tbuckley/cabot-search huggingface dataset:
A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion every 3 weeks in patients (pt) with refractory solid tumors
Authors: F. G. De Braud, N. Isambert, G. Curigliano, G. Spitaleri, E. Ferrant, C. Ramazeilles, L. Bolloni, P. Fumoleau
Journal: Journal of Clinical Oncology (2007)

2518 Background: This phase I study of SSR244738, a G2-cell cycle inhibitor cytotoxic agent, was aimed to establish the dose limiting toxicities (DLT), the maximum administered dose (MAD) and to characterize the PK profile of the proposed schedule. Methods: SSR244738 was administered as one-hour IV infusion every 3 weeks in pts (selected according common phase I criteria) starting with a modified accelerated dose escalation scheme. PK profiles (up to day 8) were obtained in each pt after the 1 st administration. CYP2C9 and CYP3A5 genotypes were analyzed to identify pts’ metabolizer status. Results: 2 centers enrolled 14 heavily pretreated pts: 5 females, 9 males, median age: 52 years (32–67), ECOG PS: 0 (93% pts); main tumor types: head and neck, lung, melanoma, and breast. 40 cycles (median = 2, range: 1–11) were administered in 6 dose levels (DL) ranging from 165 to 1,300 mg/m 2 . Accelerated dose escalation was stopped at 660 mg/m 2 for non-proportionally increase of PK parameters respect to the dose administered . SSR244738 was well tolerated up to 1,300 mg/m 2 : one DLT (abnormal liver function tests ALFT) was reported in one breast cancer pt with liver metastases. Only one pt (hepatocarcinoma) was withdrawn from the study due to toxicity (ALFT) after 3 cycles at 1,000 mg/m 2 . 2 stable diseases were reported. PK data: mean T1/2 of 23h (range: 9.20–127), mean Vss: 11.1 L (6.43–15.8) and mean Clearance (CL): 0.71 L/h (0.041–1.43). This large variability of the CL (CV% =63%) could in part be explained by CYP2C9 genotype: so far CL is &lt;0.4 in 2 poor metabolizers (PM) and &gt;0.6 in extensive metabolizers. Conclusion: Due to the high CL variability, 1300 mg/m 2 is considered as the MAD. 3 pts will be accrued at 1,300mg/m 2 to complete the DL (a reduced dose will be given to CYP2C9 PM). Weekly and twice-weekly schedules will be tested. No significant financial relationships to disclose.
Expression and function of the sphingolipid receptors S1P1–5 in Ewing and adult type soft tissue sarcoma cells: Examples of G protein-coupled receptors as potential new treatment targets
Authors: R. Möhle, C. Skala, C. Kuhnen, J. T. Hartmann
Journal: Journal of Clinical Oncology (2008)

10581 Background: Sphingolipid receptors represent a family of G protein-coupled receptors (GPCR) that mediate a broad range of cellular effects, including growth and migration. In the tumor microenvironment, activated platelets release the sphingolipid sphingosine 1-phosphate (S1P). We analyzed the functional expression of S1P receptors in Ewing and adult type soft tissue sarcoma (STS) cell lines and primary STS, to elucidate a potential contribution to sarcoma growth and progression. Methods: Ewing sarcoma (TC-71, A-673, RD-ES) and STS (HT-1080 / fibrosarcoma, U-2197/ pleomorphic sarcoma/NOS ) cell lines were cultured in vitro. Primary sarcoma cells were isolated by collagenase digestion. Real-time RT-PCR allowed quantitative determination of S1P receptor mRNA. For functional analysis, actin polymerization (as a first step in cell migration) was measured by fluorescence microscopy and flow cytometry. Cell viability was quantitated using the WST-1 test, while phosphorylation of MAP-kinase/Erk was assessed by Western blot. Results: mRNA of the five S1P receptors (S1P1–5) was consistently found in Ewing sarcoma and STS cell lines, and in all primary STS samples (n=35). Synovial sarcomas expressed on average the greatest mRNA levels of S1P1, S1P3, and S1P5. In contrast, S1P2 and S1P4 mRNA was most abundantly found in liposarcoma and pleomorphic sarcoma/NOS, respectively. S1P induced an 1.5-fold increase in polymerized f-actin in Ewing sarcoma cells, while reduced apoptosis was noted in STS cells (optimum: 10 nM S1P). Strong phosphorylation of the proliferation-related MAPK/Erk1/2 in response to 100 nM S1P was observed in Ewing sarcoma and STS cell lines, as well as primary STS cells. Preincubation with the S1P analogue FTY720 (downmodulates S1P1 and used as an immunosuppressant) abrogated MAPK phosphorylation. Conclusions: Sphingolipid receptors, particularly S1P1, are expressed and functionally active in Ewing and soft tissue sarcoma cells. Involvement of S1P receptors in sarcoma cell proliferation and MAPK/Erk signaling, and the availability of S1P analogues for clinical use suggest to evaluate these GPCRs as candidates for a targeted therapy. No significant financial relationships to disclose.
Cost-minimization comparison of infusion based FOLFIRI (5-fluorouracil and leucovorin) versus oral based XELIRI (capecitabine and irinotecan) in metastatic colorectal cancer (mCRC)
Authors: R. Baran, E. McKenna, Y. Patt, N. Ghali
Journal: Journal of Clinical Oncology (2004)

3762 Background: Capecitabine (Xeloda), an oral fluoropyrimidine, has been explored as an alternative to infusional 5-FU in irinotecan regimens, assuming capecitabine can clinically replace infusional 5-FU. This cost-minimization model compares the total cost of care for FOLFIRI versus XELIRI regimens in first line mCRC. Methods: Clinical response endpoints (objective response rates, time to tumor progression) and patient populations reported for FOLFIRI (Tournigand C. JCO 2004) and XELIRI (Patt YZ. ASCO 2003) are similar in published clinical trials, justifying the cost-minimization comparison method. Costs of drug acquisition and administration were projected over 24 weeks, corresponding to therapy in trials. Analysis included 2 week cycles of FOLFIRI and 3 week cycles of XELIRI. Costs of drugs, adverse events (AEs), reimbursement of services, and supplies were based on Dec 2003 Medicare fee schedules. Treatment costs for adverse events in each regimen were based on documented incidences and costs. Resu...
Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: Long term outcome of the Temporary Authorization for Use program in France.
Authors: Nadine Houede, Philippe Beuzeboc, Sophie Gourgou, Diego Tosi, Laura Moise, Gwenaelle Gravis, Remy Delva, Aude Flechon, Igor Latorzeff, Jean-Marc Ferrero, Stephane Oudard, Sophie Tartas, Brigitte Laguerre, Delphine Topart, Guilhem Roubaud, Hanane Agherbi, Xavier Rebillard, David Azria
Journal: Journal of Clinical Oncology (2015)

264 Background: COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a temporary use authorisation (TUA) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TUA. Methods: Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TUA for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors. Results: Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years. Conclusions: Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders’ patients could beneficiate from AA for more than 3 years.
Phase II study of bavituximab plus docetaxel in locally advanced or metastatic breast cancer.
Authors: D. Tabagari, G. Nemsadze, M. Janjalia, M. Jincharadze, J. Shan
Journal: Journal of Clinical Oncology (2010)

1042 Background: Bavituximab, a novel IgG1 monoclonal antibody which targets membrane phosphatidylserine complexed with β2-glycoprotein I on tumor vasculature was tested in combination with docetaxel in a multicenter open label phase 2 trial in adults (n=46) with locally advanced or metastatic breast cancer. Methods: Subjects received intravenous administration of weekly doses of 3 mg/kg bavituximab on days 1, 8, and 15 of a 28-day cycle for up to 6 cycles along with docetaxel 35 mg/m2 in a Simon 2-stage design. Tumor response was determined by use of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: 46 caucasian female subjects median age 49 (range 30-72) were treated. Prior treatment included chemotherapy in all 46 pts (100%), surgery in 40 pts (87%), and radiation therapy in 13 pts (28%). Overall response rate (CR+PR) was seen in 28/46 (60.9%, CI 45.4-74.9) with clinical complete response seen in 10.9% and partial response seen in 50%; median progression-free survival (PFS) of 7.4 mos (95% CI, 6.0-9.0); median duration of response (MDR) of 6.0 mos (95% CI 5.6-7.0). AEs have been reported in 44/46 patients (95.7%) which were mostly mild or moderate, with the 6 most frequent of alopecia (73.9%), diarrhea (63.0%), epistaxis (60.9%), lacrimation increased (56.5%), fatigue (43.5%), onycholysis (41.3%). Safety analysis revealed 8 SAEs in 7 subjects, including 3 patients with venous thrombosis (DVT/PE). Conclusions: Bavituximab a unique phosphatidylserine targeting monoclonal antibody producing immune cell-mediated destruction of tumor vasculature and immune enhancement (He et al, Clin Cancer Res 2009) was safe and well tolerated when given in combination with docetaxel and has produced a promising 61% overall response rate (ITT) using RECIST for locally advanced and metastatic breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Peregrine Pharmaceuticals Peregrine Pharmaceuticals Peregrine Pharmaceuticals
A systems pathology model for predicting overall survival in patients with refractory, advanced non-small cell lung cancer (NSCLC) treated with gefitinib
Authors: M. J. Donovan, A. Kotsianti, V. Bayer-Zubek, D. Verbel, M. Clayton, S. Hamann, P. Capodieci, H. Pang, C. Cordon- Cardo, D. Parums, B. Holloway
Journal: Journal of Clinical Oncology (2007)

18065 Background: The abundant expression of the epidermal growth factor receptor (EGFR) in a variety of solid tumors including non-small cell lung cancer (NSCLC), head and neck, breast, colon and brain has made it an attractive target for various selective molecular therapeutics, including the tyrosine kinase inhibitor gefitinib. The recent evidence of activating mutations in EGFR combined with clinical - demographic features has suggested that subgroups of patients with NSCLC are most likely to respond to selective therapies. We sought to determine whether the integration of clinical variables, tumor morphometry and quantitative protein profiles using support vector machines could identify a set of features which predicts overall survival in patients with NSCLC treated with gefitinib. Methods: We analyzed tumor samples from 109 patients with advanced refractory NSCLC treated with gefitinib. Formalin fixed, paraffin embedded tissue samples were evaluated with the following assays: Hematoxylin and Eosin image morphometry, EGFR DNA mutation analysis, EGFR protein immunohistochemistry and quantitative immunofluorescence with the following antibodies: CK18, Ki67, Caspase 3 activated, cd34, EGFR, phosphorylated-EGFR, phosphorylated-ERK, phosphorylated-AKT, PTEN, Cyclin D1, phosphorylated-m-TOR, PI3-K, VEGF, KDR (VEGFR2) and phosphorylated KDR. A predictive model was developed using support vector regression for censored data. Results: 4 of 87 patients had tyrosine kinase domain mutations in exons 19, 20 or 21. Utilizing 51 patients with complete data profiles (i.e. clinical, image morphometry and immunofluorescence), a model predicting overall survival was developed with a concordance index of 0.74. Poor performance status, poorly differentiated histology by morphometry and increased levels of activated caspase 3, phosphorylated KDR (VEGFR2) and cyclin D1 were associated with reduced survival. Conclusion: The integration of clinical, imaging and biomarker data identified a set of features which were associated with a more aggressive disease phenotype and resulted in overall poor survival. [Table: see text]
Preclinical evaluation of bafetinib for treatment of glioblastoma multiforme.
Authors: V. Velcheti, B. Peterson, D. Levitt, O. Prakash
Journal: Journal of Clinical Oncology (2010)

2082 Background: Despite the several advances in surgical and radiation techniques and the use of multiple chemotherapeutic drugs, a cure for glioblastoma multiforme (GBM) remains elusive. Increased expression of membrane transport protein such as P-glycoprotein in glioblastoma cells is one of the factors associated with resistance to chemotherapeutic agents. An earlier study showed increased Lyn kinase activity in glioblastoma tumor samples compared to normal brain tissue. We examined the therapeutic potential of a clinically relevant Lyn kinase inhibitor bafetinib (formerly INNO-406) alone and in combination with a P-glycoprotein inhibitor, cyclosporine A on the growth of human glioblastoma cells. Methods: Bafetinib was obtained from CytRx Corporation. Human glioblastoma U-138MG cells were cultured in a 96-well plate and treated for 24 or 48 h with bafetinib alone or with cyclosporine A. Cell viability was measured by Titer-Glo Luminescent Cell Viability Assay (Promega). The apoptotic effect was assessed by measuring the activation of caspase-3/7 by using Caspase-Glo 3/7 Assay Kit (Promega). VEGF in culture supernatants was quantified by ELISA (R&D Systems). Results: Bafetinib treatment at 2.5 μ M and 5 μ M concentrations for 48 h decreased cell viability by ∼30% and ∼50%, respectively (p < 0.05). Cyclosporine A at 5 μ M concentration augmented the in vitro activity of bafetinib by ∼2 fold. Bafetinib treatment alone for 24 h at 5 μ M concentration increased the caspase 3/7 activity by 2 fold (p < 0.05). Whereas, a ∼4-fold increase was observed in combination with 5 μ M cyclosporine A (p < 0.05). No significant increase in the caspase-3/7 activity was observed with clyclosporine A alone (p = 0.09). VEGF is highly expressed in GBM and its expression is associated with poor prognosis. We found that treatment of the cells with 2.5 μ M concentration of bafetinib or a combination of bafetinib and cyclosporine A (5 μ M) decreased VEGF production by ∼30% and ∼50%, respectively. Decreased VEGF production correlated with decreased viability of glioblastoma cells. Conclusions: These preliminary findings suggest that targeting Lyn kinase pathway with bafetinib may have a therapeutic potential for GBM. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CytRx Corporation CytRx Corporation
Single-agent nab-paclitaxel given weekly (3/4) as first-line therapy for metastatic breast cancer (an International Oncology Network study, #I-04–012)
Authors: B. Mirtsching, T. Cosgriff, G. Harker, M. Keaton, T. Chidiac, M. Min
Journal: Journal of Clinical Oncology (2008)

1118 Background: Nab-paclitaxel for injectable suspension given weekly has shown activity in patients whose metastatic breast cancer was refractory to taxane therapy. The purpose of this phase II study is to evaluate the efficacy and safety of administering nab-paclitaxel weekly to patients with locally advanced or metastatic breast cancer as first-line treatment. Methods: Patients ≥ 18 years with histologically or pathologically confirmed and documented locally advanced or metastatic breast cancer received nab- paclitaxel (125 mg/m2) by 30-min IV infusion weekly for the first 3 weeks of each 4-week cycle. HER2-positive patients were allowed to receive trastuzumab. Results: At the time of analysis, 72 patients have received study medication and 47 are evaluable for response and are included in the analyses. Patient characteristics include gender male/female, 2/45; median age 59 years (range 36–84); ECOG performance status 0/1, 30/17; HER2 status ±/missing, 17/29/1; and 27 patients (79.4%) had received prior chemotherapy. The median number of cycles administered was 5 (range 1–22) with a median weekly delivered dose of 125.0 mg/m2 (range 78.1–163.4 mg). The treatment phase is complete and patients who remain on study are in follow-up. The primary endpoint is overall response rate. The overall response rate was 42.6% (95% CI, 28.3 to 57.8). Two HER2-positive patients had a CR and 9 patients had a PR (overall RR of 64.7%). Nine HER2-negative patients had a PR (overall RR of 31%). Median time to progression was 12.4 months (range 3–25) and median survival was 25 months (range 3–30). Forty-five patients are surviving. The most common toxicities (G3–4) were neutropenia (11.1%), infection (9.7%), neuropathy (8.3%), fatigue (4.2%), and nail disorder (4.2%). Conclusions: These results suggest that nab-paclitaxel is well tolerated as a first-line treatment of locally advanced or metastatic breast cancer. Moreover, a response rate of 42% is encouraging, particularly in the HER2-positive population where 64% of patients responded. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis
A phase II trial of the epothilone B analog BMS-247550 in patients (pts) with hepatobiliary cancer (HBC): An updated analysis
Authors: D. A. Singh, D. Taber, R. Ansari, H. J. Lenz, E. Agamah, S. Nattam, K. Wade-Oliver, K. Kasza, E. E. Vokes, H. L. Kindler
Journal: Journal of Clinical Oncology (2006)

14050 Background: BMS-247550 is a semi-synthetic analog of epothilone B that induces mitotic arrest at G2M by microtubule stabilization. We previously reported (Proc ASCO 2003) a RR of 17% in HBC and present our final analysis. Methods: Pts with histologically confirmed hepatocellular cancer (HCC), gallbladder cancer (GB) and cholangiocarcinoma (C) were eligible. Pts had no prior chemotherapy, PS 0–2 and ≤ grade 1 neuropathy. Pts received BMS-247550 40mg/m2 intravenously over 3 hours every 21 days. A Simon, optimal two-stage design was employed. We proceeded to the 2 nd stage of accrual after 3 confirmed PRs in the first 21 pts. Primary endpoint: Response rate (RR). Results: From 1/02–4/05, 54 pts (52% male) were enrolled, 53 pts evaluable for toxicity, 48 pts evaluable for response. 1 pt was ineligible due to incorrect diagnosis but evaluated for toxicity. Pt characteristics: median age 65 (range 19–88); ECOG performance status 0(48%), 1(48%), 2(4%); HCC (38%), GB (40%), C (22%); metastatic disease (75%); 129 cycles were administered (median 2; range 1–14). There were 3 Gr 5 toxicities: 1 pt died unexpectedly 48 hours within drug administration; 1 complication of neutropenic fever; 1 found unresponsive after fall. Gr 3–4 toxicities (% pts): neutropenia (39%), neutropenic fever (6%), anemia (6%), thrombocytopenia (2%), nausea (13%), transaminase elevation (9%), fatigue (7%), and hypersensitivity (4%). Neuropathy: Gr 3–4 (5%); Gr 1–2 (39%). 3 pts were removed from study due to persistent neuropathy. Responses: 8% PR (2 HCC, 1 GB, 1C); 56% SD. 4/7 HCC pts received ≥ 10 cycles. Median survival: 7 months [95% CI (5.0, 10.8)]; PFS: 2.6 months [95% CI [1.4, 4.1)]; Conclusions: Despite initial tumor responses and a few pts with prolonged SD in HCC, BMS-247550 does not appear to have clinically significant activity in HBC. Supported by NCI grant N01-CM-17102. [Table: see text]
Alternating temozolomide and low doses rIL-2 in patients with metastatic melanoma. An open non-randomized phase I/II study
Authors: G. V. Masucci, E. Djuren-Mårtensson, J. Hansson, E. Månsson-Brahme, B. Ragnarsson-Olding, G. Wagenius
Journal: Journal of Clinical Oncology (2004)

7541 Background: Temozolomide (Temodal) is a novel chemotherapeutic agent that is rapidly absorbed, it offers 100% bioavailability as an oral preparation and achieves significant CNS penetration. It has been shown that combination rIL-2 in high doses and DTIC in melanoma gave higher response rate than the single agents alone. Temozolomide in sequence with low doses IL-2 might be an efficacious treatment where a cytostatic drug and a cytokine, which activates the immune system, may synergistically eliminate the tumour with low cumulative toxicity. Methods: The primary objective of this study was to determine the safety and tolerance of Temozolomide 200 mg/m2 orally once dayly from day 1 to 5, in sequential combination with subcutaneous injection of 4.5 × 106 IU rIL-2 (Proleukin™) at days 8–11, 15–18 and 22–25 in patients with measurable progressive metastatic malignant melanoma without radiological signs of CNS metastases. The secondary objectives were to determine tumour response and time to progression (TTP). Results: Forty-seven patients were recruited and 27 were included of which 4 were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to WHO . Two patients suspended the treatment because of side effects above WHO grade 3 already during the first course with Temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. These, consequently, continued to receive the combined treatment and to be monitored, until signs of relapse or max 21 courses. Two patients had CR, 3 PR and 2 SD. Six of twenty-five treated patients (24%) developed brain metastases during follow up. Conclusions: Temozolomide in combination with rIL-2 is a well tolerated regimen for out-patient treatment. Responders have long TTP, possibly due to rIL-2 treatment. No significant financial relationships to disclose.