Green Bay, WI, United States
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Hoang T.,University of Wisconsin - Madison | Campbell T.C.,University of Wisconsin - Madison | Zhang C.,University of Wisconsin - Madison | Kim K.,University of Wisconsin - Madison | And 12 more authors.
Investigational New Drugs | Year: 2014

Introduction: The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods: Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40% of patients being free of progression at that time point. This study followed a two-stage minimax design. Results: Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8%). Median PFS was 1.5 months, 3m-PFS rate 11.1%, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions: Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients. © Springer Science+Business Media 2013.


Bible K.C.,Mayo Medical School | Peethambaram P.P.,Mayo Medical School | Oberg A.L.,Mayo Medical School | Groteluschen D.L.,Green Bay Oncology | And 14 more authors.
Gynecologic Oncology | Year: 2012

Purpose: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers. Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression > vs. ≤ 6 months following prior platin-based therapy). Measurable disease (RECIST) - or evaluable disease plus CA125 > 2X post-treatment nadir - and ECOG performance ≤ 2 were required. Results: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual. Conclusions: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study. © 2012 Elsevier Inc.


Crozier J.A.,Mayo Medical School | Advani P.P.,Mayo Medical School | Laplant B.,Alliance Statistics and Data Center | Hobday T.,Mayo Medical School | And 3 more authors.
Clinical Breast Cancer | Year: 2016

Background Irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan. Patients and Methods We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m2 on day 1 cycle 1 then 250 mg/m2 weekly thereafter and irinotecan 80 mg/m2 on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1). Results Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P =.49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early. Conclusion The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered. © 2016 Elsevier Inc. All rights reserved.


PubMed | Mayo Medical School, Alliance Statistics and Data Center and Green Bay Oncology
Type: Clinical Trial, Phase II | Journal: Clinical breast cancer | Year: 2016

Irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan.We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m(2) on day 1 cycle 1 then 250 mg/m(2) weekly thereafter and irinotecan 80 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1).Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P = .49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early.The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered.


Kenkre V.P.,University of Wisconsin - Madison | Long W.L.,University of Wisconsin - Madison | Eickhoff J.C.,University of Wisconsin - Madison | Blank J.H.,Green Bay Oncology | And 6 more authors.
Leukemia and Lymphoma | Year: 2011

Mantle cell lymphoma (MCL) is challenging to manage, with a median survival of 35 years. While intensive strategies are often appropriate for younger patients, these approaches are often not appropriate for older patients. In 2006, we reported our initial results using modified R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with maintenance rituximab. The complete response rate was 64%, and median progression-free survival (PFS) 37 months. Herein, we update our results, now with a median follow-up of 62 months. The median PFS is unchanged and the median overall survival (OS) is 70 months. The proportion of patients surviving at 5 years is 62%, comparable to studies using intensive strategies in similar patient populations. No late toxicities were noted in our cohort. These long-term results suggest that the modified R-hyperCVAD regimen with maintenance rituximab is an excellent option for older patients with newly diagnosed mantle cell lymphoma. © 2011 Informa UK, Ltd.


Loconte N.K.,University of Wisconsin - Madison | Holen K.D.,University of Wisconsin - Madison | Schelman W.R.,University of Wisconsin - Madison | Mulkerin D.L.,University of Wisconsin - Madison | And 8 more authors.
Investigational New Drugs | Year: 2013

Summary: Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID. © 2012 Springer Science+Business Media New York.


Sparano J.A.,Yeshiva University | Wang M.,Dana-Farber Cancer Institute | Zhao F.,Dana-Farber Cancer Institute | Stearns V.,Johns Hopkins University | And 9 more authors.
Cancer | Year: 2012

BACKGROUND: Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated. METHODS: The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided. RESULTS: When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥30 kg/m2) and overweight (BMI, 25-29.9 kg/m 2) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P =.0006) and overall survival (OS; P =.0007), but not in HER-2/neu-overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P =.0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P =.002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P =.02) and showed a strong trend for DFS (P =.07). Similar results were found in 2 other trials (E5188, E3189). CONCLUSIONS: In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy. © 2012 American Cancer Society.


Sparano J.A.,Yeshiva University | Wang M.,Dana-Farber Cancer Institute | Zhao F.,Dana-Farber Cancer Institute | Stearns V.,Johns Hopkins University | And 8 more authors.
Journal of the National Cancer Institute | Year: 2012

Background The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy. Methods The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline-and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided. Results Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P <.001) and a higher body mass index (median: 31.7 vs 27.4 kg/m 2; P <.001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor-positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor-positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086). Conclusion Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor-positive breast cancer. © 2012 The Author.


Makielski R.J.,University of Wisconsin - Madison | Lubner S.J.,University of Wisconsin - Madison | Mulkerin D.L.,University of Wisconsin - Madison | Traynor A.M.,University of Wisconsin - Madison | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2015

Abstract Purpose: Fluoropyrimidines and oxaliplatin have demonstrated some efficacy against pancreatic adenocarcinoma, but survival remains brief. Sorafenib is an oral multikinase inhibitor which we sought to combine with a unique capecitabine and oxaliplatin regimen for pancreatic adenocarcinoma. Methods: We performed a multicenter phase II study of sorafenib 200 mg orally twice daily along with oxaliplatin 85 mg/m2 IV on days 1 and 15, followed by capecitabine 2250 mg/m2 orally every 8 h for six doses starting on days 1 and 15 of a 28-day cycle in patients who had no more than one previous chemotherapy regimen for their pancreatic adenocarcinoma. The primary objective was response rate; secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-four patients were enrolled; median age was 63 years (range 48-83). The most common related toxicities were fatigue, neuropathy, anemia, thrombocytopenia, diarrhea, nausea, leukopenia, and hand-foot syndrome. Grade 3 hand-foot syndrome was rare (4 %). Other grade 4 toxicities included abdominal pain (8 %), pulmonary embolism (4 %), and anemia (4 %). Three partial responses were seen (13 %), and 11 patients had stable disease (46 %) as their best response. Median PFS was 6.0 months (range 1.5-13 months). Median OS was 8.1 months (range 1.5-13.6 months). Conclusions: Sorafenib, oxaliplatin, and capecitabine produced partial responses in patients with advanced pancreatic cancer including previously treated patients and demonstrated a PFS of 6 months with few grade 3/4 toxicities. © 2015 Springer-Verlag Berlin Heidelberg.

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