Rowland, Kendrith M.

Abstract Background: Treatment of aromatase refractory metastatic breast cancer (MBC) is difficult and challenging. Estrogen receptor (ER) resistance causes enhanced expression of the vascular endothelial growth factor (VEGF).Several studies have shown that the ER interacts with the VEGF pathway and is an important mechanism of resistance. Therefore we embarked on a phase II study of fulvestrant, a complete ER suppressor and bevacizumab, a well studied VEGF monoclonal antibody in aromatase refractory MBC patients. Methods: A single stage phase II study with an interim analysis of fulvestrant and bevacizumab was conducted with these objectives: 6 month progression-free survival rate (PFS), tumor response, toxicity, and overall survival. Regimen: fulvestrant 250 mg day1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and bevacizumab 10mg/kg days 1 and 15 of each 4 weeks is a cycle. Results: At the time of interim analysis, 11/20 evaluable patients achieved 3-month progression-free survival status while remaining on treatment for at least 3 months, not meeting the protocol specified efficacy requirements and thus halting accrual. 36 patients were enrolled from September 2007-December 2008; 33 patients were evaluable. Number of prior metastatic chemotherapy regimens: 0 in 26 patients and 1 in 7 patients. 22 (67%) patients received prior hormonal therapy in the metastatic setting. 18 (55%) had measurable disease. A median of 6 cycles (range 1-19) were administered. 12/33 evaluable patients (95% CI:20-55%) achieved 6-month progression-free survival status while remaining on treatment for a least 6 months. Among 18 patients with measurable disease, 2 (11%) patients CI:1.4-35%) had a confirmed tumor reponse (both PR). Additionally, 2 patients had stable disease for greater than 6 months, for a clinical benefit rate of 22%. Median follow up was 8.5 months (range 1.7-17.5 months). Median progression-free survival was 6.2 months (95% CI:5.4-10.1 months). The 6 -month overall survival rate was 84.8% (95% CI 73.5-98%). The median dose level administered was 250 mg for fulvestrant and 10 mg/kg for bevacizumab for cycles 1-19. The most common grade 3/4 adverse events (AEs) were hypertension 2 (6%), headache pain 2 (6%), and confusion 2 (6%). There was 1 grade 5 central nervous system hemorrhage. 13 (39%) patients experienced a grade 3 non-hematologic AE and 4 (12%) experience a grade 4+ non-hematologic AE. Conclusion: Fulvestrant/bevacizumab is safe and tolerable. Although this regimen did not meet its statistical endpoint, 22% of evaluable patients with aromatase refractory diesease achieved clinical benefit with minimal toxicity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4096.

Abstract Background: Microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves and the binding of paclitaxel to tubulin may lead to neuropathy. Peripheral neuropathy is a common dose limiting toxicity of paclitaxel. We hypothesized that the occurrence of peripheral neuropathy may correlate with outcome (disease-free survival; DFS).Methods: This analysis sought to describe incidence of peripheral neuropathy following paclitaxel and its association to outcome (DFS) in patients who received paclitaxel (weekly x 12) in the adjuvant HER2+ intergroup trial N9831. Only eligible pts who initiated paclitaxel and did not have peripheral neuropathy at initiation of paclitaxel that were randomized to arms A (955 pts; chemotherapy alone) and C (889 pts; chemotherapy plus concurrent trastuzumab) of N9831 were included. Cox regression analysis stratified by ER/PR status and nodal status was used to compare DFS within arm between patients with and without peripheral neuropathy.Results: Out of 1844 eligible pts, 379 developed neuropathy (20.5%). For pts in arm A, those who developed neuropathy had better DFS than pts who did not (3 yr DFS: 86.2% vs 81.8%; HR 0.65; p=0.01), despite lower doses of paclitaxel in the pts with neuropathy. Grade of neuropathy did not appear to impact DFS. No statistical difference was noted for pts treated in the trastuzumab-containing arm (3 yr DFS: 92.8% vs 91.1% for pts with neuropathy vs not; HR 0.79; p=0.34). There were no differences in paclitaxel dose intensity between arms A and C.Conclusion: Patients with early stage HER2+ breast cancer who received adjuvant paclitaxel-containing chemotherapy in arm A and developed peripheral neuropathy had a better DFS than pts who did not develop neuropathy. This effect was possibly abrogated by the use of trastuzumab in Arm C. This side effect may represent effective bindings of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site and/or lack of selective overexpression of β-III tubulin. This is a hypothesis generating study and additional analysis needs to be conducted from other large taxane-based trials.Partial support from Genentech and the Breast Cancer Research Foundation Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2100.

Purpose Functional iron deficiency may impair response to erythropoiesis-stimulating agents (ESAs) in iron-replete patients with chemotherapy-associated anemia (CAA). This study evaluated whether coadministration of parenteral iron improves ESA efficacy in patients with CAA. Patients and Methods This prospective, multicenter, randomized trial enrolled 502 patients with hemoglobin (Hb) less than 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies. All patients received darbepoetin alfa once every 3 weeks and were randomly assigned to receive either ferric gluconate 187.5 mg intravenously (IV) every 3 weeks, oral daily ferrous sulfate 325 mg, or oral placebo for 16 weeks. Results There was no difference in the erythropoietic response rate (ie, proportion of patients achieving Hb ≥12 g/dL or Hb increase ≥ 2 g/dL from baseline): 69.5% (95% CI, 61.9% to 76.5%) of IV iron-treated patients achieved an erythropoietic response compared with 66.9% (95% CI, 59.1% to 74.0%) who received oral iron and 65.0% (95% CI, 57.2% to 72.3%) who received oral placebo (P = .75). There were also no differences in the proportion of patients requiring red cell transfusions, changes in quality of life, or the dose of darbepoetin administered. Adverse events (AEs) tended to be more common in the IV iron arm: grade 3 or higher AEs occurred in 54% (95% CI, 46% to 61%) of patients receiving IV iron compared with 44% (95% CI, 36% to 52%) who received oral iron and 46% (95% CI, 38% to 54%) who received oral placebo (P = .16). Conclusion In patients with CAA, addition of IV ferric gluconate to darbepoetin failed to provide additional benefit compared with oral iron or oral placebo.

Purpose Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid–based topical keratolytic agent (ULABTKA) may prevent HFS. Patients and Methods A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m2 per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. Results The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. Conclusion These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Purpose Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes. Patients and Methods A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and χ 2 tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo. Results Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline week decreased by 50%, 65%, and 71% in the placebo, and target 75 mg twice daily and 150 mg twice daily pregabalin arms, respectively (P = .009 and P = .007, comparing respective pregabalin arms to the placebo arm). While some toxicities were significantly more common in the pregabalin arms, being more evident with the higher dose, pregabalin was generally well tolerated by most patients. Conclusion Pregabalin decreases hot flashes and is reasonably well tolerated. A target dose of 75 mg twice daily is recommended. Its effects appear to be roughly comparable to what has been reported with gabapentin and with some newer antidepressants.

Purpose To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome. Patients and Methods Patients with previously treated NSCLC received pemetrexed (500 mg/m2 intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome. Results Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C→T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C→T polymorphism in GGH correlated with OS (P = .04). Conclusion The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed.

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

Purpose We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease. Patient and Methods Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle. Results Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months. Conclusion Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.