3rd Line Therapy Research Articles

SL-401, A Targeted Therapy Directed to the Interleukin-3 Receptor Present On Leukemia Blasts and Cancer Stem Cells, Is Active As a Single Agent in Patients with Advanced AML

Abstract 3625 Background:SL-401 is a novel biologic targeted therapy, comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis, directed at the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on leukemia blasts and cancer stem cells (CSCs) relative to normal hematopoietic cells. Since SL-401 uniquely targets both the leukemia blasts (tumor bulk) and CSCs, it would be expected to induce tumor regression (anti-tumor bulk effect), as well as inhibit tumor repopulation (anti-CSC effect), thereby improving survival. SL-401 has been evaluated in a Phase 1/2 clinical trial in patients with advanced hematologic cancers. In this study, SL-401 has demonstrated objective clinical responses, including durable complete responses (CRs) and protracted overall survival (OS) in patients with heavily pretreated AML. The current report is a final analysis of the patients with AML or MDS. Study Design:Seventy-eight patients with advanced hematologic cancers, including relapsed or refractory AML (n = 59), de novo AML unfit for chemotherapy (n = 11), high-risk MDS (n = 7), and other (n = 1), were enrolled in a multicenter study. Among the patients with relapsed or refractory AML, the numbers of patients receiving SL-401 as 2nd, 3rd, or >3rd line therapy were 24, 16, and 19, respectively. The median (range) age for AML patients was 65 (7, 84) years. Patients received SL-401 as a 15-minute intravenous infusion in one of two dosing regimens for a single cycle to determine the maximum tolerated dose (MTD) and assess antitumor activity. In Regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. In Regimen B, 33 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses. Results:A single cycle of SL-401 demonstrated single agent activity in patients with relapsed or refractory AML, including 2 durable CRs of 8 and >25 months duration and 5 partial responses (PRs). OS was also notable among patients who received one cycle of SL-401 as ≥3rd line therapy for AML; the median OS was 3.6 (2.3, 6.1) months. Moreover, at therapeutically relevant doses, defined as the MTD or one or two dose levels below the MTD (9.4, 12.5, or 16.6 μg/kg/day), the median OS among AML patients who received SL-401 as ≥3rdline therapy (n = 16) was 5.6 (2.5, 10.8) months. These OS values compared favorably to historical results of 1.5 months for patients treated with standard chemotherapy.SL-401 was well tolerated. The MTD was not achieved with Regimen A, whereas the MTD for Regimen B was 16.6 μg/kg/day, with manifestations of capillary leak syndrome, including hypoalbuminemia and edema, as the dose-limiting toxicity (DLT) at the 22.1 μg/kg/day dose level. Transient (i.e., lasting ≤2 weeks) transaminase elevations were among the most common ≥Grade 3 AEs. Notably, there was no evidence of treatment-related bone marrow suppression. Conclusion:SL-401 demonstrated single agent anti-tumor activity and was well tolerated in patients with advanced AML. Improved survival was observed among patients who received a single cycle of SL-401 as ≥3rd line treatment, a disease setting in which there is no standard therapy. SL-401 may be an attractive treatment option for these patients given their tendency to be myelosuppressed and therefore are often poor candidates for myelosupressive therapies that have limited benefit on clinical response and survival in this setting.Based on these positive findings, SL-401 will be advanced into a randomized Phase 2b trial to treat patients with AML in the 3rd line setting. Patients will be randomized to treatment with either multiple cycles of SL-401 or physician's choice, which will consist of available standard therapeutic agents. In addition, the efficacy and safety of SL-401-based combination therapy will also be studied in earlier lines of AML given the lack of overlapping toxicities with existing hematologic cancer therapies. Disclosures:Konopleva:Stemline Therapeutics: Research Funding. Cirrito:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Hoberman:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Consultancy, Equity Ownership. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Frankel:Stemline Therapeutics: Research Funding.

Phase I/II Trial of the MEK1/2 Inhibitor Trametinib (GSK1120212) in Relapsed/Refractory Myeloid Malignancies: Evidence of Activity in Patients with RAS Mutation-Positive Disease

AbstractAbstract 677 Background:Activating mutations of NRAS and KRAS (‘RAS') are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods:Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results:Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible.Table 1Best response (n=87)NRAS or KRAS mutated (n=57)RAS wild type or unknown (n=30)CR/CRp, n (%)7 (12)0Marrow CR*/MLFS, n (%)4 (7)0PR, n (%)1 (2)1 (3)HI/HI-Neutrophil/HI-Platelet, n (%)4 (7)5 (17)ORR, % (95% CI)28 (17.0–41.5)20 (7.7–38.6)CR, complete remission; CRp, CR with incomplete platelet recovery; MLFS, morphologic leukemia-free state; ORR, overall response rate; PR, partial remission; HI, hematologic improvement.*Marrow CR response (for MDS patients only), ≤ 5% myeloblasts in marrow and decrease by ≥ 50% over pre-treatment. Conclusion:At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures:Borthakur:GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

Survival After Second, Third, and Fourth Line Therapy Better Than Expected in Patients with Previously Treated AL Amyloidosis Who Were Not Transplant Candidates At Diagnosis.

AbstractAbstract 946 Background:The emerging therapies directed at the plasma cell clone have dramatically increased overall survival (OS) for both myeloma and amyloidosis patient populations. As more treatment trials are done in patients (pts) with AL, benchmarks for outcomes among previously treated AL pts are required, especially for those pts who are not candidates for high-dose chemotherapy with peripheral blood stem cell transplantation (ASCT). Inadequate information is available about the number of non-transplant pts who go on to receive second line treatment for AL amyloidosis. Methods:To ascertain the outcomes of pts who did not receive ASCT as primary therapy but who required a second line of therapy, we reviewed the experience of pts seen at Mayo Rochester between 1990 and 2010 according to an IRB approved retrospective review protocol. 1828 pts had their first Mayo visit for AL during this time period. Pts were excluded from this study for the following reasons: 571 had upfront transplant; 907 pts had received only one line of treatment for their amyloid; 91 had longstanding other associated malignancy [Waldenstrom's macroglobulinemia (8), lymphoma (15), CLL (6), multiple myeloma (62)]; and 93 had inadequate follow-up information. One-hundred and sixty-six pts received 2 or more lines of therapy for their AL amyloid and are the subject of these analyses. Statistical analyses were done using JMP statistical software (SAS, Carey, NC). Results:Of the 166 pts, the median age was 64 years (range 34, 84). 49% were male. Baseline organ involvement was as follows: cardiac 84/166 (50%); renal 118/166 (71); liver 23/166 (13.8%); peripheral nerves 19/166 (11.4%); and gastrointestinal 14/166(8.4%). Thirty-one percent (52/16) had both cardiac and renal involvement. Only 73 pts had cardiac biomarkers (NT pro BNP and Troponin T) done at baseline. Of these pts, 26% were stage 1, 49.3% were stage 2, and 24.6% were stage 3 according to original Mayo cardiac biomarker staging system.By inclusion criteria definition, all 166 pts received 1st and 2nd line therapies; 53 (32%) pts received 3rd line of treatment; 20 (12%) received 4th line of treatment; and 10 (6%) received 5th line of treatment. For first line therapy, the most common drugs given either singly or in combination were corticosteroid (147/166; 88.5 %), alkylator (99/166; 59.6%), IMID (34/166; 20.4 %), and bortezomib (19/166; 11.4%). The median time from diagnosis to 2nd line therapy was 10.3 months. Second line regimens received included: corticosteroid, 108/166 (65.1%); alkylator, 76/166 (45.8 %); IMID, 46/166 (27.7%); and bortezomib, 46/166 (27.8%). The median time from diagnosis to 3rd line therapy was 19.8 months. For the 53 pts who received 3rd line treatment, regimens included: corticosteroid, 41/53 (77.3%); IMIDs, 17/53 (32.1%); alkylator, 17/53 (32.1%); bortezomib, 12/53 (22.6%). The median time from diagnosis to 4th line therapy was 31.8 months. For the 20 pts receiving 4th line treatment, regimens included: corticosteroids, 15/20(75%); alkylator, 12/20 (60%), bortezomib, 7/20 (35%); and IMIDs, 4/20(20%). Eighty-three pts have died. The 1 year mortality of our study population was only 8%. The median follow-up of surviving pts was 47.6 months. Figure 1 demonstrates Kaplan-Meier estimates of overall survival (OS) from initiation of each successive therapy. The median OS from initiation of 1st, 2nd, and 3rd lines of treatment were 65, 49.5 and 36.7 months respectively. The median OS after the 4th line of treatment was not reached. The 4 year OS rates from initiation of 1st, 2nd, 3rd and 4th lines of therapy were 58%, 50.8 %, 50 % and 53.4% respectively. Conclusion:Outcomes among relapsed or refractory AL pts are better than what one might expect. Multiple publications have demonstrated that the 1 year mortality of newly diagnosed AL is in the vicinity of 40%. Thereafter, the rate at which pts die dramatically decreases. Our study provides explicit data characterizing the fate of pts unfortunate enough to require additional therapy but fortunate enough to survive past the exceedingly high risk period of death that occurs within 6–12 months of diagnosis. These data provide useful information for benchmarking future trials for treatments of AL amyloidosis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Comparison of Treatment Changes for Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched From Imatinib to Nilotinib or Dasatinib As Second-Line Therapy

AbstractAbstract 4443 Background:Nilotinib and dasatinib are two therapies approved by the US Food and Drug Administration for pts with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to 1st-line imatinib. Although these therapies were shown to be generally effective and tolerable, sometimes they are not, requiring treatment changes (e.g., discontinuation, dose modification, and drug holidays). To date, no head-to-head study has been conducted to compare treatment changes between 2nd-line nilotinib and dasatinibin clinical practice. Methods:Through an online chart abstraction form, participating community physicians retrospectively submitted de-identified information on Ph+ CML-CP pts ≥ 18 years old who switched after 10/28/2007 from imatinib to 2nd-line nilotinib or dasatinibwith at least 30 days of follow-up. When multiple pts met the selection criteria, pts were selected randomly by physicians. Pts enrolled in clinical trials or with concurrent malignancies were excluded. Information was collected on clinical characteristics and therapy changes in 2nd-line treatment, including dose modification (increase or decrease), drug holiday, and discontinuation of current therapy with or without switch to a 3rd-line therapy. Reasons for therapy changes were also collected, and treatment changes were classified as due to (1) lack of effectiveness if reasons included progression to accelerated phase or blast crisis, failure to achieve satisfactory response, or loss of satisfactory response; (2) intolerance if reasons included adverse events; (3) other reasons, including non-adherence, vacation, pregnancy, or economic reasons. Rates of treatment changes were compared between treatment groups using chi-square tests. Results:122 hematologists and oncologists provided information on 597 pts (301 nilotinib pts and 296 dasatinib pts). The median follow-up was 11 months (range 1–54 months) for pts on nilotinib and 10 months (range 1–56 months) for those on dasatinib. The two groups had similar age, sex, race, and comorbidities. Overall, treatment change was infrequent for both nilotinib and dasatinib patients (10% vs. 13%, p=0.40), but nilotinib pts had significantly fewer dose increases vs. dasatinib pts (0.0% vs. 1.4%, p=0.04), and they tended to have fewer drug holidays (1.7% vs. 4.4%, p=0.05). When treatment changes were classified by reason for change, nilotinib pts were less likely to change treatment due to lack of effectiveness vs. dasatinib pts (2.0% vs. 5.1%, p=0.04). Further, among pts who discontinued, fewer nilotinib pts discontinued due to lack of effectiveness (29% vs. 61%, p=0.03). Nilotinib and dasatinib pts had similar rates of treatment changes due to intolerance or other reasons, except for drug holiday, where nilotinib pts had fewer events than dasatinibpts (0% vs. 1.7%, p=0.02). The table below summarizes the changes in treatment by reason for treatment change. Conclusions:For Ph+ CML-CP pts on 2nd-line nilotinib or dasatinib, pts on nilotinib were less likely than those on dasatinibto change treatment due to lack of effectiveness.NilotinibDasatinibP-value(n=301)(n=296)Treatment change due to lack of effectiveness, n (%)6 (2.0)15 (5.1)0.04Discontinuation with or without switch to 3rd-line6 (2.0)14 (4.7)0.06Dose increase0 (0.0)4 (1.4)0.04Treatment change due to intolerance, n (%)11 (3.7)11 (3.7)0.97Discontinuation with or without switch to 3rd-line2 (0.7)3 (1.0)0.64Drug holiday0 (0.0)5 (1.7)0.02Dose decrease9 (3.0)3 (1.0)0.09Treatment change due to other reasons, n (%)18 (6.0)13 (4.4)0.38Discontinuation with or without switch to 3rd-line13 (4.3)6 (2.0)0.11Drug holiday5 (1.7)8 (2.7)0.38 Disclosures:Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Luo:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Griffin:Novartis: Consultancy, Research Funding.

Quality of life across chemotherapy lines in patients with cancers of the pancreas and biliary tract

BackgroundIn patients with cancers of the pancreatic and biliary tract quality of life (QOL) improvement is the main treatment goal, since survival can be prolonged only marginally. Up to date, knowledge on QOL impairments throughout the entire treatment process, often including several chemotherapy lines, is scarce. Our study aimed at investigating QOL trajectories from adjuvant treatment to palliative 3rd-line therapyMethodsPatients were included in routine electronic patient-reported outcome monitoring at Kufstein County Hospital at the time of diagnosis and assessed with the EORTC QLQ-C30 during each chemotherapy cycle.ResultsEighty out of 147 patients with pancreatic cancer or cancer of the bile ducts treated at the Kufstein County Hospital, fulfilled inclusion criteria and could be included in the study (mean age 67.4 years; 53.8% women). Physical, Emotional and Cognitive Functioning, and Global QOL deteriorated across chemotherapy lines, whereas Fatigue, Pain, Dyspnoea, Sleeping Disturbances, Diarrhoea, and Taste Alterations increased. With regard to Physical Functioning, Global QOL, Fatigue, Dyspnoea, Diarrhoea and Taste Alterations, the patients receiving adjuvant or 1st-line palliative chemotherapy did not differ significantly. Most patients in 2nd- or 3rd-line chemotherapy showed significantly higher impairments and symptom burden. However, patients under 1st and 2nd-line treatment showed stable QOL trajectories, whereas 3rd-line patients perceived substantial deteriorations.ConclusionsThe results suggest early palliative treatment initiation to stabilise QOL on a level as high as possible. The continuous QOL improvement during adjuvant treatment, probably reflecting post-operative recovery, may indicate that deleterious effects of adjuvant chemotherapy on QOL are highly unlikely.

875 - Everolimus in the Sequence after Failure of Vegfr-Directed Therapy in MRCC - A Retrospective Analysis

ABSTRACT In a retrospective NIS, 81 patients receiving everolimus after failure of VEGFR directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients (57 m, 24 f) with 93% ccRCC and 6% ncRCC (1% undefined) have been analyzed. The median age was 58 years (23–78 y). 36% had synchronous and 63% metachronous metastases. According to the MSKCC score at initial diagnosis, 24% have been “favorable”, 26% “intermediate”, 7% “poor prognosis” and in 43% there was no initial prognostic score defined by the treating physicians. The major locations of metastases have been lung (56.8%), lymph nodes (34.6%), skeleton system (17.3%), 36 44% of the patients had multiple locations. As 1st line therapy, 24% had cytokine or immunotherapy based therapies, 52% sunitinib and 17% sorafenib. The duration of 1st line therapy was 7.0 months in median for all patients (including cytokines) and 7.8 and 13.7 months for those treated with sunitinib or sorafenib, respectively. 50 patients achieved a second line therapy prior to everolimus, 22 patients were treated with sorafenib and 26 patients with sunitinib dependent on the 1st line therapy. Most patients treated with everolimus in 2nd or 3rd line therapy had an ECOG of 1 (49.4%) followed by ECOG 0 (39.5%) and ECOG 2 (9.9%). The median duration of treatment with everolimus was 4.5 months (0.6–22.5), 36% of the patients were more than 6 months on treatment with everolimus. Best response was CR in 2.5%, PR in 12% and SD in 47% of the patients (CBR 61%). Reasons for discontinuation were PD (72%), intolerance (16%), patients request (6%) and others (6%). 77/81 patients (95%) received a further therapy after discontinuation of everolimus. The agents administered beyond everolimus were sunitinib (29%), sorafenib (29%) and 36% received other therapies as temsirolimus, pazopanib or dovitinib. Best reported responses have been CR (1%), PR (9%), SD (48%) of the reported patients. 27 patients received an additional sequence of therapy (4th to 5th line). In summary, these data confirm the results of the RECORD-1 trial in clinical practice and demonstrate a clinical benefit of therapies beyond everolimus. 58% of the patients were still alive at time of evaluation. Disclosure L. Bergmann: The retrospective analysis was supported by a grant of Novartis Pharma. The presenter has been an advisor for Novartis Pharma. V. Grunwald: Advisory board Novartis. S. Weikert: Advisory board Novartis. T.C. Gauler: Advisary board Novartis. All other authors have declared no conflicts of interest.

602P - Comparative Budget Impact Analysis of Treatment Sequences in Metastatic Colorectal Cancer (MCRC): From First (1st) Line to Third (3RD) Line Therapies

ABSTRACT Background In the context of personalized cancer care, patients (pts) should receive the therapy that best meets their needs while optimizing the use of healthcare resources. A budget impact model was developed to compare each of the most commonly used mCRC treatment sequences – from 1st line to 3rd line in a Canadian context. Methods This Excel based model considers the price of each agent, the number of cycles per treatment course, the relative dose intensity of the regimens to determine the cost of the most commonly used mCRC therapies and calculates the costs per overall sequence from 1st line to 3rd line. It takes into account the percentage of pts who benefit from a R0 resection post 1st line chemotherapy and who forego subsequent treatments. Factors such as different percentage use of 1st line FOLFOX vs FOLFIRI and pts' volumes per line of therapy are considered in this model. Users can choose the scenarios they would like to examine. Key variables can be extracted through expert opinion, the literature or, to assess real-world local practices, through chart reviews. Results As scenarios considered, the budgetary impact of the 1st line use of FOLFOX or FOLFIRI both given with bevacizumab (bev) on 1st to 3rd line therapy costs was assessed. The relative use of FOLFOX and FOLFIRI with bev was varied from 80% use of FOLFOX and 20% use of FOLFIRI to the opposite. As key variables, the model compares, as 1st line therapy, 18 cycles of FOLFIRI and bev to 8 cycles of mFOLFOX6 followed by 10 cycles of 5FU/LV given with 18 cycles of bev. Also 80% of 1st line pts receive a second line chemotherapy. Assuming a cohort of a 100 pts, when FOLFOX's 1st line use varies from 80% to 20%, the budget varies from $4.14M to $3.85M, with all pts undergoing a R0 resection varying from 11.8 to 8.2 pts. Conclusions Focusing on drug costs only, this dynamic and flexible model goes beyond the comparison of upfront 1st line mCRC costs and considers cascading costs on subsequent lines (2nd and 3rd line) and consequences. It can be used to assess variability in local and provincial practice patterns and their impact on overall budget costs and number of pts benefiting from a R0 resection. Disclosure J.A. Maroun: Advisory board member for Roche and Sanofi. Involved in research projects with Roche and Sanofi. T. Boucher: Employee of Sanofi. K. Alloul: Employee of Sanofi Canada Inc.

340P - Fulvestrant After Failur of Adjuvant Hormonal Therapy: Multicenter Retrospective Observational Study

ABSTRACT Background Aromatase inhibitors (AI) are superior to TAM in the treatment of hormonal receptor positive metastatic breast cancer (MBC). Fulvestrant (F), an estrogen receptor antagonist demonstrated activity when used after failure of previous TAM or AI. Objective: To evaluate the position of F in the hormonal strategy sequence in hormonal responsive MBC related to the evolution of adjuvant hormonal therapy (HT). Material and methods MBC patients with disease progression after adjuvant HT or after treatment (CT or HT) for metastatic disease, candidate to receive F at the dose of 250 mg/ month (registered in AIFA database) from May 1st 2006 to July 31st 2008. The study registered the HT sequence in clinical practice. Overall 201 patients were collected from 13 Italian Centers. Main patients' characteristics are summarized in the table. Table: 340P Characteristics N 201 (%) Characteristics N 201 (%) T size Tis-T1-T2 T3-T4 T Unk 138(68,6) 40 (20) 23 (11,4) PgR Pos Neg Unk 142(70,6) 33 (16,4) 26 (13) Nodal Status N0 N+ Nx 54 (26,9) 120 (59,7) 27 (13,4) Adj CT Yes No Unk 105 (51,7) 94 (46,8) 3 (1,5) ER Pos Neg Unk 169 (84) 12 (6) 20 (10) Adj HT Yes No Unk 141 (70,1) 46 (22,9) 14 (7) Results ORR were: CR 2%; PR 7%; SD 43%; PD 41%; NE 7%. Eighty-six patients (43%) had visceral metastases. Median duration of F was 7 months (1-42); 8 patients are ongoing and for 1 patient the duration was unknown. 16, 39 and 56 patients received F as 1st, 2nd and 3rd line therapy respectively. For the remaining patients F was administered as more than the 4th line therapy. The possibility to obtain a benefit from F did not seem to correlate with the line of treatment. One of the 2 CR occurred in a patient with visceral disease (lung). Among the patients who progressed under treatment 42% had visceral disease, that was almost the same rate of the whole population. This data suggests that there is lack of correlation between the sites of disease and the probability of benefit. Toxicity was negligible. Conclusions More than 50% of the patients benefited from F notwithstanding 73% of them received the treatment as third or more line of HT. This study does not show any correlation between the sites of the metastases and the treatment results. Disclosure All authors have declared no conflicts of interest.

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC). Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m(2) twice daily on days 1-14 and docetaxel 75 mg/m(2) on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as ≥3rd line of therapy. All patients were evaluable for response and toxicity. Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7-62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4-64.2), the median time to disease progression 9.3 months (range 1.2-58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %. The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.

Clinical benefit of panitumumab after cetuximab failure in patients with metastatic colorectal cancer.

e14178 Background: Panitumumab (Pmab) is a fully humanized monoclonal IgG-2 antibody against epidermal growth factor receptor (EGFR). It was approved by the FDA in September 2006 as 3rd line therapy in metastatic colorectal cancer with disease progression on or following fluoropyrimidine (5-FU), oxaliplatin, and irinotecan chemotherapy regimens. Cetuximab (Cmab) is a chimeric monoclonal IgG-1 antibody and has been on the market since February 2004. It is unclear whether patients who have previously progressed on Cmab will benefit from therapy with Pmab. Methods: This is a retrospective analysis of 13 patients previously treated at OSUMC. The primary aim was to assess clinical benefit rate of Pmab in patients who failed Cmab. Patients were identified through our database from Sep 2006 until Dec 2011. Patient characteristics, length of treatment duration, response rate, and time elapsed from Cmab to Pmab were recorded. Clinical benefit (CR, PR, SD) was assessed by RECIST criteria. CEA was recorded. Results: Median age was 61 years (range 29-80), 8 males and 5 females. One patient had one FU-based line of chemotherapy while 12 patients had two FU-based lines of chemotherapy before starting Pmab. Five patients were KRAS wild-type, 8 were unknown. Five patients got Pmab as a single agent, 6 with FOLFIRI, 1 with irinotecan and 1 with capecitabine. Median time elapsed from stopping Cmab to starting Pmab was 4 months (range 0-25 months). One patient had a partial response to Pmab, 6 had stable disease, 2 had progressive disease and 4 patients did not have imaging studies. CEA decreased in 7 patients with mean decrease of 55% (SD +/- 34%). Median time to progression on Pmab was 5 months (range 1-13 months). Of 3 patients without clinical benefit to Cmab, 2 (67%) had clinical benefit from Pmab. Of 8 with clinical benefit to Cmab, 5 (63%) had clinical benefit from Pmab. Median duration of time from stopping Cmab to starting Pmab was similar for responders (3.5 months) and nonresponders (2.5 months). Conclusions: Our data suggest that Pmab can be given to patients previously treated on Cmab with clinical benefit seen in 2/3 of cases. Of interest, patients who did not have clinical benefit from Cmab did so with Pmab in 2/3 of cases.

Treatment patterns among metastatic colorectal cancer patients by line of therapy and original stage of diagnosis.

e14013 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend use of approved biologics combined with common chemotherapy agents for treatment of metastatic colorectal cancer (CRC). Five classes of chemotherapy/biologics are available for treatment of CRC. Methods: Adult patients with a diagnosis of CRC between 01/01/05 and 05/31/10 were identified from the Impact Intelligence Oncology Management (IIOM) registry. Patients with either stage 4 CRC at original diagnosis or development of a metastasis were included. Registry data included original date of diagnosis and stage information. Linked healthcare claims from a large US health insurance database affiliated with OptumInsight were used to identify lines of therapy and patient characteristics (e.g., development of metastases). Lines of therapy were based on patients’ use of chemotherapy/biologic agents after becoming metastatic. Treatment regimens were assessed and stratified by line of therapy (1st, 2nd, 3rd, 4th) and stage at diagnosis (0-2, 3, 4, unknown). Results: 16% of the 598 study patients who developed metastasis received no chemotherapy. Of those who did, 84%, 52%, 27%, and 14% received a 1st, 2nd, 3rd, and 4th line of therapy, respectively. 71% of patients who progressed from stage 0-2 or 3 received a 2nd line compared to 90% of patients who initially presented with stage 4 CRC. In the 1st line, 59% received an oxaliplatin-based regimen, 15% received an irinotecan-based regimen, and 11% received 5-FU alone. In 2nd and 3rd line therapy, percentages of patients treated with irinotecan-based regimens increased to 45% and 50%, respectively, and use of oxaliplatin-based regimens dropped to 27% and 16%, respectively. Overall, use of anti-EGFR agents increased steadily from 4% in the 1st line to 12%, 29%, and 38%, respectively in the 2nd, 3rd, and 4th lines. Conclusions: Patients who presented with stage 4 CRC had the highest rates of chemotherapy use. Despite NCCN guidelines, 11% of patients received 5-FU monotherapy as 1st line treatment.

A phase II study of second-line bendamustine in relapsed or refractory small cell lung cancer (SCLC).

7094 Background: Bendamustine is an alkylating agent with a nitrogen mustard group and purine-like benzimidazole group. Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JCO 2007]. This study aims to investigate the efficacy and safety of single agent bendamustine as 2nd or 3rd line therapy in patients with extensive-stage disease, small-cell lung cancer (ED-SCLC). Methods: This is an open-label, single-arm, multicenter phase II trial. Eligible patients had previously treated ED-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles. Evaluation occurred every 2 cycles. Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity. Results: 48 patients were enrolled; 56% were male and 96% were Caucasian. 33 patients were evaluable for response. There was 1 CR, 9 PR, 13 SD (48% disease control rate) and 10 PD. Median TTP was 3.37 months (95% CI 2.30 to 4.47 months). At the time of analysis, 13 patients were alive and with a median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia. Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%), and diarrhea (8.3%). Conclusions: These data indicate that single agent bendamustine appears to be well tolerated and effective in the second or third line setting for patients with SCLC.

BCR-ABL kinase domain mutations and resistance in Ph+ acute lymphoblastic leukemia from the imatinib to the second-generation TKI era.

6531 Background: Advent of 2nd-generation TKIs has brought additional treatment options for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients (pts). To analyze the changes they have determined in mutation frequency and type, we have reviewed the database recording the results of BCR-ABL mutation analyses done in our laboratory from 2004 through 2011. Methods: 781 tests on 258 pts were performed by direct sequencing. Results: 143 pts were analyzed because of imatinib resistance; 101 (71%) had one or more mutations (a single mutation in 91 pts; two mutations in 10 pts). Three mutation types were by far the most frequent: T315I (38 pts, 37%), E255K (19 pts, 18%) and Y253H (19 pts, 18%). Of 84 pts who had developed resistance to 2nd- or 3rd-line therapy with dasatinib, nilotinib or bosutinib after imatinib failure, 65 (77%) were positive for Bcr-Abl mutations; 30 (46%) carried multiple mutations (up to four) and in 19 of them (63%) this was consequence of multiple lines of therapy. The most frequent newly acquired mutation in this setting was the T315I, detected in 35/57 (61%) cases acquiring mutations on dasatinib. Mutation analysis was also performed in 15 resistant pts enrolled in a study of dasatinib as 1st-line treatment of Ph+ ALL; 12 pts were positive, 11 of them had a T315I. Taking advantage of a next-generation sequencer (Roche 454), allowing a high sensitive and quantitative mutation scanning of Bcr-Abl, serially collected samples from 24 selected cases who developed mutations and resistance to one or more TKIs were retrospectively analyzed to study the kinetics of expansion of mutant clones. Results will be presented. Conclusions: Although 2nd generation TKIs are more potent and have much fewer insensitive mutations, long-term disease control remains a problem and the T315I becomes an even tougher enemy. The high genetic instability fosters mutational events anytime during TKI treatment and some mutation types (T315I, Y253H) have been observed to emerge and take over very quickly (from <0.01% to 90% in one-two months). Supported by PRIN, AIL, AIRC, Fondazione CARISBO.

Treatment patterns and site of metastasis in patients with metastatic colorectal cancer (mCRC).

e14030 Background: The real-world impact of metastatic (met) site on Tx choice in mCRC is unknown. Therapeutic associations across metastases can identify gaps in care and inform clinical decision support systems. This study assessed Tx patterns in mCRC pts by met site. Methods: 4656 stage III/IV pts ≥18 yrs at mCRC diagnosis receiving anticancer agents were followed in a retrospective observational study using electronic medical records from the largest oncology database (SDI) from 1/1/04-7/31/11. 1st- (1L), 2nd- (2L), and 3rd-line (3L) therapies were identified for top 4 met sites. Logistic regression adjusting for met site overlap determined Tx use by met site and therapy line. Results: Pts were mostly male (54.1%) and on average 61.6 yrs. The top 4 met sites were liver (34.2%), lung (15.9%), lymph (15.8%), and bone (7.5%). Leading regimens are presented in the table below. Bevacizumab (B) use varied by met site and therapy line. Against other/unknown met sites, 1L B was more common in liver (OR=2.06 [1.75-2.42]) and bone (OR=1.46 [1.16-1.84]), less common in lymph (OR=0.60 [0.50-0.73]), and statistically equal in lung (OR=1.01 [0.85-1.20]). In 2L, B was more likely to be given for liver (OR=1.77 [1.48-2.11]) and lung (OR=1.45 [1.21-1.74]) vs no significant difference for bone (OR=1.17 [0.92-1.50]) and lymph (OR=0.87 [0.71-1.07]) sites. B use in 3L mirrored 2L. Conclusions: Besides 1L in pts with lymph metastases, top regimens across met sites for 1L, 2L, and 3L were FX + B, FR + B, and IRI + C, respectively; however, significant differences in B Tx patterns were evident. Further research should examine the impact of differential B use on outcomes. [Table: see text]

Does RECIST-defined progression correlate with lack of further sunitinib (SU) benefit in advanced renal cell carcinoma (aRCC)?

e15093 Background: RECIST defined radiographic progression on SU may be confounded by the intermittent dosing schedule and scan timing. Response rates to second line agents are typically lower and of shorter duration We analysed the potential for continued clinical benefit from continuation on Sunitinib following RECIST-defined progression in selected pts . Methods: Our institutional database was reviewed to identify aRCC pts who: 1) received SU, 2) achieved response or stable disease, and 3) had continuation of SU after documentation of RECIST-defined progression. Treatment history was obtained from medical chart review. CT scans were retrospectively assessed by RECIST criteria, pattern of progression was documented. SU cessation reasons were identified. Progression-free survival (PFS), post-progression treatment duration (PPD) and overall survival (OS) estimated by Kaplan Meier method. Results: Of 39 patients (pts) treated with SU between 2006 and 2009, 13 met entry criteria. Median age was 62 years (range: 33 – 66) with 11(85%) males. Eleven (85%) had prior nephrectomy and 4 (31%) had prior immunotherapy. Number of pts with MSKCC good/intermediate/poor risk groups were 5/7/1. Best radiographic response achieved was complete response/partial response/stable disease in two, five and six pts. Median PFS was 16.4 mos (11.8 – 23.8). Seven (54%) had progression of existing lesions while the six developed new lesions. Pts continued on SU as progression was relatively minor and clinical status was maintained. Median PPD was 4.2 months (0.6 – 40.5). Most common reasons for SU cessation were on-going radiographic progression (71%) and toxicity (18%). Only 2 pts stopped SU secondary to clinical deterioration. 62% of pts received subsequent lines of treatment, with half receiving 3rd line therapy. Median OS for the cohort was 31.7 mos. Conclusions: Continuation of treatment with SU following RECIST progression appears feasible and safe with prolonged disease control in selected pts . This approach should be further validated prospectively in a larger patient cohort. In this group, current standards for disease response assessment may underestimate the duration of clinical benefit conferred.

Abstract 1884: Resistance to second-line tyrosine kinase inhibitor treatment in imatinib-resistant Philadelphia-positive leukemia patients can be anticipated by ultra-deep sequencing of the BCR-ABL kinase domain using Roche 454 technology

Abstract Definite spectra of point mutations in the Bcr-Abl kinase domain (KD) are known to confer resistance to the 1st-generation tyrosine kinase inhibitor (TKI) imatinib (IM) and to the 2nd-generation TKIs dasatinib (DAS) and nilotinib (NIL) in Philadelphia-positive (Ph+) leukemias. Currently, European LeukemiaNet guidelines recommend mutation analysis to be performed by denaturing-high performance liquid chromatography (D-HPLC) and/or direct sequencing. Using Roche 454 next-generation sequencing (NGS) technology on a GS Junior instrument, we investigated whether an ultra-deep amplicon sequencing strategy for mutation screening of the Bcr-Abl KD could highlight emerging clones harbouring critical mutations, ultimately anticipating the development of drug-resistance. A lower detection limit of 0.05% - 5 mutated Bcr-Abl transcripts in a total of 10,000 Bcr-Abl transcripts - could routinely be achieved. Serially collected samples from IM-resistant CML and Ph+ ALL pts who received DAS and/or NIL as 2nd- or 3rd-line therapy and developed DAS- or NIL-resistant mutations were retrospectively analyzed from the time of switchover to the time of relapse. NGS was able to confirm all mutations known to be present in >20% of cells, allowed to follow quantitatively the dynamics of mutated clones over time and showed that i) 9/12 IM-resistant pts who failed to achieve a satisfactory response to 2nd-line therapy (primary resistance) were already harbouring mutations known to be insensitive to DAS (T315I, F317L/V) or NIL (E255K/V, Y253H, F359V/C) at 1-10% level before the TKI start - despite they had been scored as wild-type by D-HPLC; ii) in 9/13 IM-resistant pts who relapsed after an initial response (acquired resistance), the emerging resistant clone(s) carrying DAS- or NIL-insensitive mutation(s) could be identified up to six month in advance than when D-HPLC and conventional sequencing were used. In addition, when used for mutation monitoring of newly diagnosed Ph+ ALL pts enrolled in clinical trials with DAS or NIL, NGS again highlighted emerging resistant clones in 7/8 pts who later relapsed. We conclude that the higher sensitivity of NGS allows to detect emerging mutant clones earlier than the currently used methods; this is particularly relevant: i) in IM-resistant CML and Ph+ ALL pts before switching to and during treatment with a 2nd-line TKI, where NGS may anticipate the presence of DAS- or NIL-insensitive mutations, ensuring the most effective and timely therapeutic decisions; ii) more in general, for mutation monitoring of Ph+ ALL pts, that are known to be highly genetically unstable, hence markedly prone to develop resistance and mutations while on TKI therapy. Based on our data, further evaluation of the routine applicability of NGS is warranted. Supported by AIL, AIRC, PRIN, ELN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1884. doi:1538-7445.AM2012-1884

Cost-effectiveness of tapentadol prolonged release compared with oxycodone controlled release in the UK in patients with severe non-malignant chronic pain who failed 1st line treatment with morphine

Objectives:The aim of this analysis was to assess the cost-effectiveness of tapentadol PR (prolonged release) compared with oxycodone CR (controlled release) in severe non-malignant chronic pain patients in whom controlled release morphine was ineffective or not tolerated.Methods:A Markov model was developed to assess costs and benefits over a 1-year time horizon from the National Health Service perspective in the UK. Patients could either continue on 2nd line therapy or switch to 3rd line opioid due to lack of efficacy or poor tolerability. Patients failing also 3rd line therapy entered the final absorbing health state (4th line). Data on tolerability, efficacy, and utilities for tapentadol and oxycodone were obtained from the three comparative phase III clinical trials. Costs of resource consumption associated with opioid treatment were derived from a retrospective database analysis of anonymized patient records.Results:The model results predicted that initiating 2nd line therapy with tapentadol leads to higher effectiveness and lower costs vs oxycodone. For the overall population included in the clinical trials, mean annual costs per patient when treated with tapentadol and oxycodone were £3543 and £3656, respectively. Treatment with tapentadol, while cheaper than oxycodone, was more effective (0.6371 vs 0.6237 quality-adjusted life years (QALYs) for tapentadol and oxycodone, respectively), meaning that tapentadol dominated oxycodone. For the sub-group of opioid-experienced patients with severe pain at baseline the ranking in terms of costs and QALYs remained unchanged. Extensive sensitivity analyses showed that conclusions about the cost-effectiveness are consistent.Conclusions:The cost-effectiveness study suggested that initiating 2nd line treatment in patients with severe non-malignant chronic pain in the UK with tapentadol instead of oxycodone improves patients’ quality-of-life and is less costly. Key limitations when interpreting the results are the use of different sources to populate the model and restricted generalizability due to data extrapolation.

Outcome of Risk Adapted Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia in Children: Results From a Single Institution

Abstract 4237Although the outcome of first line therapy for childhood ALL has improved significantly, the results of second line therapy remains suboptimal. The most important predictive factors identified for second line therapy are timing and site of relapse; early relapse and bone marrow (BM) involvement invoking poorer outcomes.At our institution we have utilized a risk stratified therapeutic strategy for relapsed/refractory ALL which includes these factors. Re-induction for patients with first remission (CR1) duration of <18 months or those with remission failure was with high dose cytarabine (HDAraC) containing regimens, most often with idarubicin (Ida). For patients with CR1 >18 months, we utilized a standard 4-drug (prednisone, vincristine, daunomycin, asparaginase [PVDA]) induction regimen. Patients who relapsed in the BM while on chemotherapy or within 1 year of being off therapy were eligible for hematopoietic stem cell transplantation (SCT) after achieving CR, as were patients with isolated extra-medullary relapse with CR1 <18 months. Patients with late relapse were treated with post consolidation maintenance chemotherapy alone. Data collected prospectively in our database were reviewed. ALL patients who relapsed after receiving first line therapy at our institution and those who were referred to us at first relapse were included in this analysis. Only overall survival (OS) is presented as all patients who failed to achieve a CR or relapsed after achieving CR eventually died regardless of further therapeutic interventions.Fifty-nine patients with ALL failed their first line therapy between January 1, 2005 and May 31, 2011. There were four induction failures and 55 relapses. These 59 patients included 39 males; 53 of the patients had B-cell ALL and 6 had T-cell ALL. The age at original diagnosis ranged from 0.55 to 13.8 years (mean 6; median 4.8; SEM 0.50) whereas the age at first failure ranged from 0.68 to 16.4 years (mean 8.0; median 7.8; SEM 0.50). 36/55 (65.5%) relapses occurred on first line chemotherapy, 17 (30.9%) after completion of therapy and 2 (3.6%) following SCT. For the relapsed patients, the duration of CR1 ranged from 0.09 to 9 years (mean 2.0; median 1.7; SEM 0.22); 24 (44.4%) patients relapsed less than 18 months from CR1. 36 (61%) patients had isolated BM relapse, 13 (22.1%) had isolated extra-medullary (7 CNS; 6 testicular) and the remaining 10 had BM with other sites.Twenty four patients (40.7%) were re-induced with HDAraC/Ida (HIda), 28 (47.5%) with PVDA, 4 (6.8%) Fludarabine/AraC (FA) and 3 did not receive any second line therapy. For those who were treated 37 (62.7%) achieved a CR; 13 of the 19 patients who did not achieve CR with second-line therapy received third-line induction therapy (9 FA; 1 HIda; 1 VM26/AraC; 1 PVDA; 1 VP/CTX) and 7 (53.8%) achieved CR. The overall survival for all 59 patients at 2 years is 45.3%; for those who achieved CR the overall survival at 2 years is 64.7%.When we compared those patients who had CR1 durations >18 months with those who were induction failures or had CR1 duration <18 months, we found no significant difference in CR2 induction rates (76.7% v. 80%; p=1.0), nor in OS (56.9% v. 34.5% at 2 years; p=0.14). CR induction rates did not change when we further categorized CR1 duration into 18 months, 18–36 months and >36 months (80% v. 72.2% v. 80%; p=0.74). However, the OS was significantly higher for the >36 month group (83.3%; p=0.023) when compared to the other 2 groups (38.7% and 38.4%, respectively). In patients with <36 months of CR1, HSCT resulted in a significantly improved OS as compared to chemotherapy alone (51.4% v. 30.9 at 2 years; p=0.05).For those patients who achieved a CR2 there was no difference in the OS between those who underwent HSCT v. those who continued on chemotherapy (68% v. 58.5% at 2 years; p=0.33). Patients who achieved a CR after 2nd line therapy fared much better than those who achieved a CR after 3rd line therapy (25/36 [69.4%] alive v. 2/7 [28.6%] alive; OS at 2 years 68.3% v. 29.2%; p=0.06).In conclusion, we believe that this risk stratified approach to the treatment of relapsed/refractory ALL in children is effective. While the majority of the patients can be re-induced into remission, maintenance of the remission is dependent on the duration of CR1; patients with late relapse do as well as treatment naïve patients. Increased intensity induction therapy for early relapses and SCT for patients with <36 months of CR1 may be beneficial. Disclosures:No relevant conflicts of interest to declare.

Bendamustine and Rituximab for the Treatment of Chronic Lymphocytic Leukemia: The Moffitt Cancer Center Experience

Abstract 4620 Introduction:Although bendamustine is approved for the treatment of chronic lymphocytic leukemia (CLL), the combination of bendamustine and rituximab (BR) is currently under active investigation in the relapsed/refractory setting as well as for front-line use. Emerging data now suggests BR is acceptable for first-line use and indeed is listed in the NCCN Compendia as a first-line option. Herein, we report the results of a single-center retrospective review of BR use in first-, second- and third-line and beyond and its effects on response rate. Methods:We retrospectively reviewed 21 consecutive patients with CLL that received BR at the Moffitt Cancer Center (MCC) between July 2008 and November 2010. Bendamustine was dosed at 70 mg/m2 IV on Days 1 and 2 every 3–4 weeks; rituximab was dosed at 375 mg/m2 IV once with each cycle along with anti-microbial prophylaxis. Data collected included, but was not limited to age, gender, cytogenetic profile, number of previous therapies, Rai stage at time of treatment and response (based on 1996 NCI-WG definition). The primary objective was to assess response rates. The major secondary objective was to assess the effect of cytogenetics on response rates. All analyses were performed using descriptive statistics. Results:Twenty-one patients received treatment with BR; 7 patients received BR as first-line therapy, 7 received BR as second line therapy and the remaining 7 received BR as third-line therapy or beyond. The median age at time of treatment was 66; 12 of 21 patients were male (57%); All Rai Stages were represented, Stage 0 (n=1), Stage 1 (n=4), Stage 2 (n= 3), Stage 3 (n=5), Stage 4 (n=6). 38% of patients were positive for Del11q, 33% for Del13q, 9.5% for Del17p, and 9.5% for mutated IgVH. In previously untreated patients, 6/7 had a documented complete remission (CR) (71.4%) or partial (PR) (14.3%) response; one patient progressed (PD) on therapy. In second-line therapy, all patients had a documented CR (28.6%) or PR (71.4%). In patients treated with BR as 3rd or 4th line therapy, 3 patients had a CR, 2 patients had stable disease (SD), and 2 had PD. Of the 8 patients with Del11q, 37.5% achieved a CR, 4 had PR and 1 had PD. Of the 7 patients with Del13q, 4 achieved CR and 3 had a PR. Both patients with Del17p had PD. Of the 2 patients with mutated IgVH, one patient achieved a PR while the other had PD. Conclusion:Based on these results, the combination of bendamustine and rituximab in patients with CLL is efficacious and well tolerated in patients with both newly diagnosed and relapsed/refractory disease. Disclosures:Off Label Use: Bendamustine and rituximab for CLL. Ho:Genentech: Honoraria; Cephalon: Consultancy. Cultrera:Genentech: Speakers Bureau. Sotomayor:Genentech: Membership on an entity's Board of Directors or advisory committees. Pinilla-Ibarz:Genentech: Speakers Bureau; Cephalon: Speakers Bureau.

PS2-29: KRAS Testing in Metastatic Colorectal Cancer: The CERGEN-C Comparative Effectiveness Study

Pamala Pawloski, PharmD on behalf of the CERGEN Study Team HealthPartners Research Foundation