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Purpose/Objective(s) Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC). Materials/Methods Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients. Results The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05). Conclusion Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non-small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable-0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.

Purpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. Experimental Design Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m2)/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a “3 + 3” phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. Results Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m2 + carboplatin AUC = 6. Conclusions The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.

Purpose Overexpression of COX-2 correlates with advanced stage and worse outcomes in non–small-cell lung cancer (NSCLC), possibly as a result of elevated levels of COX-2–dependent prostaglandin E2 (PGE2). Exploratory analyses of studies that used COX-2 inhibitors have demonstrated potentially superior outcome in patients in whom the urinary metabolite of PGE2 (PGE-M) is suppressed. We hypothesized that patients with disease defined by PGE-M suppression would benefit from the addition of apricoxib to second-line docetaxel or pemetrexed. Patients and Methods Patients with NSCLC who had disease progression after one line of platinum-based therapy, performance status of 0 to 2, and normal organ function were potentially eligible. Only patients with a ≥ 50% decrease in urinary PGE-M after 5 days of treatment with apricoxib could enroll. Docetaxel 75 mg/m2 or pemetrexed 500 mg/m2 once every 21 days per the investigator was administered with apricoxib or placebo 400 mg once per day. The primary end point was progression-free survival (PFS). Exploratory analysis was performed regarding baseline urinary PGE-M and outcomes. Results In all, 101 patients completed screening, and 72 of the 80 who demonstrated ≥ 50% suppression were randomly assigned to apricoxib or placebo. Toxicity was similar between the arms. No improvement in PFS was seen with apricoxib versus placebo. The median PFS for the control arm was 97 days (95% CI, 52 to 193 days) versus 85 days (95% CI, 67 to 142 days) for the experimental arm (P = .91). Conclusion Apricoxib did not improve PFS, despite biomarker-driven patient selection.

Background: Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the immune system for checkpoint inhibitors. The combination of a taxane + immune checkpoint inhibitor has been reported to improve response in non-small cell lung cancer (NSCLC; Giaccone et al. ESMO 2015 [abstract 247]). This analysis provides interim results from the first of the 2 lung cohorts of a phase I study of nivo with the standard dose and schedule of nab-P/C. Methods: The 2 lung cohorts (Arms C and D) were initiated sequentially in part 1 of the study. In Arm C, patients (pts) with stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received 4 cycles of nab-P 100 mg/m2 on days 1, 8, and 15 + C area under the curve 6 on day 1 of a 21-day cycle in combination with nivo 5 mg/kg on day 15 starting at cycle 1. Nivo was continued as monotherapy at cycle 5. The same regimen was administered in Arm D, with nivo starting at cycle 3.The primary objective of part 1 was the number of dose-limiting toxicities (DLTs) in each treatment arm, including grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Pts treated with ? 2 cycles of nivo + nab-P/C or who discontinued due to DLT after the start of nivo and prior to completing 2 cycles of nivo + nab-P/C were considered DLT evaluable. If deemed safe per DLT evaluation, the treatment arms may be expanded to further assess safety, tolerability, and antitumor activity. Results: As of Nov 9, 2015, 12 pts had been enrolled in Arm C; of these, 9 received nivo + nab-P/C before the data cut off date. Overall, most pts were aged ? 65 years (67%) and female (58%); 58% had adenocarcinoma, and 42% had squamous cell carcinoma. No DLTs were observed. The most frequent grade ? 3 TEAEs common to all treated pts and, separately, those treated with nivo + nab-P/C were neutropenia (25% and 22%) and hypokalemia (17% and 22%, 2 out of 3 pts had history of thyroid disorder). No pneumonitis has been reported to date. Of the 9 nivo-treated, response evaluable pts, 6 had a partial response, and 3 had stable disease (SD). In pts not receiving nivo, 1 patient had SD. Overall tumor burden decrease from baseline in total length of target lesions of responding pts ranged from 31% to 83%. Two pts discontinued treatment prior to nivo administration (1 due to AEs and 1 due to voluntary withdrawal); 1 additional pt received nivo after the data cut off date. One pt discontinued due to progression after 23 weeks of nivo + nab-P/C. No treatment-related deaths have been reported to date. Conclusions: In Arm C of the lung cancer cohort, the addition of nivo on day 15 to the standard dose and schedule of nab-P/C did not appear to result in added toxicity or raise new safety/tolerability concerns. Preliminary assessments of antitumor activity were encouraging. Expansion of this treatment arm to further assess safety and tolerability is underway and will be updated (NCT02309177). Citation Format: David M. Waterhouse, Ben George, Martin Gutierrez, Greg A. Otterson, Amy Ko, Teng Jin Ong, Sotirios Stergiopoulos, Nataliya Trunova, Karen Kelly. Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in advanced NSCLC: safety and efficacy results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT141.

Rad51c is a tumor suppressor gene and known for its function in homologous recombination and DNA repair in early and late stages of HR (Homologous Recombination). Studies from breast and ovarian cancer patients reveled a bi-allelic homozygous germline missense mutation in the codon 773 and 258 of Rad51C gene. At the cellular level the effects include chromosomal instability (increased chromosomal breakage) associated with hypersensitivity to DNA damaging agents, and defective DNA damage repair. Mutations, which include base insertions and missense, have been reported in the Rad51C gene. Alternatively spliced transcriptomes have been shown to play a different or antagonistic biological role compared to the full length wild type mRNA. Some of the important diseases caused by cis acting or trans acting protein splicing factors include cystic fibrosis, dementia, premature aging and cancer. In addition, promoter methylation has been associated with gene silencing, while DNA methylation at both intronic and exonic regions are shown to correlate with isoform-specific transcription by alternative splicing or by utilizing alternate promoters. DNA methylation at the cytosine residues (5-methylcytosine) of the CpG di-nucleotides is carried out by DNA methyltransferases (DNMT) and is generally considered to be a repressive epigenetic modification. By RT-PCR, we identified splice variants of Rad51C gene that include variant-1 (without exon-7), variant-2 (without exon-6, 7) and variant-3 (without exon-7, 8) in colorectal tumors. Of the 38 colorectal tumors, 18 contained variant 1, 12 contained variant 2, 14 contained variant 3, and eight had no expression of any of the variants. Bisulfate DNA sequencing and Methylation Specific PCR (MS-PCR) showed promoter methylation of Rad51C in tumor cells. 5-Azacytidine treatment of LS-174T cells caused a 14 fold increase in variant 1, a 4.8 fold increase for variant 3 and 3.4 fold for variant 2 compared to no treatment. Real time PCR analysis of 9 pair-matched colorectal tumors and non-tumors showed that variant 1 was overexpressed in tumors comparing to matched non-tumors. Expression of Rad51C variants in these tumors was associated with microsatellite stability and with maintenance of functionality of the fanconi anemia repair pathway. In vitro transient overexpression of Rad51C variant-1 in colorectal tumor cells over the wild type Rad51C caused a 1.8 fold increase in the cell proliferation as analyzed by BrdU immunofluorescence staining and FACS. Given that the Rad51C splice variant-1 is overexpressed in colorectal tumors and has a role in promoting cell proliferation, further investigation regarding its potential role in oncogenesis in colorectal tumor cells is warranted. Citation Format: Arjun Kalvala, Li Gao, Kathleen Dotts, Fernando Ochoa Cortes, Brittany Barnwell, Greg Otterson, Miguel Villalona Calero, Wenrui Duan. Potential oncogenic function of Rad51C splice variant in colorectal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3866. doi:10.1158/1538-7445.AM2015-3866

The Fanconi Anemia (FA) pathway is a major mechanism of homologous recombination DNA repair in response to genotoxic insults. Formation of FANCD2 foci has been reported as a predictor of resistance to cisplatin and mitomycin C (MMC) treatment in cancer cells. Defects in Rad51C (FANCO) have been documented as the cause of Fanconi Anemia (FA) complementation group O (FANCO) disorder. A fusion gene formed between Rad51c (exon 1-7) and ATXN7 (ataxin7, involved in neurocerebral ataxia) exons 6-13 have been demonstrated by next generation sequencing in MCF-7 breast cancer cells. Given our observation of higher prevalence of somatic functional FA deficiency in colorectal tumors based on FA triple staining immunofluorescence (FATSI) method that we developed to assess FANCD2 foci in tumors, we evaluated the presence of the fusion gene Rad51C-ATXN7 in the FANCD2 foci negative and foci positive tumors using RT-PCR, immunoprecipitation and immunoblot analysis. RNA and DNA isolated from frozen colon tumor tissues with TRIzol reagent. RT-PCR primers spanned the region between Rad51c exon5 and ATXN7exon 8 to amplify fusion gene in colorectal tumors. To identify the fusion break point in RNA from colorectal tumors, we RT-PCR amplified six tumors and their products were Topo TA cloned. We identified three previously unknown isoforms of fusion mRNAs between Rad51c and ATXN7 among the 40 Topo TA clone sequences analyzed. We named the mRNA fused between Rad51c from exons 1-7 and ATXN7 exons 6-13 long form. From RNA sequence analysis by translation tool, we identified that the long form extends for only five amino acids (aa) after the fusion junction and results in a premature stop codon without producing a fusion protein. We also identified two short variants (1 & 2) in 40 clones. Sequencing confirmed the short variant form 1 between Rad51c (exon 1-6) and ATXN7 (exon 6-13). Immunoprecipitation and western blot analysis further confirmed a 110 KDa protein to be the short variant 1 in colorectal tumor cells. Sequence analysis of the short variant 2 showed that this variant formed between Rad51c (exon 1-5) and ATXN7 (exon 6-13), resulting in a fusion chimera of unknown protein with additional 37 aa and stop codon post fusion junction at C-terminus, but with an N-terminus resembling Rad51c. Thus only the variant 1 is able to produce a Rad51c-ATXN7 fusion protein. We further investigated the presence of the fusion gene according to FA functionality (FancD2 foci positive versus negative) by RT-PCR. Among 30 colorectal tumors evaluated 16 tumors were FANCD2 foci negative and 14 were positive. The Rad51c-ATXN7 short variant-1 was present in 6 of the 16 FANCD2 foci negative colorectal tumors as compared to 9 of the 14 FANCD2 foci positive tumors (p=0.153, t-test). In conclusion, a novel fusion protein was identified at relatively higher frequency in colorectal tumors. Further studies are required to investigate its function in either malignant transformation, tumor progression or in response to genotoxic insults. Citation Format: Arjun Kalvala, Li Gao, Brittany Barnwell, Greg A Otterson, Miguel A Villalona-Calero, Wenrui Duan. Investigation of Novel Rad51c-ATXN7 fusion gene in colorectal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2407. doi:10.1158/1538-7445.AM2014-2407

Background: Protein arginine methylation is a post translational modification that influences signal transduction, mRNA splicing, gene transcription and DNA repair. Among the PRMT family members, PRMT5 is a type II enzyme that symmetrically methylates histone H4 at Arginine 3 and histone H3 at Arginine 8. Studies have recently linked this modification to carcinogenesis and metastasis. The function of PRMT5 in carcinogenesis is related to cell proliferation through modulation of E2F1, p53, EGFR, and CRAF. It is known to accelerate progression through the G1 phase of cell cycle by influencing proteins like CDK4 and CDK6. Previous work on human lung cancer specimens has demonstrated an overexpression of PRMT5 in cancerous tissue when compared to normal lung parenchyma. Suppression of PRMT5 significantly inhibits cell proliferation in lung cancer cell lines A549 and H1299. We hypothesized inhibition of PRMT5 can lead to increased radiosensitivity in lung cancer cells. Method: Several lung cancer cell lines were used in the experiments, including A549, H1299 and H23. SiRNA (Dharmacon) and lentiviral shRNA (Sigma) were used to knock down (KD) PRMT5 levels transiently or stably in A549 cell line in which p53 is present in its wild type form. Forty eight hours after transient transfection, cells were plated for clonogenic survival assay and subsequently exposed to ionizing radiation at 0, 2, and 8 Gy. Cellular PRMT5 protein levels were estimated by western blotting analysis for PRMT5 KD and scramble control cell lines. The scramble control and siRNA knockdown cells were subjected to cell cycle analysis by flow cytometry. We also tested specific PRMT5 inhibitors with and without radiation therapy in the lung cancer cell lines to see if PRMT5 inhibitors could lead to increased radiosensitivity. Results: We observed a >90% PRMT5 KD in transiently transfected cells at 48 h and 72 h post transfection as verified by western blot analysis. This transient KD lead to a small but significant decrease in colony survival after radiation. This radiosensitization was not observed in cells selected for stable KD of PRMT5 protein by lentiviral RNA transfection. There is an increase of cell population in G1 arrest in PRMT5 transient KD cells but not in stable KD cells. Additionally, cells treated with PRMT5 specific inhibitors (“cpd5” or “cpd65”) demonstrated increased radiosensitivity in A549 cells but not in H1299 suggesting that this effect may be p53-dependent. Conclusion: PRMT5 inhibition by siRNA or its specific inhibitors lead to radiosensitivity in A549 lung cancer cell line. This effect may be partially dependent on p53-dependent cell cycle arrest. Further work to inhibit PRMT5 in other lung cancer cell lines with different p53 activities will be investigated. Citation Format: Smitha Sharma, X Wu, P Smith, N Denko, C Li, H Lai, F Yan, K Shilo, A Chakravarti, S Sif, R Baiocchi, G Otterson, Meng Xu-Welliver. Inhibition of PRMT5 results in radiosensitization in lung cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 854. doi:10.1158/1538-7445.AM2014-854

Fanconi anemia (FA) is a rare inherited chromosomal instability genetic disorder characterized by congenital musculoskeletal abnormalities, bone marrow failure and cancer susceptibility. At the genetic level, monoubiquitination of FANCD2 and I by an FA core complex (FANCA, B, C, E, F, G M and L) is impaired. Monoubiquitinated FANCD2 and I co-localize with DNA damage response proteins such as Rad51C (FANCO) to mediate homologous recombination (HR) repair. Defects in Rad51C have been documented as the cause of FA complementation group O (FANCO) disorder.In cells the effects include chromosomal instability, hypersensitivity to DNA damaging agents and defective DNA damage repair. Germline mutations for Rad51C gene in patients have been reported in breast and ovarian cancers. Although germline mutations for Rad51C gene are known to cause an FA like phenotype, somatic mutations for Rad51C in colon or other tumors have not been previously described. We evaluated 40 formalin fixed paraffin embedded (FFPE) colorectal adenocarcinomas by an immunofluorescence based triple staining method (FATSI) that we have developed to assess for potential somatic functional deficiency of the FA pathway. Thirteen of the 40 (33%) FFPE samples had been noted to lack FANCD2 foci formation. Among the 40 tumors, we analyzed 31 available frozen tumors that included all 13 foci negative tumors and matching non-tumor tissues for mutations in Rad51C coding region. The tumor and non-tumor tissue samples were procured following an IRB protocol of the Ohio State University. RNA and DNA were isolated from the fresh frozen tissue samples with TRIzol reagent. Direct sequencing of PCR amplicons was performed. Two of the 31 tumor DNA samples contained point mutation at the codon 319 (from CGA to TGA, a stop codon) which technically results in a truncated FANCO protein. The Rad51C protein domain shows amino acid 125 to132 (exon 2 to 5) is important for exerting single stranded DNA dependent ATPase activity, a functional nuclear localization signal located from aa 366 to 370 (exon-9). The mutation substitutes arginine at codon 319 to a premature stop codon terminating the protein abruptly, without producing a full length Rad51C protein. Thus the altered protein is unable to localize in the nucleus. Of interest, both tumors with RAD51C mutations lacked formation of FANCD2 foci by FATSI staining. In both cases, the mutation was absent from the matched non-tumor tissues, suggesting a somatic mutation. The underlining molecular alterations that cause deficiency in FANCD2 foci formation in other 11 foci negative tumors are still under investigation currently. Given that the FA pathway plays essential role in response to DNA interstrand cross-link damage agent, and that cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, our findings have the potential significance of identifying a subpopulation among colorectal cancer patients specially susceptible to these type of treatments. Citation Format: Arjun Kalvala, Li Gao, Brittany Barnwel, Greg Otterson, Miguel A Villalona Calero, Wenrui Duan. Mutations in Rad51C in colon tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4221. doi:10.1158/1538-7445.AM2013-4221

2602 Background: Triapine (T), an inhibitor of ribonucleotide reductase, enhances the activity of gemcitabine (G), and the synergism is most evident when the pre-exposure time to T is prolonged. In...

Patients (pts) with cancer receiving chemotherapy commonly have chemotherapy-induced anemia (CIA), often resulting in reduced quality of life. The primary objective of this analysis was to summarize the effectiveness of darbepoetin alfa (DA) administered at 300mcg every 3 weeks (Q3W), in achieving and maintaining a hemoglobin (Hb) target range of 11–13g/dL in pts with hematologic malignancies and CIA, versus pts with solid tumors and CIA. Data for all 1493 pts enrolled in this multicenter, open-label, 16-week study who received at least one dose of DA are included in this exploratory analysis stratified by tumor type. Pts ≥18 years of age receiving multicycle chemotherapy and with Hb

Darbepoetin alfa (Aranesp®) administered at 300 mcg Q3W appears to be an effective dose in patients with hemoglobin (Hb) 10–12 g/dL to maintain Hb, and in patients with Hb 8–10 g/dL to elevate Hb to within the National Comprehensive Cancer Network (NCCN)-recommended target range of 11–12 g/dL. The objective of this multicenter, open-label study of cancer patients with chemotherapy-induced anemia was to evaluate the effectiveness of darbepoetin alfa 300 mcg Q3W, administered over a 16 week treatment period, in achieving and maintaining the therapeutic objectives of anemia treatment consistent with NCCN guidelines. This objective was assessed by determining the percentage of patients who achieved a post baseline target Hb level ≥11.0 g/dL in the absence of a transfusion within the previous 28 days, and the percentage of patients maintaining an average Hb within the NCCN target range. Secondary hematologic endpoints included the incidence of transfusion and the proportion of patients achieving a hematopoietic response (increase in Hb ≥2 g/dL from baseline or achieving a Hb ≥12 g/dL). Patient-reported outcomes were assessed using the FACT-Fatigue subscale with four additional questions relating to fatigue, energy, activity, and overall health. The relationship between clinical endpoints and the ability to achieve and maintain Hb within the NCCN target range were also assessed. Anemic patients (baseline Hb levels < 11 g/dL) with nonmyeloid malignancies receiving chemotherapy were eligible for enrollment in this study. Doses could be escalated after 6 weeks (2 doses) to 500 mcg Q3W if Hb levels remained < 10 g/dL and the increase in Hb from baseline was < 1 g/dL, or, based on physician discretion if Hb levels were > 10g/dL. To date, 539 patients have been enrolled. The majority of patients were female (59%), white (82%) with a median age of 64 years. The predominant cancers in these patients were lung (24%), gastrointestinal (22%), and breast (21%). The majority of patients had stage IV disease (45%) and a Karnofsky performance status score of 80 to 90 (65%). The mean (SD) baseline Hb level was 10.1 g/dL (0.7); 32% of patients had a baseline Hb of < 10.0 g/dL [mean (SD) Hb 9.3 (0.6) g/dL] while 66% had baseline Hb levels ≥10.0 g/dL [10.6 (0.3) g/dL]; 2% of patients (n = 12) received a transfusion within 28 days of baseline Hb measurement and were excluded from analysis. Since the majority of chemotherapy regimens are delivered on a Q3W basis, the ability to administer darbepoetin alfa at a fixed dose, synchronized with the chemotherapy schedule may reduce the number of injection-centric visits. This provides important benefits for patients and their caregivers, and represents a simplification in the treatment of chemotherapy-induced anemia in oncology practice.