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Traynor A.M.,University of Wisconsin - Madison | Lee J.-W.,Dana-Farber Cancer Institute | Bayer G.K.,Saint Vincent Hospital | Tate J.M.,Merit Care Hospital CCOP | And 5 more authors.
Investigational New Drugs | Year: 2010

Background: The objective of ECOG 1503 was to determine the response rate of this combination in the second-line treatment of advanced NSCLC. Methods: Triapine 105 mg/m2 IV on days 1, 8, and 15, and gemcitabine 1,000 mg/m2 on days 1, 8, and 15, of a 28 day cycle. Results: Eighteen patients enrolled. Three patients were not eligible due to protocol violations. No objective antitumor responses were seen. Three patients (20%) experienced stable disease (90% CI 5.7-44%). Median overall survival: 5.4 months (95% CI 4.2-11.6 months); median time to progression: 1.8 months (95% CI 1.7-3.5 months). Five patients developed acute infusion reactions to Triapine® related to elevated methemoglobinemia. Patients with MDR1 variant genotypes of C3435T experienced superior overall survival compared to non-variants (13.3 vs. 4.3 months, respectively, p = 0.023). Conclusion: This regimen did not demonstrate activity in relapsed NSCLC. Prolonged survival seen with MDR1 variant genotypes is hypothesis-generating. © 2009 Springer Science+Business Media, LLC.


PubMed | Illinois Cancer Care, McGill University, Belfast Health and Social Care Trust, Sloan Kettering Cancer Center and 11 more.
Type: Journal Article | Journal: Gynecologic oncology | Year: 2016

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged 40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02).Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.


Dranitsaris G.,Cancer Clinics of Excellence | Beegle N.,Cancer Clinics of Excellence | Ravelo A.,Genentech | Kalberer T.,Cancer Clinics of Excellence | And 2 more authors.
Clinical Lung Cancer | Year: 2013

Background: In patients with advanced-stage non-small-cell lung cancer (NSCLC) with nonsquamous histology, bevacizumab maintenance therapy after initial combination with platinum-based chemotherapy has been approved in the United States and Europe. In this study, a comparative effectiveness analysis of bevacizumab maintenance therapy after initial chemotherapy with bevacizumab is described. Methods: A retrospective analysis of patients treated in 17 community oncology practices across the United States was conducted. Inclusion criteria consisted of patients with stage IIIb or IV disease who received bevacizumab maintenance after an initial first-line induction regimen. Overall survival (OS) was evaluated by using the method of Kaplan-Meier and Cox proportional hazard modeling. To control for selection bias that is inherent in observational studies, an 18-week landmark and propensity score analysis was conducted. The hazard ratio (HR) for OS was then evaluated in a sensitivity analysis. Results: A total of 272 patients with advanced-stage NSCLC met the inclusion criteria. Only 74 (27.2%) patients received bevacizumab maintenance therapy. Patients in the bevacizumab maintenance group tended to be younger and fitter, with a more favorable disease profile, which resulted in an improvement in the crude unadjusted OS (23.1 vs. 10.3 months; hazard ratio (HR) 0.44 [95% CI, 0.32-0.59]). Landmark and propensity score analyses supported the finding of a reduced risk of death with bevacizumab maintenance therapy (HR 0.52 [95% CI, 0.37-0.73] for landmark analyses and HR 0.70 [95% CI, 0.39-1.28] for propensity score analyses). Conclusions: Bevacizumab maintenance therapy contributed to an OS benefit in this retrospective sample of patients with NSCLC, even after multiple statistical adjustments for selection bias. © 2013 Elsevier Inc. All rights reserved.


Jain N.,University of Chicago | Curran E.,University of Chicago | Iyengar N.M.,University of Chicago | Diaz-Flores E.,University of California at San Francisco | And 20 more authors.
Clinical Cancer Research | Year: 2014

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractoryAMLor 60 years old or more with untreatedAMLwere enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. Results: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490-8. © 2013 American Association for Cancer Research.


Sharma M.R.,University of Chicago | Wroblewski K.,University of Chicago | Polite B.N.,University of Chicago | Knost J.A.,Illinois Cancer Care | And 7 more authors.
Investigational New Drugs | Year: 2012

Background Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Patients and methods We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. Results Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. Conclusion Dasatinib is inactive as a single agent in previously treated metastatic CRC patients. © 2012 Springer Science+Business Media, LLC.


Crawford J.,Duke University | Swanson P.,Hematology Oncology Asociates | Schwarzenberger P.,Louisiana State University Health Sciences Center | Sandler A.,Hematology Oncology Asociates | And 6 more authors.
Journal of Thoracic Oncology | Year: 2013

Introduction: This two-part phase 2 study evaluated the efficacy and safety of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, combined with carboplatin/paclitaxel in patients with previously untreated advanced non-small-cell lung cancer. Methods: In part 1, patients were sequentially enrolled to receive paclitaxel 200 mg/m2 and carboplatin (area under the concentration-versus-time curve, 6 mg/min/ml) plus panitumumab (1.0, 2.0, or 2.5 mg/kg). In part 2, patients were randomized 2:1 to receive paclitaxel/carboplatin with (arm A) or without (arm B) the maximum tolerated dose of panitumumab identifed in part 1. Primary endpoints in parts 1 and 2 were the incidence of dose-limiting toxicities and time to progression (TTP), respectively. Results: In part 1, four of 19 patients had dose-limiting toxicities: three at 2.0 mg/kg (fatigue, pain in extremity, dyspepsia) and one at 2.5 mg/kg (rash). The maximum tolerated dose was not reached; panitumumab 2.5 mg/kg was selected for part 2. In part 2, TTP was 18.1 weeks (95% confidence interval [CI], 13.6-23.3) in arm A and 23.0 weeks (95% CI, 15.9-24.1) in arm B (hazard ratio, 0.9; 90% CI, 0.66-1.21; p = 0.555). Progression-free survival in arms A and B was 17.6 weeks and 18.3 weeks, respectively, and the objective response rate was 15.2% and 11.1%. Adverse events occurring more frequently in arm A than in arm B included skin toxicity, diarrhea, stomatitis, vomiting, and dizziness. Exploratory analyses did not demonstrate associations between potential biomarkers and outcomes. Conclusion: Although toxicity was predictable and manageable, the addition of panitumumab to paclitaxel/carboplatin did not improve TTP in patients with previously untreated advanced non-small-cell lung cancer. Copyright © 2013 by the International Association for the Study of Lung Cancer.


PubMed | Illinois Cancer Care and Foundation Medicine
Type: | Journal: Head & neck | Year: 2016

Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options.We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case.Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control.Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. 2016 Wiley Periodicals, Head Neck, 2016.


PubMed | Illinois Cancer Care, McGill University, Belfast Health and Social Care Trust, Illinois College and 2 more.
Type: | Journal: Familial cancer | Year: 2016

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.


Witzig T.E.,Mayo Medical School | Fishkin P.,Illinois Cancer Care | Gordon L.I.,Northwestern University | Gregory S.A.,Rush University Medical Center | And 5 more authors.
Leukemia and Lymphoma | Year: 2011

Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan or 131I-tositumomab combines a radiation-emitting radionuclide with an antibody targeting CD20 to treat B-cell non-Hodgkin lymphoma. Multiple studies demonstrate favorable RIT efficacy and safety profiles in follicular lymphoma (FL). The primary toxicity is reversible myelosuppression. Various FL treatment options include single-agent immunotherapy, radiation, chemoimmunotherapy, and RIT. Examining RIT clinical effects and position within treatment algorithms is important to optimal patient benefit. Clinical studies support using single-agent RIT in relapsed/refractory FL, in selected patients with new, untreated FL, and as consolidation after induction chemotherapy or chemoimmunotherapy. RIT as consolidation enhances response rates (with conversion of partial to complete responses following induction therapy) and prolongs disease control versus observation. The overall response rate is 60-80% in the relapsed setting. Time to progression is longer with low-bulk disease, fewer prior therapies, and retained rituximab sensitivity. RIT apparently does not preclude subsequent therapies or increase risk of secondary malignancies compared with chemotherapy's known risk. This article summarizes consensus recommendations for RIT and presents RIT treatment algorithms developed by hematologists/oncologists who regularly treat patients with FL. Maximizing RIT benefit requires healthcare providers to utilize algorithms assisting with treatment decisions. © 2011 Informa UK, Ltd.


PubMed | Illinois Cancer Care and University of Chicago
Type: | Journal: Clinical genitourinary cancer | Year: 2016

Traditional imaging assessment criteria might not correlate well with clinical benefit from vascular endothelial growth factor pathway-directed therapy in metastatic renal cancer. Preclinical data suggest tumor growth is preceded by a rise in KPatients with metastatic renal cancer were treated with pazopanib at 800 mg oral daily until disease progression. MRI of the abdomen and pelvis with a DCE-MRI sequence was obtained at baseline and every 8 weeks.Seventy-three DCE-MRI scans were completed and 66 were technically assessable. Of the 17 patients with at least 1 DCE-MRI scan after the baseline scan, 16 (94%) had a decline in KWe show that K

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