tbuckley/cabot-search huggingface dataset:
Temozolomide, irradiation and hypoxia promote homing of hematopoietic progenitor cells towards gliomas
Authors: W. Wick, G. Tabatabai, B. Frank, M. Weller
Journal: Journal of Clinical Oncology (2006)

20044 Background: Temozolomide and irradiation are essential parts of the standard therapy and hypoxia is a critical aspect of the microenvironment of gliomas. IN the present study, we aimed at investigating the impact of these stimuli on the previously defined transforming growth factor beta (TGF-β)- and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1α/CXCL12)-dependent migration of adult hematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and the homing to experimental gliomas in vivo. Hyperthermia served as control. Methods and Results: Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumor satellite formation and enhances the glioma tropism of HPC in vivo. Supernatants of temozolomide-treated, irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 glioma cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1α), but not on p53. Induction of transcriptional activity of HIF-1α by hypoxia and irradiation requires an intact signaling cascade of TGF-β. Conclusions: Thus, we delineate a novel stress signaling cascade in glioma cells involving TGF-β, HIF-1α and CXCL12. Stress stimuli can be temozolomide, irradiation and hypoxia but not hyperthermia. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with anti-angiogenic therapies which induce tumor hypoxia. [Table: see text]
A phase II trial of salirasib in patients with stage IIIB/IV lung adenocarcinoma enriched for <i>KRAS</i> mutations
Authors: M. L. Johnson, N. A. Rizvi, M. S. Ginsberg, V. A. Miller, M. G. Kris, W. Pao, G. J. Riely
Journal: Journal of Clinical Oncology (2009)

8012 Background: KRAS mutations are present in 30% of lung adenocarcinomas and are associated with primary resistance to erlotinib and gefitinib. Salirasib severs RAS proteins from the membrane, decreasing function of all RAS isoforms. Salirasib inhibits KRAS-dependent growth in cell lines and xenograft models. This phase II study was designed to determine the activity of salirasib in patients (pts) with advanced NSCLC enriched for KRAS mutations. Methods: Two cohorts of pts with stage IIIB/IV NSCLC were eligible. Group A: pts with KRAS mutations previously treated with chemotherapy. Group B: previously-untreated pts with ≥15 pack-year smoking history. Salirasib was given orally, for days 1–28 of a 35 day cycle, with response assessment on day 28, day 63, and every 10 weeks (wks) thereafter. The primary endpoint was rate of RECIST non-progression at 10 wks. Secondary endpoints were response rate (RR), time to progression (TTP), overall survival (OS) and toxicity. Results: From August 2007-December 2008, 33 pts were enrolled (20 women); median age 68 (range 46–79). Pts in Group A had received a median of 2 lines of prior chemotherapy. All 23 pts in Group A and 7/10 pts in Group B had KRAS mutations. Of the 30 pts with KRAS mutations, 7 were never smokers or smoked ≤15 pack-years. Three pts withdrew due to drug-related diarrhea in the first 10 wks of therapy. Four pts have not reached 10 wks of therapy. After 10 wks of salirasib, 5/18 (28%) previously treated pts with KRAS mutations and 3/8 (38%) previously untreated pts showed no progression. The RR in pts was 0/18 for Group A and 0/8 in Group B. For all pts with KRAS mutations, the RR was 0/23. The median TTP was 1 month (mo) and 2 mo in Groups A and B, respectively. The median OS was 13 mo for Group B and not reached in Group A (median follow-up 3 mo). Grade 3 diarrhea and fatigue were the most common toxicities. Conclusions: After 10 wks of salirasib, 28% of previously treated pts with KRAS mutations and 38% of untreated pts had stable disease. No partial or complete responses were seen in pts with KRAS mutations. The successful enrollment over 15 months of 29 pts with tumors with known KRAS mutations demonstrates that trials of a KRAS-specific genotype in lung cancer are feasible, and should be standard in future studies targeting the KRAS pathway. [Table: see text]
A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors
Authors: K. P. Papadopoulos, B. Markman, J. Tabernero, A. Patnaik, E. I. Heath, A. DeCillis, D. Laird, S. K. Aggarwal, L. Nguyen, P. M. LoRusso
Journal: Journal of Clinical Oncology (2008)

3510 Background: XL765 is a selective dual oral inhibitor of Class I PI3K isoforms and mTOR. XL765 is a potent in vivo inhibitor of PI3K pathway signaling leading to tumor growth inhibition or tumor shrinkage in a dose dependent manner in multiple human xenograft tumor models exhibiting dysregulated PI3K pathway signaling. Methods: Pts with advanced solid malignancies are enrolled in successive cohorts of 3 to receive XL765 orally bid for cycles of 28 days. Cycle 1 safety data determine dose-limiting toxicities (DLT). Pharmacodynamic samples are collected. Tumor response is assessed by RECIST criteria every 8 weeks. Results: To date, a total of thirteen pts have been treated with XL765 across four dose levels up to 120 mg bid. There have been no DLTs. One grade 4 transaminitis possibly related to XL765 (120 mg bid) has been reported. Of the 9 pts enrolled into cohorts 1 to 3, 6 have completed ≥3 cycles of treatment. One patient (30 mg bid) with NSCLC has stable disease after 6 cycles and another patient (120 mg bid) with testicular carcinoma that had progressed under multiple chemotherapy regimes has a clinically significant reduction in alfa-fetoprotein from 11,000 to 7,000 U/L and radiological stable disease after 1 cycle. Plasma PK analyses indicated exposure increased less than dose-proportionally with increasing XL765 dose (range: 15–120 mg bid). Median Tmax occurred at 1–3 hrs post-dose. Mean terminal plasma half life ranged from 3–9 hours at steady state, which was reached by Dosing Day 8. No to moderate drug accumulation was evident following repeat daily bid dosing. Preliminary results suggest that XL765 administration augments food-induced changes in plasma insulin in an exposure dependent fashion. There are signs of pharmacodynamic modulation of PI3K and mTOR in patient hair bulbs as determined by reductions in phosphorylation of AKT, the AKT substrate PRAS40, and 4E- BP1. Conclusions: In this Phase 1 study, XL765 has been generally well tolerated at doses up to 120 mg bid. The MTD has not yet been established and dose escalation is ongoing. XL765 demonstrates biologic activity, as assessed by pharmacodynamic read-outs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis Exelixis Exelixis
Tumor genomics and proteomics and drug pharmacokinetics in predicting chemotherapy response in breast cancer
Authors: S. C. Lee, P. Tan, M. Watson, T. T. Yip, P. Iau, S. Norita, L. S. Tham, H. S. Lee, H. McLeod, B. C. Goh
Journal: Journal of Clinical Oncology (2005)

3009 Significant inter-individual variation exists in tumor response and chemotherapy toxicity because of unique tumor and patient factors. Individual drugs with distinct mechanisms of action may induce specific genomic and proteomic changes that may be used as predictor for response. We studied serial genomic and proteomic profiles in primary breast tumor treated with one of two sequences of alternating adriamycin (A) and docetaxel (T), A→T→A→T→A→T, or T→A→T→A→T→A, at 75mg/m2 3 weekly for each drug. Pharmacokinetic analysis of both drugs was performed; amplified tumor RNA was hybridized on Affymetrix HG-U133+2 array; tumor proteins were fractionated and profiled with ProteinChip Array SELDI MS (Ciphergen). 88 of the target 100 patients were recruited and preliminary genomic and proteomic analyses are presented. Median size of the primary tumor was 11cm (range 4–30cm), 72% had cT4 tumors, and 38% were metastatic. Objective clinical response was 81% (11% CR, 70% PR). 47 patients underwent surgery, and 9% achieved pathological CR, 15% had good pathological response (residual tumor <2cm and no involved nodes), and 36% had poor pathological response (residual tumor >5cm or >10 positive nodes). Docetaxel area under the curve (AUC) correlated with tumor reduction after cycle 1 (r=0.416, p=0.034). 105 and 187 non-overlapping RNA transcripts (p<0.05) in the pre-treatment tumor were differentially expressed between responders and non-responders to cycle 1 adriamycin or docetaxel respectively, while pair-wise comparison of pre- and post-cycle1 samples yielded 36 and 33 transcripts (p<0.05) respectively specific to adriamycin or docetaxel. Adriamycin and docetaxel affected different sets of tumor proteins: adriamycin in at least 4 entities representing 11 peaks, and docetaxel more complex changes. CART analysis identified protein entities that distinguished between good and poor clinical responders (peak 81, p=0.005) and pathological responders (peak 150, p=0.013). Distinct tumor genomic and proteomic changes occur in response to different drugs and between responders and non-responders. Further validation on the larger data set would further our understanding on individualized drug therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Neopharm, Orion Genomics, Sanofi- Synthelabo, Veridex Ciphergen Biosystems Merck
Phase I Study of Paclitaxel Given by Seven-Week Continuous Infusion Concurrent With Radiation Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: David I. Rosenthal, Jason H. Lee, Robert Sinard, Denise A. Yardley, Mitchell Machtay, D. Marc Rosen, Merrill J. Egorin, Randal S. Weber, Gregory S. Weinstein, Ara A. Chalian, Linda K. Miller, Eugene P. Frenkel, David P. Carbone
Journal: Journal of Clinical Oncology (2001)

Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT).Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks).Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%).CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.
Pharmacokinetics (PK) and pharmacodynamics (PD) of RG7112, an oral murine double minute 2 (MDM2) antagonist, in patients with leukemias and solid tumors.
Authors: A. Beryozkina, G. L. Nichols, M. Reckner, L. T. Vassilev, R. Rueger, L. Jukofsky, S. Middleton, M. Andreeff, S. Padmanabhan, R. Strair, M. L. Delioukina, P. G. Maslak, P. Hillmen, R. Kurzrock, L. Gore, A. Patnaik, R. G. Maki, G. K. Schwartz, A. J. Wagner, J. Zhi
Journal: Journal of Clinical Oncology (2011)

3039 Background: RG7112 is a selective inhibitor of p53-MDM2 binding and frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. Results of clinical PK (plasma RG7112 concentrations) and PD (serum macrophage inhibitory cytokine-1, MIC-1, a potential indicator of p53 activation) are reported here from two phase 1 studies of RG7112 in patients (pts) with AML, ALL, CML in blast phase or refractory CLL/SCLL, and pts with advanced solid tumors and refractory lymphomas. Safety, tolerability, and clinical responses are reported separately. Methods: 49 leukemia pts and 76 solid tumor pts took RG7112 tablets once or twice daily in escalating oral doses (20 – 1920 mg/m2/day) for 10 days followed by 18 days of rest between cycles. Serial PK samples were drawn pre-dose and up to 120 hours post-dose on Days 1 and 10 and pre-dose on Day 5. MIC-1 samples were collected at the anticipated PK Cmax and up to 48-hr post- dose on Days 1 and 10. Limited confirmatory PK and PD samples were also taken in cycle 2. Results: Plasma RG7112 concentrations peaked ~ 4 hr post-dose at steady-state (SS) on Day 10 and then declined with a mean terminal elimination t1/2 ~ 1.5 days. The PK exposure (plasma Ctrough, Cmax, and AUC) was ~ dose-proportional without accumulation in the dose range studied. Inter-patient variability was ~70%; PK exposure tended to be higher in patients with solid tumors compared to those with leukemias at comparable dose levels. Serum MIC-1 levels were elevated from individual baseline starting from RG7112 doses > 320 mg/m2 and plasma concentrations > 1 µg/mL, suggesting a potential mechanistic PD relationship (p53 activation). The increase in MIC-1 (% of change from baseline) was highly associated with plasma RG7112 concentrations (R=0.60 and 0.80 in pts with leukemias and solid tumors, respectively). Conclusions: As expected from mechanism of action, RG7112 exhibited exposure-related PD response for the p53 biomarker MIC-1 within the dose range tested in pts with leukemias and solid tumors.
A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens
Authors: P. Zoran, D. Tarabar, R. Doder
Journal: Journal of Clinical Oncology (2007)

14555 Background: This is a phase II study combination of capecitabine plus bevacizumab for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. Methods: The dose of capecitabine was 1000 mg/m2, administered twice daily for 14 days every 3 weeks. Bevacizumab was given at a dose of 5mg/kg on day 1 as i.v. infusion every 3 weeks. Treatment was repeated until the occurrence of disease progression or unaccepted toxicity. Results: Twenty-eight patients were enrolled. Of 28 patients, the overall response rate was 14.3% and the disease control rate was 42.9%. With a median follow-up period of 7 months, median time to progression and overall survival duration were 3 months and 14 months, respectively. The 1-year survival rate of all patients was 60.7%. The most common treatment-related grade 3/4 hematological toxicities included leukopenia/neutropenia in 4 patients and thrombocytopenia in 3 patients. Nonhematologic toxicities attributable to bevacizumab included bleeding in 3 patients, hypertension in 4 patients, thromboses in 3 patients, proteinuria in 5 patients, and gastrointestinal perforation in 1 patient. Conclusions: This drug regimen was well tolerated and combination of bevacizumab and capecitabine shows potential as third line chemotherapy in heavily pretreated patients with metastatic colorectal cancer. No significant financial relationships to disclose.
The efficacy of low-dose gefitinib for advanced non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations: A post-hoc analysis from NEJ002.
Authors: A. Inoue, M. Maemondo, K. Kobayashi, S. Oizumi, H. Isobe, A. Gemma, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa
Journal: Journal of Clinical Oncology (2010)

7571 Background: NEJ002, a phase III trial comparing gefitinib with carboplatin-paclitaxel as the first-line treatment for advanced NSCLC with sensitive EGFR mutations, showed a significant improvement in progression-free survival (PFS) in the gefitinib arm. Although standard schedule of gefitinib was the administration of 250 mg tablet every day, more than half of patients in the gefitinib arm reduced the dose of gefitinib mainly because of toxicities. However, the efficacy of such low-dose (LD) gefitinib has rarely been evaluated. Methods: A post-hoc analysis of the efficacy (response rate and survival) in patients who took gefitinib without any dose reduction during their treatment period and those in patients who received LD gefitinib at any point during the treatment period was performed. Results: Among 114 patients of the first-line gefitinib group in NEJ002, 52 (46%) continued gefitinib without break until their diseases progressed (categorize as group A), and 62 (54%) was reduced their dose of gefitinib (most of them moved into every-2-days schedule) because of some toxicities (same as group B). There was no significant difference of patient characteristics between two groups. Interestingly, PFS of group B seemed to be better than that of group A (median PFS, 301 days in group A versus 351 days in group B; p = 0.450) and overall survival was also similar between the groups (median survival time, 852 days versus 928 days, respectively; p = 0.674). Conclusions: The results suggest that LD gefitinib may be clinically not inferior to standard schedule of gefitinib for NSCLC with sensitive EGFR mutations. Considering the merit in terms of risk-benefit balance, prospective study of LD gefitinib is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
A prospective randomised comparative study of the short-term effects of infliximab (remicade) and intravenous pulse methylprednisolone in rheumatoid arthritis patients with active disease despite methotrexate
Authors: Patrick Durez, AN Toukap, Bernard Lauwerys, Rene Westhovens, Frédéric Houssiau
Journal: Annals of the Rheumatic Diseases (2003)
Granulocyte macrophage: Colony stimulating factor (GM-CSF), ketoconazole, and mitoxantrone as second-line therapy in patients (Pts) with progressive hormone refractory prostate cancer (HRPC)
Authors: G. Doshi, P. Cen, P. Ramirez, R. Amato
Journal: Journal of Clinical Oncology (2009)

e16033 Background: A variety of docetaxel regimens have been tested in HRPC pts, yielding response rates between 38% - 69%. Docetaxel therapy has been widely used as first line therapy. Second line therapies, which are non - taxane based with comparable activities do not exist. This trial is built on the significant body of work which has demonstrated anti-tumor activity of GM-CSF, Ketoconazole and Mitoxantrone alone and in combination in pts with HRPC. The trial is designed to assess the combination of all three agents. Methods: No more than two prior chemotherapy regimens (one which contained docetaxel), progressive disease, and adequate marrow / organ function. Treatment consisted of: Ketoconazole daily 400mg po tid, GM-CSF subcutaneous 250mcg / m 2 (14 days on/ 7 days off) and Mitoxantrone 12mg / m 2 every 3 weeks (maximum cumulative dose of 140mg / m 2 ), until either the completion of Mitoxantrone or maximum anti-tumor benefit. Pts continued Ketoconazole/ GM-CSF until disease progression. PSA was evaluated every 3 weeks and radiographic studies were performed every 9 weeks. Results: 31 pts were enrolled; 4 pts with PSA only, 9 bone only, 5 soft tissue only, and 13 bone and soft tissue. 2 pts withdrew from study due to toxicity. 8 pts had a PSA response of ≥ 50%, 5 pts had a PSA response of ≥ 80%, and 7 pts had a PSA response of ≥ 90%. 9 pts progressed. The majority of pts had stabilization of their bone and soft tissue involvement and 2 pts with nodal involvement demonstrated a radiographic CR. Significant adverse events included grade III/IV neutropenia, thrombocytopenia, and nausea. Median duration of treatment was 6.22 months (range 2 months - 20.5 months). Conclusions: GM-CSF, Ketoconazole and Mitoxantrone in combination demonstrate significant anti-tumor activity and reversible toxicity in pts who have failed prior docetaxel therapy. Information regarding PSA response, radiographic outcome and adverse event data will be presented. This data warrants further investigation such as a randomized phase II study. [Table: see text]
Weekly bortezomib in the treatment of patients (pts) with previously treated multiple myeloma: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: F. A. Greco, D. R. Spigel, J. H. Barton, C. Farley, M. T. Schreeder, R. C. Hermann, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2006)

7547 Background: Bortezomib, administered on a twice-weekly schedule, is now a standard part of treatment for patients with multiple myeloma. Weekly bortezomib schedules have shown activity in other cancer types, and are more convenient than twice weekly schedules. In this multicenter, community-based phase II trial, we evaluate the feasibility, toxicity, and efficacy of weekly bortezomib in pts with previously treated multiple myeloma. Methods: Eligibility criteria included a diagnosis of multiple myeloma treated with 1 or 2 previous systemic regimens (only 1 if first-line therapy included high-dose therapy); ECOG PS 0–2; creatinine &lt; 2.0 mg/dL; WBC ≥ 3000/μL; ANC &gt; 1000/μL; platelets ≥ 50,000/μL; no peripheral neuropathy &gt; grade 1; informed consent. All pts received bortezomib 1.6mg/m 2 IV on days 1, 8, 15, and 22 of each 5-week cycle. Pts were reevaluated at 10-week intervals; treatment continued for 8 cycles (40 weeks) or until myeloma progression. Results: Between 5/04 and 12/05, 37 pts entered this trial. Pt characteristics: median age 70 years; male/female, 20/17; 24 pts (65%) had received 2 previous regimens (previous high dose therapy, 2 pts); elevated β-2 microglobulin, 27 pts (73%). Of 26 pts evaluated, 13 pts (50%) had major responses, 11 pts (42%) stable disease, and 2 pts (8%) had progression. After a median follow-up of 7 months, projected median PFS is 9.6 months; overall survival at 1 year is 81%. Weekly bortezomib was well tolerated by most pts. Grade 3/4 toxicities included fatigue (21%), diarrhea (11%), neutropenia (7%), thrombocytopenia (4%), all others &lt; 5%. No grade 3/4 neuropathy occurred. Only 1 pt required bortezomib dose reduction during treatment, and 2 pts discontinued treatment because of toxicity (myelosuppression, 1; fatigue/dehydration, 1). Conclusions: Weekly bortezomib is a convenient, well tolerated treatment for pts with previously treated multiple myeloma. Overall response rates with this schedule are similar to those previously reported with the standard twice-weekly schedule. Further followup is necessary to better evaluate the duration of response and the incidence of cumulative toxicities. [Table: see text]