 39%/39%/29% of pts. Medication adherence (cycles 1–5) was ‘excellent’/‘very good’ in ≥78% of pts reporting adherence. QoL/treatment satisfaction were maintained in pts completing questionnaires. Actigraphy data showed normal activity levels & sleep durations. Conclusions: US MM-6 pts are representative of the RW US MM population & results show that iCT to an oral PI may permit prolonged PI-based therapy with promising efficacy & without impacting pts’ QoL or treatment satisfaction. Clinical trial information: NCT03173092 . [Table: see text]

Purpose The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. Patients and Methods Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m2, days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m2 and oral prednisone 60 mg/m2, days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m2, days 1, 8, 15, and 22). The primary end point was progression-free survival. Results After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. Conclusion Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice.

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib. Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res; 17(10); 3304–15. ©2011 AACR.

Background Current chemotherapy regimens for breast cancer result in high incidences of anemia, which can be treated with erythropoietic agents. The relative efficacy of darbepoetin alfa and epoetin alfa was explored in this phase II, open-label, randomized, multicenter trial in anemic patients with breast cancer receiving chemotherapy. Patients and Methods Patients were randomized at a 1:1 ratio to receive darbepoetin alfa 200 μg every 2 weeks (n = 72) or epoetin alfa 40,000 U weekly (n = 69) for ≤ 16 weeks. Clinical and hematologic endpoints and validation of a novel patient satisfaction questionnaire for anemia treatment were evaluated for all patients randomized to receive ≥ 1 dose of study drug. Results Baseline characteristics were generally similar between treatment groups. Mean changes in hemoglobin (Hb) level from baseline were similar at 1.9 g/dL for darbepoetin alfa and 1.7 g/dL for epoetin alfa. Hematopoietic responses (≥ 2 g/dL increase in Hb level from baseline or Hb level ≥ 12 g/dL) were also similar between groups (88% for darbepoetin alfa and 81% for epoetin alfa). The proportions of patients who received a transfusion during treatment were 6% (95% CI, 0—11%) for darbepoetin alfa and 16% (95% CI, 7%–25%) for epoetin alfa. Most patients (67 patients receiving darbepoetin alfa [93%]; 61 patients receiving epoetin alfa [90%]) exhibited a clinically meaningful target Hb level ≥ 11 g/dL. No differences in safety were observed. Conclusion These results suggest that, in patients with breast cancer, darbepoetin alfa 200 μg every 2 weeks and epoetin alfa 40,000 U weekly result in comparable clinical outcomes for the treatment of chemotherapy-induced anemia.

Fatigue is a common problem among multiple myeloma (MM) patients. Armodafinil is a drug known to promote wakefulness, which is related to modafinil, a compound that improves fatigue in some cancer patients treated with chemotherapeutic agents. We investigated whether armodafinil could reduce cancer-related fatigue in MM patients. This double-blind, placebo-controlled phase 3 trial evaluated the efficacy of armodafinil in MM patients with evidence of moderate fatigue. Patients were randomized to one of two arms: treatment-only, with armodafinil given at 150 mg/daily for 56 days, or placebo-first, with placebo given on days 1–28, followed by armodafinil administered at 150 mg daily on days 29–56. Fatigue was measured on days 1 (pre-dose: baseline), 15, 28, 43, and 56 using seven separate assessments, including four patient-reported outcomes of fatigue and related quality of life measures, as well as three objective measures of cognitive function. Overall toxicities were similar between treatment groups. No significant differences were observed between the placebo-first and the treatment-only arms after 28 days. Treatment with armodafinil for 28 additional days did not produce responses. Both placebo-first and treatment-only patients showed similar significant improvements in three patient-reported measures and one objective task at day 28 compared to baseline. Placebo-first patients improved on eight additional measures (one patient-reported measure, six subscales, and one objective task), suggesting a strong placebo effect in this patient population. Evaluation and treatment of cancer-related fatigue continues to be challenging; a clear definition of this symptom and better assessment tools are needed.

Background: Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. Methods: Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. Findings: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76-0.90]; P < 0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P = 0.13). Conclusion: Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer. (C) 2012 Elsevier Ltd. All rights reserved.

Purpose To evaluate the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to dysfunctional central venous catheters (CVCs). Materials and Methods In this double-blind, placebo-controlled study, eligible patients with dysfunctional nonhemodialysis CVCs were randomly assigned to two treatment arms. In the first arm (TNK-TNK-PBO), patients received an initial dose of intraluminal tenecteplase (TNK) (up to 2 mg), a second dose of tenecteplase if indicated, and a third placebo (PBO) dose. In the PBO-TNK-TNK arm, placebo was instilled first followed by up to two doses of tenecteplase, if needed, for restoration of catheter function. After administration of each dose, CVC function was assessed at 15, 30, and 120 minutes. Results There were 97 patients who received either TNK-TNK-PBO ( n = 50) or PBO-TNK-TNK ( n = 47). Within 120 minutes of initial study drug instillation, catheter function was restored to 30 patients (60%) in the TNK-TNK-PBO arm and 11 patients (23%) in the PBO-TNK-TNK arm, for a treatment difference of 37 percentage points (95% confidence interval 18–55; P = .0002). Cumulative restoration rates for CVC function increased to 87% after the second dose of tenecteplase in both study arms combined. Two patients developed a deep vein thrombosis (DVT) after exposure to tenecteplase; one DVT was considered to be drug related. No cases of intracranial hemorrhage, major bleeding, embolic events, catheter-related bloodstream infections, or catheter-related complications were reported. Conclusions Tenecteplase was efficacious for restoration of catheter function in these study patients with dysfunctional CVCs.

BACKGROUND: Epoetin-α initiated once weekly, followed by once-every-3-weeks maintenance, was effective and well tolerated for chemotherapy-induced anemia. This study evaluated a starting dose of epoetin-α 120,000U once every 3 weeks for chemotherapy-induced anemia using early and late initiation regimens. METHODS: Patients with baseline hemoglobin 11.0-12.0 g/dL were randomly assigned to early intervention with immediate epoetin-α (n = 68) or to standard intervention with epoetin-α when hemoglobin decreased to

Background. There is a misconception that elderly cancer patients cannot tolerate standard doses of chemotherapy because of the frequency and severity of myelosuppressive complications. The reactive use of colony-stimulating factors (i.e., in response to severe neutropenia) commonly observed in this setting contributes to the frequency and severity of these complications. This study evaluated the incidence of febrile neutropenia and related events in elderly cancer patients receiving pegfilgrastim beginning with cycle 1 (proactive) in comparison with pegfilgrastim initiated after cycle 1 at the physician's discretion (reactive). Methods. Patients (≥65 years of age) with either solid tumors or non-Hodgkin's lymphoma (NHL) were randomly assigned to receive pegfilgrastim either proactively or reactively. The primary endpoint was the proportion of patients experiencing febrile neutropenia. Results. There were 852 patients enrolled (median age, 72 years). Proactive pegfilgrastim use resulted in a significantly lower incidence of febrile neutropenia for both solid tumor and NHL patients compared with reactive use. Proactive pegfilgrastim use also led to fewer hospitalizations resulting from neutropenia and febrile neutropenia by approximately 50%. Antibiotic use was lower for solid tumor patients receiving proactive pegfilgrastim and equivalent in the two NHL groups. Conclusions. This is the largest, randomized, prospective trial evaluating growth factor support in typical elderly cancer patients. Proactive pegfilgrastim use effectively produced a lower incidence of febrile neutropenia and related events in elderly patients with either solid tumors or NHL receiving an array of mild to moderately neutropenic chemotherapy regimens. Pegfilgrastim should be used proactively in elderly cancer patients to support the optimal delivery of standard chemotherapy.

The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 μg every 3 weeks) to maintain hemoglobin levels ≥10g/dl in patients with CIA (hemoglobin ≥10.5 g/dl and ≤12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to

This randomized, controlled trial evaluated the effect of darbepoetin alfa on hospitalization days, transfusion requirements, hemoglobin levels, and fatigue in patients with anemia of cancer (AOC). Eligible patients were anemic (hemoglobin ≤11 g/dl) due to cancer, ≥18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 μg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 μg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5–12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy–Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life.

This randomized, open-label, multicenter study compared the efficacy and safety of epoetin alfa (EPO) 80 000 U every 2 weeks (Q2W) to the FDA-approved regimen of 40 000 U weekly (QW) in patients with chemotherapy-induced anemia.A total of 310 patients with nonmyeloid malignancy and baseline hemoglobin (Hb)or= 11 g/dL who were scheduled to receive chemotherapy for a minimum of 12 weeks were randomized to EPO Q2W or QW for up to 12 weeks, with dose modification to maintain Hb at approximately 12 g/dL. Efficacy analyses used the per-protocol population (patients who completed the study with a value for Hb change) for the primary endpoint only and the modified intent-to-treat (mITT) population (patients who received study drug and had at least one postbaseline Hb value) for the primary and secondary endpoints.Analysis of the primary endpoint revealed that the mean change in Hb from baseline to study end was comparable between the Q2W and QW groups in the per-protocol population (1.6 g/dL vs 1.8 g/dL, respectively; treatment difference, -0.2 g/dL; one-sided 95% confidence interval [-0.56, -]); similar results were observed in the mITT population. Among patients on study at Day 29, 9.6% (13/135) and 11.1% (14/126) of patients in the Q2W and QW groups, respectively, received a transfusion between Day 29 and the end of the study (p = 0.709). Dose withholds (21% vs 42%, p0.001) and dose reductions (41% vs 59%, p = 0.003) were less common for Q2W than QW. Safety profiles were similar between groups; clinically relevant thrombotic vascular events occurred in 8% of patients in each group. The open-label dosing and the patient attrition rate did not appear to influence overall study results.Extended dosing (80 000 U Q2W) and once-weekly dosing (40 000 U QW) of EPO provided comparable safety and efficacy for chemotherapy-induced anemia.

This is the first randomized, open-label, multicenter trial designed and powered to directly compare the hemoglobin (Hb) response to epoetin alfa (EPO), 40,000 U once weekly (QW), with that to darbepoetin alfa (DARB), 200 μ g every 2 weeks (Q2W), in anemic patients with cancer receiving chemotherapy (CT). Transfusion requirements, quality of life (QOL), and safety also were evaluated. Adults with solid tumors scheduled to receive CT for ≥12 weeks and with baseline Hb ≤11 g/dl were randomized to receive either EPO 40,000 U QW (n = 178) or DARB 200 μg Q2W (n = 180) s.c. for up to 16 weeks. Doses were increased for nonresponders (Hb increase 1.3 g/dl [EPO] or >1.0 g/dl [DARB] within any 2-week period) or for an Hb level >13 g/dl. The proportion of patients achieving a ≥1-g/dl Hb rise by week 5, the primary end point, was significantly higher with EPO (47.0%) than with DARB (32.5%), and EPO-treated patients achieved a ≥1-g/dl Hb increase significantly earlier than those receiving DARB (median, 35 days versus 46 days). The mean increase in Hb from baseline was significantly higher at weeks 5, 9, 13, and the end of the study with EPO than with DARB. The number of units transfused per patient was significantly lower for the EPO group than for the DARB group. The proportions of patients requiring transfusions, mean QOL improvements, and tolerability profiles were similar in the two groups.

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp®; Amgen Inc.; Thousand Oaks, CA) 200 μg every 2 weeks (Q2W) and epoetin alfa (Procrit®; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 μg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11–13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 μg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.

Abstract 478 Background: The US community-based, phase 3b randomized, open-label, multicenter UPFRONT trial compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible multiple myeloma (MM) patients. This is the first phase 3 study of VcD and VcTD in this patient population. Methods: Patients with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc as before; T 100 mg/day, days 1–21; D as before); VcMP: Vc as before; M 9 mg/m2 and P 60 mg/m2, days 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc 1.6 mg/m2, days 1, 8, 15, 22. Patients in the VcTD arm received concomitant prophylaxis with aspirin, full-dose warfarin, or low-molecular weight heparin unless medically contraindicated. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR)/near CR (nCR) and very good partial response (VGPR) rates, overall survival (OS), and safety. Best confirmed responses were assessed by investigators per modified International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded by NCI-CTCAE v3.0. PFS and OS were estimated by Kaplan–Meier methodology. For the first time, we report results from the entire cohort of 502 randomized patients (VcD, n=168; VcTD, n=167; VcMP, n=167), who completed up to a maximum of 13 cycles of treatment. Results: Patients in the VcD, VcTD, and VcMP arms had a median age of 74.5, 73.0, and 72.0 years, respectively, and 71%, 62%, and 72% had ISS stage II/III disease. Patients received a median of 8 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles; 50%, 38%, and 42% of patients, respectively, received Vc maintenance. Response and safety data are summarized in the table. All three Vc-based induction regimens exhibited substantial activity, with ORR of 73% (VcD), 80% (VcTD), and 69% (VcMP) during the treatment period. After a median follow-up of 21.8 months, no significant difference in PFS was observed between the treatment arms; median PFS was 13.8 months (VcD), 14.7 months (VcTD), and 17.3 months (VcMP), respectively (Figure). 1-year OS estimates were 87.4% (VcD), 86.1% (VcTD), and 88.9% (VcMP). Rates of grade ≥3 AEs, serious AEs (SAEs), and discontinuations due to AEs during the treatment period were highest for the VcTD arm. The most common grade ≥3 AEs across all three arms during the treatment period were neuropathy peripheral (23%), fatigue (10%), and diarrhea (9%). Grade ≥3 pneumonia was reported in 10% (VcD), 6% (VcTD), and 6% (VcMP) of patients. AEs of deep vein thrombosis/pulmonary embolism were reported in 8% (VcD), 7% (VcTD), and 2% (VcMP) of patients. Compared with rates during induction, Vc maintenance produced little additional toxicity; across all three treatment arms, only 5% of patients experienced grade ≥3 peripheral neuropathy during cycles 9–13. One second primary malignancy (lung neoplasm) was reported in the VcMP arm. Conclusions: VcD, VcTD, and VcMP induction followed by weekly Vc maintenance produced similar activity in elderly, newly diagnosed, transplant-ineligible MM patients. Patients in the VcD doublet arm appear to have similar long-term outcomes to patients in the VcTD and VcMP triplet arms. Disclosures: Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu:GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership; Pfizer: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment.

Abstract 1864 Background: In addition to determining the efficacy and safety of different treatment options for MM, the impact of treatment and associated toxicities on patient-reported QoL should be evaluated. The US community-based phase 3b UPFRONT study compares the efficacy and safety of three bortezomib (VELCADE®, Vc)-based regimens, Vc-dexamethasone (VcD), Vc-thalidomide-dexamethasone (VcTD), and Vc-melphalan-prednisone (VcMP), followed by weekly Vc maintenance, in elderly, newly diagnosed, transplant-ineligible MM patients. Updated efficacy and safety data are reported elsewhere at this meeting; here we present patient-reported QoL results – a secondary endpoint of the trial – from all 502 randomized patients, who received up to a maximum of 13 treatment cycles. Methods: Patients with symptomatic MM were randomized (1:1:1) to receive eight 21-day cycles of VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]), VcTD (Vc as before; T 100 mg/day, days 1–21; D as before), or VcMP (Vc as before; M 9 mg/m2, and P 60 mg/m2, days 1–4, every other cycle) induction, followed by five 35-day cycles of maintenance with Vc 1.6 mg/m2, days 1, 8, 15, 22. QoL was assessed using the EORTC QLQ-C30 questionnaire, which includes global health status, physical, role, cognitive, emotional, and social functioning, and symptom scales of fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Global health status scores combine overall health and QoL scores, with higher scores reflecting better health status. Questionnaires were completed prior to dosing on day 1 of cycle 1 (baseline), prior to dosing on day 1 of every odd-numbered cycle, at the end-of-treatment visit, and every 12 weeks until progressive disease. Patient-reported QoL scores presented herein represent data collected within 1 year of randomization regardless of discontinuation status; for patients who died, missing assessments were assigned the worst possible score of 0. A linear mixed effect model was used to assess QoL changes over time, both within and between treatment arms. Sensitivity analyses were conducted to test the robustness of the primary analysis. Results: Patient baseline characteristics were well balanced across the VcD (n=168), VcTD (n=167), and VcMP (n=167) arms as reported previously (Niesvizky et al, EHA 2011). Median age was 74.5 (VcD), 73.0 (VcTD), and 72.0 (VcMP) years, and 71%, 62%, and 72% of patients had ISS stage II/III disease. QoL assessments were available at baseline and ≥1 post-baseline time point for 78% (VcD), 69% (VcTD), and 78% (VcMP) of patients. Observed data showed a downward trend in mean global health status score until cycle 7 (VcD, VcMP) or 9 (VcTD), followed by a trend to stabilizing/improving score thereafter (Figure). Symptom scores changed very little during induction in all arms, except for nausea/vomiting and diarrhea, with moderate improvements seen during maintenance. After fitting observed data with a linear mixed effect model, a significant decrease in mean global health status score from baseline to cycle 7 (induction period) was evident in all arms (VcD, p=0.0127; VcTD, p Conclusions: The observed data, linear mixed model estimates, and sensitivity analyses all show a common trend to a transient decrease in QoL during VcD, VcTD, and VcMP induction followed by a subsequent trend to improvement/stabilization in QoL during single-agent Vc maintenance. The trend to decreasing QoL seen during Vc-based induction may reflect the onset of treatment-related toxicities (particularly for VcTD, which was associated with somewhat higher toxicity rates). Post-induction improvements/stabilization in QoL may reflect the beneficial impact of achieving a response and the limited toxicity profile associated with weekly Vc maintenance. Disclosures: Niesvizky: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Onyx: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charu:Pfizer: Equity Ownership; Bristol-Myers Squibb: Equity Ownership; Roche: Research Funding; GSK: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Huang:Millennium Pharmaceuticals, Inc: Employment. Choi:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment.

8072 Background: The multicenter, phase IIIb UPFRONT study compares the efficacy and safety of 3 bortezomib (Vc)-based induction regimens, VcD (Vc–dexamethasone), VcTD (Vc–thalidomide–dexamethasone...

Abstract 619 The UPFRONT study is a US community-based, randomized, open-label, multicenter phase 3b trial comparing the safety and efficacy of three bortezomib (Velcade®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by Vc maintenance, in newly diagnosed multiple myeloma (MM) patients ineligible for high-dose therapy and stem cell transplantation. Patients with previously untreated, symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1–21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcMP: Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with weekly Vc (1.6 mg/m2, days 1, 8, 15, 22). Here we present updated results after 300 patients had the opportunity to undergo the entire 13-cycle treatment period (8 induction + 5 maintenance cycles). The primary study endpoint is progression-free survival (PFS); secondary endpoints include efficacy (overall response rate [ORR], complete response [CR]/near-CR [nCR] and very good partial response [≥VGPR] rates), safety and tolerability, and response duration. Responses were assessed by investigators using central laboratory data, applying modified International Myeloma Working Group (IMWG) criteria. Patients in the VcD, VcTD, and VcMP arms had median ages of 73.5, 73.0, and 72.0 years, respectively; 85%, 64%, and 74% had ISS stage II/III, and 22%, 27%, and 28% were non-Caucasian. Patients received a median of 9 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles (induction + maintenance); 56%, 33%, and 43% of patients, respectively, received Vc maintenance. In the VcD, VcTD, and VcMP arms, Vc dose intensity (mean ratio of doses received/doses planned) was 76%, 63%, and 69% during induction, and 73%, 77%, and 85% during maintenance, respectively. All three Vc-based induction regimens exhibited substantial efficacy after 8 cycles, with ORRs (≥PR; best confirmed response) of 68%, 78%, and 71% for VcD, VcTD, and VcMP, respectively. After 5 cycles of Vc maintenance, the ORR was increased to 71%, 79%, and 73% in the VcD, VcTD, and VcMP arms, respectively. Similar trends were seen in CR+nCR and ≥VGPR rates after Vc maintenance in the VcD, VcTD, and VcMP arms: CR+nCR rates were 24%, 36%, and 31% after induction versus 31%, 38%, and 34% after Vc maintenance, and ≥VGPR rates were 36%, 44%, and 40% after induction versus 39%, 47%, and 44% after Vc maintenance, respectively (Table). After 13 treatment cycles, the rates of grade ≥3 adverse events (AEs) were 74%, 86%, and 80% for patients in the VcD, VcTD, and VcMP arms, respectively; similar to the rates reported after 8 cycles, 70%, 84%, and 79%, respectively. After 13 cycles, the five most common grade ≥3 AEs were peripheral neuropathy (PN) (18%, 28%, and 21% for VcD, VcTD, and VcMP, respectively), fatigue (10%, 15%, 8%), diarrhea (11%, 5%, 10%), neutropenia (1%, 3%, 21%), and pneumonia (11%, 6%, 6%). The incidence of serious AEs was highest in the VcTD arm (61%, vs 57% with VcD and 51% with VcMP). All-grade PN was most frequently reported in the VcTD arm (61%), versus the VcD (49%) and VcMP (45%) arms; these rates are similar to those reported after 8 induction cycles (59%, 45%, and 43% for the VcTD, VcD, and VcMP arms). Rates of deep vein thrombosis and pulmonary embolism were 7%, 4%, and 2%, and 4%, 3%, and 1%, respectively, in the VcD, VcTD, and VcMP arms. Study drug discontinuation due to AEs was highest in the VcTD arm (41%, vs 29% with VcD and 35% with VcMP). In conclusion, maintenance with Vc monotherapy is well tolerated when administered after VcD, VcTD, and VcMP induction regimens. Response rates, including CR and ≥VGPR, improved after Vc maintenance with no concomitant increase in the incidence of PN. Patients continue to be monitored for PFS and response duration. Disclosures: Niesvizky: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: Discussion of Velcade in a novel combination in frontline myeloma is included. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc.: Research Funding. Charu:Amgen: Equity Ownership, Research Funding; Pfizer: Equity Ownership; GSK: Equity Ownership, Research Funding; Lilly: Equity Ownership, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Reeves:Celgene: Common stock in Celgene.

Abstract 173 Introduction: Central venous catheters (CVCs) are vital to the management of many acute and chronic diseases. These catheters facilitate infusion of therapeutic agents and nutritional products, withdrawal of blood and its constituents, and accurate assessment of hemodynamic variables. A common cause of CVC dysfunction is occlusion, most frequently due to thrombosis. In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to occluded CVCs. Methods: A dysfunctional CVC was defined as a catheter from which one could not withdraw 3 mL of blood (1 mL of blood for subjects weighing Results: A total of 97 subjects received TTP (n = 50) or PTT (n = 47). The mean age was 39.6 years (range, 1–87 years); 34 subjects (35.1%) were Conclusions: Tenecteplase is safe and effective for restoration of catheter function in pediatric and adult subjects with dysfunctional CVCs. Disclosures: Off Label Use: Tenecteplase is a thrombolytic agent under study for clearance of dysfunctional central venous catheters . Sandler:Governors Cancer Control and Reserach Advisory Board: Chair; Children's Oncology Group: Voting body steering committee; Wolfson Children's Hospital: Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Membership on an entity's Board of Directors or advisory committees. Charu:Glaxo-Smith-Kline: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anas:Genentech: Honoraria. Blaney:Genentech: Employment, Equity Ownership. Ashby:Genentech: Employment, Equity Ownership. Gillespie:Quintiles: Employment, Quintiles is a contract research organization contracted by Genentech to execute the TROPICS trials. Begelman:Genentech: Employment, Equity Ownership.

Abstract 129 In this US community-based, randomized, open-label, multicenter phase 3b study, we compare the safety and efficacy of three highly active bortezomib (Velcade®, Vc)-based regimens for multiple myeloma (MM), Vc–thalidomide–dexamethasone (VcTD), Vc–dexamethasone (VcD), and Vc–melphalan–prednisone (VcMP), in previously untreated MM patients (pts) ineligible for high-dose therapy and autologous stem cell transplantation. Use of these regimens is supported by data from phase 3 studies; only VcMP has been investigated specifically in elderly pts. Here we present data from a pre-specified interim analysis (IA) of 210 pts performed after the first 70 pts in each arm had the opportunity to complete four cycles of therapy. Pts with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4)], days 1, 2, 4, 5 [Cycles 5–8]), VcTD (Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1-21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4), days 1, 2, 4, 5 [Cycles 5–8]) or VcMP (Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m2, days 1, 8, 15, 22). Prophylactic aspirin, full dose warfarin, or low molecular weight heparin was administered to the VcTD arm unless medically contraindicated.The primary endpoint is progression-free survival; secondary endpoints include overall survival, duration of response, time to next therapy, quality of life (QoL) using the EORTC QLQ-C30 questionnaire, safety and tolerability, and efficacy (CR/nCR, VGPR, PR, and ORR). Responses were assessed by investigators using central laboratory data, applying the International Myeloma Working Group uniform criteria. An Independent Data Monitoring Committee (IDMC) assessed safety, tolerability, response rates and QoL data to determine which two of the three arms should continue enrolling pts. Pts in the VcD, VcTD, and VcMP arms had median ages of 74, 73, and 72 years, respectively; 83%, 58%, and 73% had ISS stage ll/lll and 21%, 22% and 32%, respectively, were non-Caucasian. In the VcD, VcTD, and VcMP arms, mean number of treatment cycles (for the first four cycles) and total Vc doses (16 doses for the first four cycles) were similar: 3.8, 3.6, and 3.7 cycles and 14.5, 13 and 13.8 Vc doses, respectively. The VcD arm had the lowest rate of adverse events (AEs) grade ≥3 (58% vs 71% each in the VcTD and VcMP arms, respectively), as well as the lowest rate of discontinuations due to AEs (10% vs 18% and 16% in the VcTD and VcMP arms, respectively). The VcTD arm had the highest rate of serious AEs (50% vs 39% and 36% in the VcD and VcMP arms, respectively), as well as peripheral neuropathy (PN) of any grade (48% vs 29% and 30% in the VcD and VcMP arms, respectively). PN grade ≥3 was 6%, 12% and 13% in the VcD, VcTD, and VcMP arms, respectively. The VcTD arm had higher rates of serious embolism/thrombosis (8% vs 6% and 3%) than in the VcD and VcMP arms, respectively. All three regimens demonstrated substantial activity. The overall response rate was 60%, 70%, and 52% in the VcD, VcTD, and VcMP arms, respectively (complete response (CR)/near CR: 13%, 18% and 15%; ≥very good partial response 15%, 23% and 24%, respectively). QoL functional scores improved in all arms, except for physical, role function and global health status, which worsened in the VcTD arm only. At a preplanned IA, the three Vc-based regimens were evaluated as having similar risk/benefit considerations after four cycles. The regimens were active with well-characterized and predictable toxicities. The study continues to enroll in all three arms as recommended by the IDMC. The UPFRONT trial demonstrates the feasibility of conducting a large, randomized, outpatient, phase 3b trial in community-based oncology centers in the United States. Disclosures: Niesvizky: Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc: Research Funding. Phooshkooru:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Charu:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Neuwirth:Millennium Pharmaceuticals, Inc: Employment.

A recently completed randomized open-label multicenter clinical trial in cancer pts with CT-induced anemia showed that an extended dose regimen of EPO 120,000 U administered subcutaneously Q3W effectively maintained hemoglobin (Hb) levels within the range of 11–13 g/dL whether initiated early (Hb of ≥11 and ≤12 g/dL) or at a standard threshold (Hb13 g/dL and dose reduced for Hb>12 g/dL or increase >1.5 g/dL in any 3-wk period (current labeling recommends Hb not to exceed 12 g/dL). If, at any dosing visit after the 1st EPO dose, Hb decreased to ≥65 Yrs

19589 Background: Reported here are the final Hb results for the group of patients enrolled under an amendment to a larger study that was the first to compare early vs standard intervention with EPO 120,000 U Q3W in patients with CIA and Hb of 11 to 12 g/dL. The amendment allowed for treatment of patients who had a Hb value 13.0 g/dL at any dosing visit; dose was reduced for Hb >12.0 g/dL or Hb increase >1.5 g/dL in a 3-week period (current prescribing information recommends target Hb not to exceed 12 g/dL). Hb response was analyzed using an observed case approach and Hb data following switch to 40,000 U QW were censored. Results: Fifty patients were enrolled under the amendment. BL characteristics were: mean age, 62.0 years; 67% female; mean Hb 10.1 g/dL. Mean Hb changes over time from BL for patients receiving Q3W dosing are shown in the table . PRBC transfusion rate after 4 weeks on treatment was 24.5%. 18.0% of patients had at least one dose withheld and 22.0% had at least one dose reduction. Five deaths and 6 clinically relevant TVEs were reported. Conclusions: This study shows that EPO is effective in raising Hb when initiated in patients with CIA and a Hb of No significant financial relationships to disclose. [Table: see text]

19501 Background: Chemotherapy-induced anemia (CIA) can be effectively treated with darbepoetin alfa (DA) using different dosing schedules. Since chemotherapy (CTX) regimens involve various dosing schedules, the ability to synchronize DA dose with CTX could be beneficial. Methods: This phase 2, 25-week (wk), randomized, open-label study compares the efficacy and safety of DA administered using an extended dose schedule (EDS) (every 2 wks [Q2W] or every 3 wks [Q3W]) vs weekly (QW) dosing in patients (pts) with CIA. Pts were randomly assigned to receive DA EDS (either 300 mcg Q2W [with CTX QW, Q2W, or Q4W] or 500 mcg Q3W [with CTX Q3W]) vs 150 mcg DA QW (with CTX QW, Q2W, Q3W, or Q4W). Randomization was stratified by length of CTX cycle, screening hemoglobin (Hb) (< 10 vs = 10 g/dL), and type of cancer (lung/gynecological vs other cancers). The primary endpoint was the change in Hb from baseline (BL) to wk 13; other endpoints included the change in Hb from BL to end of study (EOS), percentage of pts with = 1 transfusion (TFN) from BL to wk 13 and EOS, and safety. Results: Final data for the total 25-wk study period will be presented. Results from a planned interim analysis for all pts who were enrolled in the study and received = 1 dose of DA (n = 752) are shown for wk 13 endpoints (Table). The groups had similar mean change in Hb from BL to wk 13, with a difference (QW minus EDS) (95% CL) of 0.2 (-0.1, 0.4) g/dL. The % pts who achieved target Hb were also similar (difference [95% CL] = 0 [-7, 6]). At the time of the interim analysis, the incidence and types of adverse events were similar between the groups. Ten (3%) EDS and 15 (4%) QW pts had thromboembolic events, 5 (1%) EDS and 2 (1%) QW pts had cerebrovascular accidents, and 19 (5%) EDS and 22 (6%) QW pts had died. Conclusions: This is the first trial synchronizing DA dosing (Q2W and Q3W) with CTX schedules. The interim results suggest that DA administered once per CTX cycle is well-tolerated and efficacious in these patients. [Table: see text] No significant financial relationships to disclose.

19564 Background: Emerging data suggest that initiating EPO therapy earlier (at a higher hemoglobin [Hb] trigger) in the setting of active CT may provide better maintenance of Hb within a target range with no adverse safety consequence. Reported here are the final results of the first study to explore the efficacy and safety of early vs standard intervention with EPO initiated Q3W at 120,000 U. Methods: This 16-wk open-label randomized study enrolled pts with non-myeloid malignancy, baseline (BL) Hb =11.0 and =12.0 g/dL, and CT planned for =9 wks. Pts were randomized (1:1) to receive EPO 120,000 U subcutaneously Q3W immediately (early intervention group, EIG) or when their Hb fell to 13.0 g/dL at any dosing visit; dose was reduced for Hb >12.0 g/dL or Hb increase >1.5 g/dL in a 3-wk period (current prescribing information recommends target Hb not to exceed 12 g/dL). Hb response was defined as Percent Values in Range (PVR; the mean proportion of weekly Hb levels that were =11.0 and =13.0 g/dL) and by mean Hb change from BL. Hb data following switch to 40,000 U QW were censored. Results: A total of 136 pts were randomized (68 per group). Demographics were similar; BL Hb was 11.5 g/dL in both groups. PVR was 60% in the EIG and SIG. Mean Hb change from BL to final value on Q3W dosing was -0.1 g/dL in both groups. Among the 51 pts whose Hb fell below 11 g/dL in the SIG, their Hb decreased to a mean of 10.4 g/dL before initiation of EPO. Their subsequent mean Hb increase was 0.7 g/dL at the final visit on Q3W therapy. PRBC transfusion rates after the first 4 wks of EPO treatment were 8.8% (6/68) and 7.8% (4/51) for the EIG and SIG, respectively. In the EIG vs SIG, EPO was withheld in 38% vs 22% of pts and reduced in 43% vs 26% of pts. Two deaths and 6 clinically relevant TVEs while on EPO treatment were reported in each group. Conclusions: This is the first study to show EPO may be initiated at 120,000 U every 3 wks. Hb outcomes in the EIG and SIG were similar. These data provide further evidence that half-life of erythropoietins may not correlate with their effectiveness when used at extended dosing intervals. Future research is warranted. No significant financial relationships to disclose.

Cancer pts with CIA may experience decreased quality of life (QOL) and may require red blood cell transfusions (TFNs). DA increases hemoglobin (Hb) to levels recommended by practice guidelines (11 to 13g/dL), thereby reducing TFN requirements and improving QOL. With chemotherapy (CTX) regimens involving various dosing intervals, being able to synchronize DA dose with CTX could be beneficial. This ongoing phase 2, 25-wk, randomized, open-label, multicenter trial compares the efficacy of DA extended dosing schedule (EDS) administration (every 2 wks [Q2W] or every 3 wks [Q3W]) with DA administered weekly (QW) in pts with CIA. Eligible pts were ≥18 years, had nonmyeloid malignancies, were anemic (Hb Table QW EDS n=245 n=242 *Least squares mean; **Last value carried forward; KM: Kaplan-Meier. Mean (SD) Age, yrs 61.9 (12.8) 62.6 (13.2) Most common tumor type (%) Breast (27) Breast (31) % Pts with stage IV cancer 51 52 Mean (SD) BL Hb (g/dL) 10.1 (0.9) 10.2 (0.8) Mean* (99.9%CL) change in Hb (BL-wk 13) [n] (LVCF**) (g/dL) 1.0 (0.7,1.3) [244] 0.9 (0.5,1.2) [241] KM% (99.9%CL) pts who achieved target Hb (≥11g/dL) [n] 78 (68,89) [210] 76 (65,87) [215] Crude% (99.9%CL) pts who achieved target Hb (≥11g/dL) [n] 70 (59,80) [210] 64 (54,75) [215] Mean (SD) Hb after achieving target (g/dL) [n] 11.6 (0.8) [182] 11.7 (0.7) [166] KM% (99.9%CL) pts who had TFNs [n] 21 (12,29) [245] 22 (13,31) [242] Mean* (SE) change in FACT-F [n] 1.6 (0.85) [161] 2.7 (0.84) [168]

Background: Darbepoetin alfa (Aranesp®; DA) has been shown to be safe and effective for treating chemotherapy-induced anemia (CIA). The ability to administer darbepoetin alfa every 3 weeks (Q3W) (coincident with chemotherapy) would simplify the treatment of CIA. We report results from the first multicenter, randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluating efficacy and safety of fixed Q3W administration of an erythropoietic agent. Methods: This study enrolled subjects ≥18 years, diagnosed with anemia (hemoglobin [Hb] Results: A total of 386 randomized patients were included in the analysis. Demographic characteristics were similar between the 2 groups. Mean (SD) Hb levels at baseline were 10.03 (0.86) and 10.05 (0.92) g/dL in the placebo and DA groups, respectively. The most common tumor types were breast (23%), colon (11%), nonsmall-cell-lung cancer (10%), and hematologic malignancies (11%; 8% Non-Hodgkin’s Lymphoma). The incidence of RBC transfusions from week 5 to the end of treatment phase (EOTP) (the primary endpoint) was significantly lower for the DA group than for the placebo group (P Conclusions: Fixed Q3W administration of DA is well tolerated and effective for the treatment of CIA. Summary of Results Placebo Darbepoetin alfa KM = Kaplan-Meier estimate Week 5 to EOTP N=185 N=181 Transfusions, KM (95% CL) (primary endpoint) 41% (34, 49) 24% (18, 30) Achievement of target Hb, KM (95% CL) 48% (41, 56) 82% (76, 88) Week 1 to EOTP N=193 N=193 Transfusions, KM (95% CL) 47% (40, 54) 30% (23, 36) Median time to target Hb, weeks (95% CL) 12 (9, 16) 6 (3, 7) Figure Figure

Introduction: Although non-Hodgkin’s lymphoma (NHL) is frequently diagnosed in older patients, few randomized clinical trials are conducted in this setting. Furthermore, older patients who are included in clinical studies are a highly selected group and are not likely to be representative of patients treated in the community. Increased age is an established risk factor for chemotherapy-induced neutropenia, and older patients often receive suboptimal doses of chemotherapy as a result, especially in community practice (Lyman et al, J Clin Oncol2004;22:1–10). In a large (n=528) study of older patients with diffuse large B-cell lymphoma receiving CHOP or R-CHOP with no cycle-1 growth factor, 41% of patients had febrile neutropenia over all cycles and 20% in cycle 1 (Morrison et al, ASH 2004 poster). The benefit of pegfilgrastim in supporting moderately to highly myelosuppressive chemotherapy regimens has previously been shown. Methods: As part of a large (n=852), prospective, randomized, open-label study, we assessed the effectiveness of first-cycle pegfilgrastim among patients ≥ 65 years old receiving chemotherapy for NHL in community practice. Patients were randomized to 1 of 2 treatment arms - pegfilgrastim in first and subsequent cycles (Arm A) or no pegfilgrastim in cycle 1 with subsequent use at the physician’s discretion (Arm B). Results: The primary analysis set included 146 patients with NHL, 73 per treatment arm. Median age was 73 years, range 65 to 87, with nearly 75% of patients aged 70 and older. R-CHOP was the most common chemotherapy, administered to 82% of patients. The overall incidence of febrile neutropenia was significantly lower for patients in Arm A (15%; [95% confidence limit (CL): 8, 25]) compared with patients in Arm B (37% [95% CL 26, 49]; p=0.0043). The first cycle incidence of febrile neutropenia was also lower in Arm A (7% [95% CL: 2, 15]) than in Arm B (25% [95% CL: 15, 36]), as was the overall incidence of hospitalization due to neutropenia-related events (17% [95% CL: 10, 28] vs 37% [95% CL: 26, 49]). Pegfilgrastim was administered frequently in Arm B, with 61% of patients initiating treatment in cycle 2, and 91% of patients (29/32) receiving pegfilgrastim by cycle 6. The main reasons for pegfilgrastim use in Arm B were grade 3/4 neutropenia, followed by febrile neutropenia. Dose reductions occurred in 16% of Arm A patients (95% CL: 9, 27) and in 8% of Arm B patients (95% CL: 3, 17) and dose delays occurred in 29% (95% CL: 19, 41) and 23% (95% CL: 14, 35) respectively; however, 19% of patients in Arm B discontinued from the study after cycle 1 compared with only 5% in Arm A, confounding the incidence of both parameters. Adverse event profiles were similar between the 2 treatment arms and were consistent with the population under study. Conclusions: The results of this study support the feasibility of conducting community-based trials in older patients, demonstrate that older patients can safely receive myelosuppressive chemotherapy, and show the effectiveness of first-cycle use of pegfilgrastim among older patients with NHL treated in the community setting.

Introduction: The pivotal trials of pegfilgrastim and filgrastim demonstrated their value as primary protection if initiated 24 hours after chemotherapy (CT) administration from CT cycle 1. Current clinical use patterns for pegfilgrastim and filgrastim may differ and may include primary protection in cycle (C) 1 or secondary protection in later cycles. Additionally, the initiation day within a CT cycle could be early (primary protection), late (reactive use), or for treatment of established neutropenia or febrile neutropenia (FN). A retrospective chart review is underway to determine current use patterns and applications of once-per-cycle pegfilgrastim (approved in 2002) and daily filgrastim. Methods: Patient (pt) medical records are being retrospectively collected from 100 randomly selected US private oncology practices. Eligible pts are ≥18 years of age, diagnosed with non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease (HD), lung (LC), ovarian (OC), colorectal (CRC) or breast (BC) cancers, and have received ≥1 CT cycle. This planned interim analysis evaluates pegfilgrastim and filgrastim utilization in cancer pts receiving CT in 2003. Results: Medical records of 624 pts from 34 sites receiving pegfilgrastim or filgrastim have been abstracted to date. Pegfilgrastim was initiated in 351(56%) pts and filgrastim was initiated in 273 (44%) pts. Of the 624 pts, 120 (19%) received both pegfilgrastim and filgrastim (no pt used both products in the same cycle). Of these, 94 (78%) received pegfilgrastim after initially receiving filgrastim while 26 (22%) received filgrastim after initially receiving pegfilgrastim. The distribution of tumor types for the 325 pts receiving only pegfilgrastim was BC 43%; LC 24%; NHL 20%; HD 5%; OC 5%; CRC 3%. The planned CT cycle length (days) for pts receiving pegfilgrastim was: Q21 (56%), Q14 (11%), Q28 (11%), Q7 (2%). In C1, 58% of pts received pegfilgrastim; in C2, 86% received pegfilgrastim. In C1, pegfilgrastim was administered ≤3 days after CT in 76% (142/187) of pts and in 83% (200/240) of pts in C2. C1 use of pegfilgrastim was 68% for lymphoma and 54% for solid tumor pts. The distribution of tumor types for the 179 pts receiving only filgrastim was BC 46%; LC 24%; CRC 12%; NHL 9%; HD 6%; OC 4%. The planned CT cycle length (days) for pts receiving filgrastim was: Q21 (35%), Q28 (17%), Q14 (15%), Q7 (12%). In C1, 62% of pts received filgrastim; in C2, 83% received filgrastim. In C1, filgrastim was administered ≤3 days after CT in 31% (34/111) of pts increasing to 48% (52/108) of pts in C2. Filgrastim was initiated ≥10 days after CT in C1 in 48% (53/111) of pts and in 26% of pts (28/108) in C2. C1 use of filgrastim was 58% for lymphoma and 63% for solid tumor pts. Conclusions: From this interim analysis, most pts initiated pegfilgrastim in C1 and early within a cycle, suggesting primary protection. Most pts initiated filgrastim also in C1, however the day of initiation is much later, suggesting reactive use or treatment of established neutropenia or FN. Future analyses will evaluate factors associated with use (or non-use) of pegfilgrastim and filgrastim including baseline and treatment characteristics.

Background: We recently reported final results of a randomized, open-label, multicenter study assessing the efficacy of DA (Aranesp®) 300 mcg Q3W (Rearden et al, ASCO 2004). In this study of 201 pts, pts with grade 1 anemia were treated early with DA (n=102; early group) compared with pts treated late after developing grade 2/3 anemia (ie, hemoglobin [Hb] < 10 g/dL; n=99; observation/late intervention group [obs]). When pts were untreated in the obs group, Hb declined. DA treatment maintained Hb within the NCCN Hb target range for pts in the early group and increased Hb once administered in the obs group. The objective of this analysis was to explore the impact of declining Hb levels on pt-reported outcomes using the FACT-Fatigue (FACT-F) subscale. Methods: Pts with baseline (BL) Hb ≥10.5 and ≤12 g/dL were randomized 1:1 to either the early or obs group for up to 22 weeks. To analyze pt-reported fatigue, the FACT-F subscale was administered Q3W and at the end of treatment. The FACT-F analysis set included pts who were randomized, received study drug, and had a BL and at least 1 post-BL FACT-F score. Analyses of changes in FACT-F scores during treatment from BL were conducted; missing values were not imputed. Results: In 201 randomized and treated pts, mean BL (SD) Hb was similar for each group, 11.1 (0.7) g/dL for the early and 11.2 (0.6) g/dL for the obs groups. In the early group, mean Hb increased to near 12 g/dL in approximately 7 weeks, and due to dose-withholding rules, remained near 12 g/dL for the remainder of the study. In the obs group, Hb declined to < 10 g/dL in 65% of pts. The FACT-F analysis set included 94 pts in the early group and 86 in the obs group. Mean (SD) FACT-F scores at BL were 31.6 (11.7) for the early group and 27.7 (12.8) for the obs group. With categories of Hb change at the end of treatment, a significant trend towards greater improvements in fatigue with increasing Hb levels was observed in both groups (table). In pts in whom Hb was stabilized or improved, no decrease in fatigue scores was noted. However, when Hb declined (Hb change < 0 g/dL), a statistically significant and clinically meaningful (>3 point change in FACT-F score) increase in fatigue was observed (negative change in FACT-F score). Consistent with previous studies, pts with Hb change > 2 g/dL had clinically and statistically significant improvements in fatigue. Conclusion: In the absence of treatment, most mildly anemic cancer pts receiving ctx are at risk of developing grade 2/3 anemia within approximately 7 weeks. This decline in Hb is associated with a statistically significant and clinically meaningful increase in pt-reported fatigue. Our results indicate that DA 300 mcg Q3W may effectively ameliorate the impact of ctx on Hb levels and consequently prevent a decline in fatigue. Further, Q3W DA may provide benefits associated with less-frequent dosing. Mean (95%CL) Change in FACT-F Scores At End of Treatment By Change in Hb Category Early Obs N=94 N=86 Categories of Hb Change < 0 g/dL −6.2 (−12.9, 0.6) −2.8 (−7.2, 1.5) n=23 n=38 >0 to 2 g/dL 0.9 (−2.2, 4.0) 1.7 (−3.9, 7.3) n=52 n=32 > 2 g/dL 8.3 (3.3, 13.2) 6.4 (0.3, 12.5) n=19 n=16 P -value (Jonckheere-Terpstra Trend Test) 0.0003 0.049

8064 Background: Darbepoetin alfa (DA, Aranesp®) administered Q3W is effective for the treatment of CIA (Kotasek et al, 2003). NCCN guidelines recommend initiating erythropoietic therapy when hemoglobin (Hb) is < 11 g/dL with a suggested target Hb of 11 to 12 g/dL. This study was designed to evaluate the ability of DA to maintain Hb ≥ 10 g/dL in mildly anemic pts (early intervention) and pts who become moderately to severely anemic before treatment (late intervention). Methods: Pts with baseline Hb ≥ 10.5 and ≤ 12 g/dL were randomized 1:1 to early (DA 300 mcg Q3W) or late intervention (treated if Hb ≤ 10 g/dL with DA 300 mcg Q3W) groups for up to 23 weeks. The primary endpoint was the percentage of pts in each group with a Hb drop below 10 g/dL. Patient-reported outcomes included the FACT-Fatigue subscale. Proportion endpoints were calculated using Kaplan-Meier (KM) methods. Results: The study is fully enrolled with 204 pts. Data through week 17 for 201 evaluable pts (99 early and 102 late) were analyzed....

8063 Background: Both ASH/ASCO and NCCN evidence-based guidelines for the treatment of ctx-induced anemia (CIA) recommend achievement and maintenance of hemoglobin (Hb) near 12 g/dL to assure optim...

8084 Background: Patients (pts) with cancer who are not receiving chemotherapy (ctx) or radiotherapy (rtx) often develop anemia. A previous randomized, controlled trial evaluating the effect of recombinant human erythropoietin therapy vs placebo on transfusion (tfn) incidence in this pt population failed to show a significant reduction in tfn requirements in treated pts, relative to control (Abels, 1991). This multicenter, randomized, controlled, 25-week (wk) study is closed to enrollment (n = 298) and was designed to assess the effect of darbepoetin alfa (DA; Aranesp®) in pts with anemia of cancer (AOC) with respect to hospitalization, incidence of tfn, and pt-reported outcomes. Methods: Eligible pts (anemia [hemoglobin (Hb) ≤ 11 g/dL]) due to cancer or prior ctx and/or rtx; had no ctx or rtx within 4 wks before screening or during the study) were randomized 4:1 to DA 3.0 mcg/kg every 2 weeks [Q2W] for 21 wks (DA arm) or 12 wks of observation followed by 9 wks of DA 3.0 mcg/kg Q2W (control arm). Data wer...

8262 Background: PALO is the only 5-HT3 receptor antagonist (RA) approved by the FDA for prevention of acute & delayed CINV after moderately emetogenic CT. Aprepitant is a NK1 RA approved for prevention of acute & delayed CINV after highly emetogenic CT when used with a 5-HT3 RA & DEX. We now report the first study combining these novel antiemetics in patients (pts) receiving a wide variety of moderately to moderate-highly emetogenic chemotherapy. Methods: This multicenter, phase II, open-label study assessed the efficacy & safety of a single IV dose of PALO 0.25 mg on Day 1 of CT, along with 3 daily oral doses of APREP (125 mg on Day 1; 80 mg on Days 2–3) plus DEX (12 mg on Day 1; 8 mg on Days 2–3). Eligible pts were naive or non-naive to CT. Efficacy assessments included complete response (CR: no emetic episodes [EE] and no rescue medication) and no EE during the acute (0–24 hr), delayed (24–120 hr), and overall (0–120 hr) intervals post-CT. Adverse events were collected to assess safety. Results: Inten...