Mayo Clinic Cancer Research Consortium Research Articles

Patient-reported outcomes questionnaire compliance in Cancer Cooperative Group Trials (Alliance N0992).

The use of patient-reported outcomes in clinical trials is a focal point for research and policy. Non-compliance with planned questionnaires and missing data can threaten both internal validity and generalizability. This retrospective analysis was conducted to determine the extent of, and characteristics associated with, missing patient-reported outcomes. Study characteristics, patient characteristics and adverse events, and reasons for non-compliance were compiled from 14 closed Alliance for Clinical Trials in Oncology, Mayo Clinic Cancer Center, or Mayo Clinic Cancer Research Consortium clinical trials. Compliance rates were calculated for each patient using the number of booklets completed while the patient was on trial divided by the number of booklets the patient was expected to complete. Frequency counts and summary statistics were compiled. Logistic regression techniques were employed. The 1640 included patients had a median age of 58 years and were mostly White (90.8%) and female (73.8%). Compliance rates per study ranged from 84.7% to 97.2%. The primary endpoint of overall compliance rate was 93.1%. A total of 1267 patients were compliant. Those non-compliant were slightly older (mean = 58.6 vs 57.5, p = 0.03) and had different types of cancers (p < 0.01). There were no differences in compliance according to tumor status (p = 0.66), clinical stage (p = 0.81), baseline quality of life (p = 0.42 for ≥8 vs <8 and p = 0.12 for ≥6 vs <6), or maximum adverse event grade incidence (p = 0.33 for grade 2+ incidence and p = 0.36 for grade 3+ incidence). Reasons for non-compliance included patient refusal (N = 136), booklet not administered to patient (N = 199), no clinic visit at the scheduled time for booklet completion (N = 40), and at-home-completed booklet not returned (N = 224). Logistic regression indicates gender (p < 0.01), race (p < 0.01), performance score (p = 0.02), dose delay status (p = 0.01), and incidence of grade 3 or higher adverse event (p = 0.03) were correlates of compliance. Patient-reported outcomes have successfully been implemented into Alliance and Mayo Clinic trials with high rates of patient compliance. Further improvement in compliance can be made with staff commitment and education. Patients are typically non-compliant only when the task at hand is burdensome, unclear, or logistically challenging. Existing tracking systems used for the other trial outcomes should be utilized to ensure successful capture of patient-reported outcomes.

Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)

BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body.METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment.RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm.All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79).Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%).Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR.Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm.Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented.CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. DisclosuresShanafelt:Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int’l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees.

Real-world comparative economics of a 12-gene assay for prognosis in stage II colon cancer.

3640 Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al. Value Health 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p&lt;0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $3,228 for drugs, $750 for administration, and $3,168 for adverse events management. Overall, average total direct medical costs decreased $1,683. The net effect on average patient well-being was a gain of 0.102 QALYs. Total change in medical costs is most influenced by the cost of death due to colon cancer, time-preference discount rate, and the change in aCT recommendations. Savings are expected to persist even if the cost of oxaliplatin dropped by &gt;75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these aCT changes reduce direct medical costs and improve patient well-being.

Real-world comparative economics of a 12-gene assay for prognosis in stage II colon cancer.

391 Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al., Value Health, 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p&lt;0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $5,738 for drugs, $668 for administration, and $3,268 for adverse events management. Overall, average total direct medical costs decreased $4,203. The net effect on average patient well-being was a gain of 0.083 QALYs. Total medical costs are most influenced by change in aCT recommendations, 5-FU monotherapy efficacy, and oxaliplatin drug acquisition cost. Savings are expected to persist even if the cost of oxaliplatin dropped by &gt;75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these changes in aCT reduce direct medical costs and improve patient well-being.

Prospective evaluation of a 12-gene assay on treatment recommendations in patients with stage II colon cancer.

453 Background: A 12-gene assay (Oncotype DX Colon Cancer) has been clinically validated as a predictor of recurrence risk in stage 2 colon cancer patients following surgery. We conducted the first prospective study to characterize the impact of Recurrence Score results on medical oncologists’ recommendations regarding adjuvant chemotherapy in T3, Mismatch Repair-proficient (MMR-P) stage 2 colon cancer patients. Methods: Consecutive patients with resected stage 2A colon cancer who were candidates for adjuvant chemotherapy were consented and enrolled by 105 medical oncologists from 17 sites in the Mayo Clinic Cancer Research Consortium. Each patient’s tumor specimen was assessed by the Recurrence Score test (quantitative RT-PCR) and MMR (IHC). Prior to and after receiving these results, physicians completed surveys indicating their planned treatments given hypothetical or known MMR results, recorded as Observation (Obs), 5FU-based chemotherapy (5FU), or 5FU + Oxaliplatin (Oxal). Change in treatment recommendation intensity from baseline to follow-up was defined as: increased if change from Obs to 5FU +/- Oxal or from 5FU to 5FU+Oxal, decreased if change from 5FU + Oxal to 5FU or Obs, or from 5FU to Obs, or no change. Results: 187 of 221 patients enrolled were evaluable including 141 who were MMR-P (avg age 63, 65% ECOG PS 0, med tumor size 5 cm, 11% high grade, 91% with 12+ nodes examined). In the primary analysis treatment recommendations changed for 63 (45%) of 141 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy (5-FU +/- Oxal) decreased from 73 (52%) patients pre-assay to 42 (30%) post-assay. Increased treatment intensity was more likely at higher Recurrence Score values and decreased intensity at lower Recurrence Score values (p=0.011), and any change was more likely when MMR status was unknown at baseline (p = 0.041). Conclusions: In this prospective study, quantitative recurrence risk information provided by the Recurrence Score test was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients. Use of the 12-gene assay may lead to overall reductions in chemotherapy.

The relationship between serum hepcidin levels and clinical outcomes in patients with chemotherapy-associated anemia treated in a controlled trial.

9031 Background: The Mayo Clinic Cancer Research Consortium recently published results from a phase III, randomized study (MC04CC) of darbepoetin alfa (DA) combined with intravenous (IV) ferric gluconate 187.5 mg q3wks x 5 doses, oral ferrous sulfate, or no iron supplementation for patients (pts) with chemotherapy-associated anemia (CAA) (Steensma et al, J Clin Oncol 2011;29:97-105). There was no benefit from IV iron in the MC04CC trial, possibly due to iron parameters of enrolled pts. The peptide hepcidin is a major regulator of systemic iron homeostasis, but the relationship between hepcidin and response to erythropoiesis-stimulating agents (ESAs) or IV iron therapy has not been systematically studied in pts with CAA. Methods: Serum hepcidin concentration was measured in pre-treatment samples from 405/489 eligible pts enrolled in the MC04CC study, using a sensitive quantitative mass spectrometry-based method. Hemoglobin and transfusion endpoints were analyzed, stratified by hepcidin tertiles and treatment group. Results: See table. Conclusions: Pts with serum hepcidin levels in the lower two tertiles appeared to have a better clinical response to DA plus higher doses of IV iron than either pts with higher hepcidin levels, or pts with lower hepcidin levels who did not receive higher dose IV iron. Hepcidin measurements may help predict response to ESAs and supplemental iron. DA + placebo DA + oral iron DA + IV iron (pts receiving <4 doses IV iron) DA + IV iron (pts receiving 4 or 5 doses IV iron) Hemoglobin response Total 106/163 (65%) 109/163 (67%) 40/71 (56%) 74/92 (80%) Hepcidin 1st tertile (≤20.2 ng/mL) 30/47 (64%) 26/41 (63%) 12/20 (60%) 24/26 (92%) Hepcidin 2nd tertile (>20.2-64.3 ng/mL) 36/53 (68%) 32/53 (60%) 6/11 (55%) 20/21 (95%) Hepcidin 3rd tertile (>64.3 ng/mL) 23/36 (64%) 29/37 (78%) 14/24 (58%) 25/36 (69%) Hepcidin missing 17/27 (63%) 22/32 (69%) 8/16 (50%) 5/9 (56%) RBC transfusion Total 22/163 (13%) 21/163 (13%) 12/71 (17%) 8/92 (9%) Hepcidin 1st tertile 6/47 (13%) 4/41 (10%) 2/20 (10%) 0/26 (0%) Hepcidin 2nd tertile 8/53 (15%) 9/53 (17%) 2/11 (18%) 0/21 (0%) Hepcidin 3rd tertile 6/36 (17%) 5/37 (14%) 4/24 (17%) 6/35 (17%) Hepcidin missing 2/27 (7%) 3/32 (9%) 4/16 (25%) 2/9 (22%)

Cardiac Safety of Lapatinib Given Concurrently with Paclitaxel and Trastuzumab as Part of Adjuvant Therapy for Patients with HER2+ Breast Cancer: Pilot Data from the Mayo Clinic Cancer Research Consortium Trial RC0639.

Abstract Background: Despite the impressive results of the trastuzumab adjuvant therapy trials, 15% of patients (pts) with HER2 overexpressing or amplified breast cancer developed tumor relapse at 4 years. Lapatinib is a reversible tyrosine kinase inhibitor against ErbB1 and ErbB2. The current study was developed to assess the cardiac safety and feasibility of adding lapatinib to paclitaxel and trastuzumab following doxorubicin and cyclophosphamide as part of adjuvant therapy.Methods: A single-arm phase II study of doxorubicin (A, 60 mg/m2 day 1) and cyclophosphamide (C, 600 mg/m2 day 1) [q2w or q3w for 4 cycles]; followed by PTL: paclitaxel (P, 80 mg/m2 weekly), trastuzumab (T, 4 mg/kg loading dose then 2 mg/kg weekly), and lapatinib (L, 1000 mg PO daily which was later amended to 750 mg) [total of 12 weeks of treatment]; followed by T (6 mg/kg day 1, every 3 weeks) and L (1000 mg PO daily) [total of 40 weeks of treatment] was conducted. The primary endpoint was severe symptomatic congestive heart failure (CHF: New York Heart Association Class III or IV with a drop in left ventricular ejection fraction [LVEF] of at least 10 percentage points to below 50% confirmed by cardiologist) with secondary endpoints of cardiac death and grade 3+ cardiac adverse events (AEs).Results: From April 2007 to October 2008, 109 evaluable pts were enrolled and initiated study treatment. Median age was 51 (range 28-72). Median follow-up is 10.2 months. No pts experienced CHF or cardiac death while on active treatment. One pt had CHF and 1 pt died due to myocardial infarction (MI) after they went off study treatment. The pt with CHF refused further treatment after completing 2 cycles of PTL and had CHF 1.8 months post PTL discontinuation with LVEF of 45% and dyspnea on exertion. The pt with MI went off study treatment due to non-cardiac AEs after completing 2 cycles of PTL and died 2.9 months post PTL discontinuation. Mean LVEF at baseline was 63.6% (N=109, SD=5.7); end of AC was 63.3% (N=104, SD=6.4); end of PTL was 59.9% (N=89, SD=8.3); and cycle 12 was 59.7% (N=66, SD=7.1). Grade 3+ non-hematologic AEs with incidence &amp;gt;5% include diarrhea (N=42, 39% &amp; included both 1000mg &amp; later amended 750mg dosing), fatigue (N=15, 14%), nausea (N=7, 6%), vomiting (N=7, 6%), acne (N=6, 6%), and hypokalemia (N=6, 6%). Pre-treatment cardiac marker data (troponin-T, troponin-I, brain natriuretic peptide, creatine kinase MB isoenzyme) will also be presented.Conclusions: Preliminary data suggest that the inclusion of L does not add to the cardiac profile of T. Data from ALTTO and long-term follow data are needed to confirm the cardiac safety of this regimen. Cardiac marker data are being analyzed in the context of changes in LVEF. We gratefully acknowledge support from the Breast Cancer Research Foundation and GlaxoSmthKline for this study. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3086.

A Randomized Comparison of Standard Weekly Epoetin Alfa to Every-3-Week Epoetin Alfa and Every-3-Week Darbepoetin Alfa: A Study of the Mayo Clinic Cancer Research Consortium (MCCRC).

Abstract 3008Poster Board II-984 Introduction:The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (i.e., administration less than once weekly) is a common practice with DA, which is FDA approved for dosing once every 3 weeks (q3wks); a previous study of the North Central Cancer Treatment Group suggested that EA can also be given less often than the FDA-approved once weekly schedule (Steensma DP et al, J Clin Onc 2006; 24:1079). The present study compared 2 different q3wks extended-interval EA regimens with weekly fixed-dose EA and with q3wks DA in pts with CAA. Patients and Methods:Eligible pts were receiving chemotherapy for a non-myeloid malignancy and had Hb <10.5 g/dL, ferritin >20 ng/mL, weight >40 kg and <150 kg, and ECOG performance score £2. Pts were randomized 1:1:1:1 to receive EA 40,000 Units subcutaneously (SC) once weekly (40K arm), EA 80,000 Units SC q3wks (80K arm), EA 120,000 Units SC q3wks (120K arm), or DA 500 mcg SC q3wks (DA arm), for 15 weeks. EA and DA were held for Hb >12 g/dL and restarted at a lower dose when Hb fell to '11.5 g/dL. All pts received ferrous sulfate 325 mg orally once daily, if tolerated. Quality of life (QOL) was measured using the Symptom Distress Scale (SDS), Brief Fatigue Inventory (BFI), FACT-An, and Linear Analogue Self Assessment (LASA) tools. The primary endpoint was the proportion of pts achieving Hb≥11.5 g/dL or increment of Hb>2.0 g/dL from baseline. Secondary endpoints included RBC transfusion requirements, adverse events (AEs), and QOL. Results:239 pts (236 evaluable) enrolled at 10 MCCRC sites between Feb. 2007 and Dec. 2008; 62% of pts completed all study interventions. The median age of enrolled pts was 66 years; 42.4% were men, 91.5% had solid tumors, 26.7% had severe anemia (Hb <9.5 g/dL), and 44.9% were receiving platinum-containing regimens. Baseline characteristics were balanced between study arms, with the exception of gender (39% female for 40K, 60% for 80K, 43% for 120K, 26% for DA). There were no significant differences between treatment arms in the proportion of pts achieving a Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; p>0.41 for all comparisons), but the median Hb increment from baseline was higher in the 40K and DA arms compared to the 2 extended dosing EA arms (40K-2.8 g/dL, 80K-2.0 g/dL, 120K-2.1 g/dL, DA-2.6 g/dL; p=0.005 for 40K vs 80K). Hb response was achieved more quickly in the weekly EA arm, but the difference was not significant (40K-32 days, 80K-50 days, 120K-49 days, DA-49 days; p>0.13). The proportion of patients transfused was similar between arms (40K-27.9%, 80K-33.3%, 120K-22.4%, DA-29.8%; p>0.49). There were no significant differences in QOL changes. Deaths were also similar between arms (40K-5 pts, 80K-7 pts, 120K-7 pts, DA-1 pt, p>0.10) and were primarily due to disease progression. AEs and serious AEs were comparable between study groups; grade 3/4 AEs were observed in 22% of pts in the 40K arm, 22% on 80K, 17% on 120K, and 13% on DA; p>0.56. The median total dose of EA used was highest in the 120K arm (40K-265,000 U; 80K-240,000 U; 120K-360,000 U; p=0.0009 for 40K vs 120K), while pts on the 40K arm were more likely to omit a dose due to a high Hb (40K-63.9% of pts omitted at least one dose; 80K-30.0%; 120K-34.5%; DA-43.6%, p<0.0001 for 40K vs 80K). Conclusion:Although there was no significant difference in the proportion of responding pts (the primary endpoint), Hb increments from baseline were moderately higher with the 2 FDA-approved regimens – weekly EA 40,000 Units, and q3wk DA 500 mcg – than with the extended dosing regimens.This study was supported by a grant from Centocor Ortho Biotech, Inc. to the MCCRC. Disclosures:No relevant conflicts of interest to declare.

A Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation On the Erythropoietic Response to Darbepoetin Alfa for Patients with Chemotherapy-Associated Anemia: A Study of the Mayo Clinic Cancer Research Consortium (MCCRC).

Abstract 630 Introduction:Erythropoiesis stimulating agents (ESAs) improve hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with chemotherapy-associated anemia (CAA), but many pts with CAA do not respond to ESAs. Functional iron deficiency due to inflammation-related hepcidin production and pathological sequestration of bioavailable iron may be an important reason for lack of ESA response in iron-replete pts. The common clinical practice of co-administering oral iron with ESAs does not appear to alter the disordered iron processing in CAA. We conducted a prospective trial to evaluate whether parenteral iron might overcome functional iron deficiency and benefit iron-replete pts with CAA undergoing ESA treatment. Patients and Methods:Eligible pts were receiving chemotherapy for a non-myeloid neoplasm and had Hb level <11.0 g/dL, ferritin >20 ng/mL, transferrin saturation <60%, and ECOG performance score ≤2. All pts received darbepoetin alfa (DA) 500 mcg subcutaneously q3wks until Hb reached >11 g/dL, and thereafter DA 300 mcg q3wks; DA was held for Hb >13 g/dL until Hb fell to <12 g/dL, then restarted with 25% dose reduction. Pts were randomized 1:1:1 to receive either sodium ferric gluconate complex in sucrose (Ferrlecit) 187.5 mg intravenously q3wks (total dose 1,125 mg), oral ferrous sulfate 325 mg once daily, or oral placebo. Quality of life (QOL) was measured using the Symptom Distress Scale, Brief Fatigue Inventory, FACT-An, and LASA instruments. The primary endpoint was the proportion of patients achieving Hb ≥12.0 g/dL or ≥2.0 g/dL Hb increment from baseline by the end of the 16-week study. Secondary endpoints included transfusion requirements. changes in QOL, changes in iron parameters, and adverse events (AEs). Results:Planned enrollment was 582 pts, but the study met an early stopping rule due to an excess of serious AEs in the IV iron arm; 502 pts enrolled at 14 MCCRC sites between February 2006 and December 2008. The median age of the 490 evaluable pts was 64 years; 65% were female and 94% white; 6% had hematological neoplasms (lymphoma or multiple myeloma), 25% had severe anemia (Hb <9.5 g/dL), 48% received platinum-containing therapy, and 66% completed all 16 weeks of the study. Baseline characteristics were comparable between groups. With respect to the primary endpoint, 69.5% of IV iron-treated pts achieved a Hb response (median Hb increase from baseline to end of study, 2.7 g/dl), compared to 66.9% with oral iron (median increase, 2.4 g/dL) and 65.0% with placebo (median increase 2.3 g/dl) (p=0.73). There were no significant differences in the proportion of patients requiring RBC transfusion (12.8% for IV iron, 12.9% for oral iron, 13.5% for placebo; p=0.87) or QOL changes. A total of 17 pts (3%) died on study–8 in the IV iron arm, 6 oral iron, 3 placebo (p=0.22). Grade 3 or higher AEs occurred in 54% of IV iron pts compared to 43% for oral iron and 45% placebo (p=0.03). The end-of-study ferritin level was higher in the IV iron arm (median 501 ng/mL) compared to the oral iron (229 ng/mL) and placebo (193 ng/mL) arms (p=0.0022). The median total DA dose administered was similar between arms (p=0.71). Conclusions:Co-administration of DA with intravenous ferrous gluconate q3wks did not result in improvement in Hb levels, reduce transfusions, improve QOL endpoints, or allow lower doses of DA, compared with DA + oral iron or DA + placebo. IV iron increased AEs. The reason for discordant results with 5 previous smaller studies is unclear. Disclosure:The study was supported by a grant from Amgen (Thousand Oaks, CA) to the MCCRC. Disclosures:Off Label Use: Ferrlecit, chemotherapy-associated anemia.

HER-2 central confirmatory testing using ASCO/CAP guidelines for trastuzumab/lapatinib trial MCCR RC0639

e11527 Background: 118 Her2 positive invasive carcinomas were retested centrally at the Mayo Clinic for Her2 status confirmation prior to inclusion in Mayo Clinic Cancer Research Consortium study RC0639 phase II study of cardiac safety and tolerability of adjuvant chemotherapy plus trastuzumab with lapatinib for resected Her2+ breast cancer (MCCRC RC0639). Methods: Central confirmatory methods were immunohistochemical (IHC) Dako HercepTest on a Dako Autostainer using the manufacturer's recommendations and HercepTest kit epitrope retrieval kit and fluorescent in situ hybridization (FISH) using Vysis PathVysion probe kit. Test results are interpreted using ASCO/CAP guidelines (IHC &gt;30%, Her2:CEP 17 ratio &gt;2.2). Results: There is local and central test 3+ IHC concordance in 48 of 53 tumors (agreement 90.6%) and FISH amplification in 29 of 33 tumors (agreement 87.9%), improved or similar results using identical methods to results in NCCTG N9831 adjuvant trial (n=1063, 81.6% IHC; n=813, 88.1% FISH). Of 92 centrally tested 3+ IHC positive tumors, 88 (95.7%) were FISH amplified. 5 centrally tested patients interpreted as Her2 positive by pre-ASCO/CAP guidelines (IHC &gt;10%; HER2:CEP17 ratio &gt;2) are Her2 ineligible using ASCO/CAP guidelines. IHC not confirmed centrally was reviewed by a second pathologist in 16 of 118 specimens. IHC concordance between two central pathologists was 10/16 (62.5%) in negative or equivocal (≤30% IHC staining) specimens; 7/10 (70%) with two reader agreement were FISH amplified and 4/6 (66%) with disagreement were FISH amplified. Conclusions: Concordance in IHC and FISH results between local and central labs is similar or improved since N9831. New ASCO/CAP Her2 testing guidelines change eligibility based on Her2 status in 4.2 % of patients. Equivocal IHC results falling between pre- and post- ASCO/CAP IHC positive thresholds (&gt;10% and &lt;30% IHC strong staining) are only partially resolved by repeat IHC review and/or FISH testing. No significant financial relationships to disclose.

Tolerability of lapatinib given concurrently with paclitaxel and trastuzumab as part of adjuvant therapy in patients with resected HER2+ breast cancer: initial safety data from the Mayo Clinic cancer research consortium trial RC0639.

Abstract Abstract #2109 Background: Despite the impressive results of the recently released trastuzumab adjuvant therapy trials, 15% of patients with HER2 overexpressing or amplified breast cancer developed tumor relapse at 4 years. Lapatinib is a small molecule reversible TKI that inhibits both ErbB1 and ErbB2. The current study was developed to assess the cardiac safety and feasibility of adding lapatinib to paclitaxel and trastuzumab following as part of adjuvant therapy.&amp;#x2028; Methods: A single-arm phase II study of doxorubicin (A, 60 mg/m2 day 1) and cyclophosphamide (C, 600 mg/m2 day 1) [q2w or q3w for 4 cycles]; followed by paclitaxel (P, 80 mg/m2 days 1, 8, 15), trastuzumab (T, 4 mg/kg loading dose then 2 mg/kg days 1, 8, 15), and lapatinib (L, 1000 mg days 1-21) [12 weeks]; followed by T (6 mg/kg day 1) and L (1000 mg days 1-21) [40 weeks] was conducted. The primary endpoint was the incidence of congestive heart failure. The current unplanned safety analysis was undertaken due to the observance of a high rate of G3/4 diarrhea.&amp;#x2028; Results: From April 2007 to June 2008, 98 pts were enrolled and initiated study treatment. Median age was 51 (range 32-72). Among 83 pts with adverse event (AE) data available, 50 (60%) pts have experienced a G3/4 non-hematologic AE. During post-AC treatment, among 53 pts with AE data available, 31 (58.5%) patients have experienced a G3/4 non-hematologic AE with 24 (45%) patients reporting G3/4 diarrhea. Median cycle of onset of G3/4 diarrhea was cycle 5 (first cycle of PTL) with 16 (64%) cases first reported during cycle 5 and 5 (20%) cases first reported during cycle 6. Among 57, 46, 38, and 32 pts receiving treatment with PTL during cycles 5-8, 65%, 57%, 61%, and 72% of patients received the full L dose, respectively. 31 patients have ended active treatment with 10 due to patient refusal and 8 due to adverse events.&amp;#x2028; Conclusions: Preliminary data suggest that L given concurrently with P and T at a dose of 1000 mg per day induces an unacceptable rate of moderate to severe diarrhea. Careful monitoring of diarrhea as well as L dose reduction and initiation of loperamide at first occurrence of diarrhea are recommended. The dose of L when given concurrently with P and T has been amended to 750 mg per day in the current study and safety data for the 1000 mg and 750 mg per day cohorts will be presented. Implications for the ongoing ALTTO study will also be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2109.