tbuckley/cabot-search huggingface dataset:
A multicenter phase II study of pemetrexed (P), cisplatin (C), and bevacizumab (B) in patients (pts) with advanced malignant mesothelioma (MM)
Authors: J. Dowell, R. Taub, C. Lan, Y. Xie, F. Dunphy, V. Blake, H. Kindler
Journal: Journal of Clinical Oncology (2009)

7578 Background: Vascular endothelial growth factor (VEGF) is a key growth factor for MM. In pre-clinical models, anti-VEGF antibodies inhibit MM proliferation. Standard chemotherapy for MM, pemetrexed + cisplatin, yields a response rate of 41%, progression-free survival (PFS) of 5.7 months (mo) and median overall survival (OS) of 12.1 mo. We added the anti-VEGF antibody B to PC in an ongoing phase II multi-center study in MM pts. Methods: Eligible pts have unresectable, histologically-confirmed MM, no prior chemotherapy, and PS 0–1. Pts receive C 75 mg/m 2 , P 500 mg/m 2 and B 15 mg/kg Q21 days for 6 cycles, then B Q21 days until progression. CT scans are obtained Q 2 cycles. Primary endpoint: Progression-fere survival (PFS). Correlative studies include IHC for the VEGF/KDR complex and PCR for simian virus 40 (sv40) T antigen. Results: 43 pts enrolled at 4 centers from 3/06 to 12/08; currently, 34 are evaluable for PFS and 36 for toxicity. Pt characteristics: male 88%; median age 66 (range 24–81); histology: epithelial 62%, sarcomatoid 15%, biphasic 20%, unknown 3%; site of origin: pleural 85%, peritoneal 12%, tunica vaginalis 3%; PS 0 32%, PS 1 68%; thrombocytosis (&gt;400) 32%. Cycles administered 229 (median 4, range 1–18). Grade 3/4 toxicity (%pts): neutropenia 8%; anemia 0%; thrombocytopenia 3%; thrombosis 11%; hypertension 8%; vomiting 8%; mucositis 6%; CVA 3%; proteinuria 0%; perforation 0%. Partial response: 41%, stable disease: 35%. Median PFS: 5.6 mo (95% CI: 4.1, 7.2). Median OS 11.5 mo (95% CI: 9.4, 24). Conclusions: These data suggest that the addition of B to PC does not improve PFS when compared with historical controls of PC in advanced MM pts. Correlative studies evaluating the VEGF/KDR complex and sv40 T antigen are pending. [Table: see text]
Expression of sonic hedgehog and its receptor patched in non-small cell lung cancer.
Authors: O. Rouhi, K. A. Kaiser-Walters, D. Escarzaga, D. Steker, S. Basu, M. J. Liptay, P. Gattuso, P. D. Bonomi, J. Coon, J. A. Borgia
Journal: Journal of Clinical Oncology (2010)

7620 Background: Tumor metastasis is the primary cause of mortality in non-small cell lung cancer (NSCLC). Many pathways and biomarkers have been studied to clarify the mechanism of disease progression, but the exact mechanism of metastasis remains poorly understood. Based on previous studies, the hedgehog signaling pathway is involved in tumor growth and differentiation. However, little is known about the associations of expression of components of the hedgehog pathway and metastatic progression in NSCLC. Here we examined the differential expression of sonic hedgehhog (Shh) and its receptor patched (ptc) for its involvement in metastatic progression. Methods: Immunohistochemical staining for Shh, and ptc was performed on 115 primary NSCLC (adenocarcinoma [n = 65] and nonadenocarcinoma [n = 50]) and 55 matching metastatic lymph nodes. All patients were treated by complete anatomic resections and were limited to T1-2N1-2M0. Scoring was accomplished by evaluating stain intensity and frequency of expression by tumor cells, with 25 random fields surveyed per section. A score was then calculated based on these parameters for statistical comparisons. Parameters that were compared include differential primary and lymph nodes staining, tumor histopathological subtype, and disease-free and overall survival. All statistical comparisons were performed in SPSS v15.0 and consisted of either Mann-Whitney rank sums test (two-sided) or Kaplan-Meier curves. Results: There was no significant difference in the pattern of shh and ptc staining in primary tumor versus local lymph node metastases. (p = 0.2 and 0.5, respectively). Shh and ptc were expressed in adenocarcinoma at a significantly higher level and more frequently than compared to non adenocarcinoma samples (p = 0.001 and 0.01 respectively). Disease-free survival was higher in shh negative tumor samples compared to the positive group (p = 0.03), and shh positivity correlated with higher rate of recurrence. (p = 0.03). Conclusions: These results are consistent with observations for the expression of hedgehog pathway proteins and patient outcome in other carcinomas and suggest that the hedgehog pathway might play a similar role in the development of metastases in NSCLC. No significant financial relationships to disclose.
Double-blind randomized phase II trial of carboplatin and pemetrexed with or without OGX-427 in patients with previously untreated stage IV non-squamous non-small-cell lung cancer (NSCLC): The Spruce Clinical Trial.
Authors: David R. Spigel, Howard A. Burris, F Anthony Greco, John D. Hainsworth
Journal: Journal of Clinical Oncology (2013)

TPS8120 Background: OGXE427 is an antisense oligonucleotide (ASO) designed to bind to Hsp27 (heat shock protein 27) mRNA, resulting in the inhibition of production of Hsp27 protein. Hsp27 is over-expressed in many cancers including lung, prostate, breast, and bladder. Increased expression has been associated with inhibition of chemotherapy-induced apoptosis, increased tumor cytoprotection, and the development of treatment resistance. OGX-427 is an inhibitor of Hsp27 that effectively targets and down-regulates Hsp27 mRNA and has been shown to increase apoptosis, inhibit tumor growth, and sensitize cells to various chemotherapy regimens in a variety of malignancies. Based on this preclinical data, addition of an Hsp27 inhibitor to standard chemotherapy may improve the efficacy of treatment. In this randomized phase II study, OGX-427 will be added to a standard carboplatin/pemetrexed regimen, with the goal of improving progression-free survival when compared to carboplatin and pemetrexed alone in the first-line treatment of non-squamous NSCLC patients. Methods: A total of 155 patients will be randomized in a 1:1 ratio. Randomization will be stratified by histology (adenocarcinoma vs. large cell carcinoma) and smoking status (smoker vs. non-smoker). Treatment will include a loading dose period with OGX-427 600 mg or placebo. On day one of each 21 day cycle, patients will receive OGX-427 1000 mg or placebo, pemetrexed 500 mg/m 2 , and carboplatin AUC 6, all administered IV. On days 8 and 15, OGX-427 or placebo will also be administered. Key eligibility criteria include; untreated recurrent or stage IV predominantly non- squamous NSCLC, measureable disease by RECIST v 1.1, ECOG PS 0 or 1, adequate organ function, and no known CNS disease. Serum Hsp27 levels will be assessed at screening, baseline and during treatment. In addition, archival tissues will be collected and assessed for PTEN (protein expression by IHC) and a panel of gene mutations for correlative analyses.
Conditional survival of malignant glioma patients
Authors: J. Hu, S. G. Groshen, D. D. Tsao-Wei, M. C. Chamberlain
Journal: Journal of Clinical Oncology (2008)

13009 Background: Survival probabilities of malignant glioma (World Health Organization Grade 3 & 4 gliomas) are estimated at the time of diagnosis and provide limited information following treatment. Methods: Post-diagnosis survival in 2974 malignant glioma patients in Los Angeles County during the year 1990 to 2000, were used to estimate conditional survival probabilities and median survival, as well as 90% confidence intervals, for patients surviving 1, 2, 3, 4, or 5 years after diagnosis. In addition, potential risk factors were examined individually both at the time of diagnosis and after six months from diagnosis, from which a multivariable model was built to predict patients’ survival. Results: The conditional probabilities of surviving one additional year increase as the post-diagnosis survival time increases (from 43% conditional on surviving 1 year after diagnosis to 91% conditional on surviving 5 years after diagnosis). Patients diagnosed with WHO Grade 3 gliomas have higher conditional survival probabilities than those diagnosed with WHO Grade 4 gliomas. However, as the years after diagnosis increases, the differences in the conditional probabilities across the groups are attenuated. Both at the time of diagnosis and conditional on surviving 6 months after diagnosis, the age at diagnosis, race, tumor histology (WHO grade), tumor site and primary treatment (university vs. non-university) are statistically significantly associated with the survival for these patients after adjusting for sex and marital status. Conclusion: Conditional survival probabilities can provide useful information for predicting the prognosis for patients with malignant glioma. No significant financial relationships to disclose.
A phase I clinical, pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of PF-00562271 targeting focal adhesion kinase (FAK) in patients (pts) with advanced solid tumors
Authors: L. L. Siu, H. A. Burris, L. R. Mileshkin, D. R. Camidge, S. G. Eckhardt, A. Lamb, E. X. Chen, S. F. Jones, H. Xu, H. Fingert
Journal: Journal of Clinical Oncology (2008)

3534 Background: FAK transduces signaling from integrins and growth factors to modulate tumor cell invasion, proliferation and survival. PF-00562271 is a potent ATP-competitive inhibitor of FAK and proline-rich tyrosine kinase (Pyk2). Methods: Phase 1 dose- escalation study of PF-00562271 given orally once or twice daily in 21 day cycles. Endpoints included safety, PK, and PD using FDG-PET imaging. Results: 47 pts received doses ranging from 5 mg to 105 mg BID or 225 mg QD with demographics M:F = 19:28; median age 59 (range 25–78). Primary tumor sites: colorectal (12), SCC (7), lung (5), breast (4), ovary (3), gastric (3), neuroendocrine (2), prostate (2), others (9). A total 150 cycles were administered, range 1–14+. Adverse events (AEs) possibly related to PF-00562271 in over 10% of pts included nausea, vomiting, diarrhea, fatigue, headache, anorexia, dizziness, peripheral edema, abdominal pain. AEs were generally CTCAE grades 1–2 and reversible. At the MAD under fasting conditions of 225 mg QD, DLT included nausea, vomiting, diarrhea, orthostatic hypotension, all reversible upon dose reduction or discontinuation. Serum exposure (Cmax and AUC) of PF-00562271 increased with dose, displaying dose- and time-dependent non-linearity. Doses above 30 mg/day led to trough concentrations (Css.min) over 45 ng/mL, a target efficacious level estimated preclinically. Bioactivity measured by serial PET scans (range 15 to 46% decline in SUV, measured in over 10 metastatic lesions) corresponded with higher systemic exposures. PET responses were temporally associated with improved tumor-related symptoms in 2 pts, and central necrosis of metastatic or primary lesions. Seven pts continued over 6 cycles with disease stabilization. Conclusions: PF-00562271 is tolerable with extended oral administration, and bioactivity can be evaluated by FDG-PET. The clinical safety, PK and bioactivity support further development as single agent or combinations. Given methods developed in this multi-national study for functional imaging and data management, FDG-PET appears to be a practical, noninvasive marker for bioactivity of PF-00562,271 and possibly other agents that modulate integrin-related signal pathways. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc. Pfizer Inc. Pfizer Inc.
Prospective study on prognostic significance of DNA ploidy and Ki-67 expression in colorectal cancer
Authors: C. Saggia, A. Santagostino, G. Forti, G. Biaggi, G. Angeli, M. Dacorsi, D. Cerrato, G. Loi, G. Porcile, O. Alabiso
Journal: Journal of Clinical Oncology (2007)

21184 Background: The prognostic value of flow cytometry DNA ploidy and Ki-67 expression in colorectal carcinomas has not been defined yet. The study tries to correlate tumoral DNA ploidy and proliferative activity (Ki-67) with therapy response, Overall Survival (OS), Disesase Specific Survival (DSS) and Disease Free Survival (DFS). Methods: From 01/09/02 to 30/06/05, 3 samples of cancer tissue and 1 sample of normal mucosa has been collected from all operating pieces of colorectal cancer. These samples were frosen and later disgregated, treated and coloured with Propidium Iodide. DNA ploidy was evaluated by FACSCalibur cytofluorimetry. Normal mucosa tissue was our internal control. Ki-67 was evaluated by immuno-histochemistry in all tumoral samples. All the patients were cured with chemo- and/or radiotherapy in our divisions. Results: 67 patients (M/F 35/32); median age was 70; staging: 19% I, 33% II, 30% III, 18% IV. We found aneuploidy in 65,7% of carcinoma and Ki-67 median expression was 55%. DNA tumoral heterogeneity was present in 27% of patients. DNA aneuploidy correlates with advanced disease stage at diagnosis (p&lt;0,01), with high number of metastatic lymphnodes (p&lt;0,005) and with serological markers positivity (p&lt;0,04). After surgery and chemotherapy 35% of the patients with aneuploid carcinoma and high proliferative activity (Ki-67&gt;55%) do not show evident disease versus 100% of patients with DNA diploidy and lower Ki-67. Tumoral aneuploidy correlates in a significative way with lower OS (48% vs 89% of diploid patients), lower DSS (tumor death happened just in patients with aneuploid DNA in every disease stages), with lower DFS (18% vs 86% of diploid patients). Univariated analysis stated that aneuploidy determinates an Odd Ratio=5,7 to develop disease progression (p=0,033). At the moment Ki-67 expression with 55% cut-off does not seem to correlate with OS, DSS and DFS. Conclusions: Preliminar results (the study is still in progress) seem to suggest that cytofluorimetric DNA-ploidy has a prognostic and predictive significance in colo-rectal carcinomas. Ki-67 expression (immuno-histochemistry) has an uncertain significance. The small number of patients and the short follow-up do not allow us to reach any definitive conclusions, but the study is worth to go on. No significant financial relationships to disclose.
Evaluation of the safety of C-1311 administered in a phase I dose-escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumors
Authors: N. Isambert, M. Campone, E. Bourbouloux, M. Drouin, A. Major, P. Loadman, R. Capizzi, C. Grieshaber, P. Fumoleau
Journal: Journal of Clinical Oncology (2006)

2069 Background: C-1311 is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of other cancer therapies such as the anthracenediones (e.g. mitoxantrone) and the anthracyclines (e.g. doxorubicin). This first-in-man clinical trial was designed to assess the safety profile of C-1311 and determine the recommended dose upon weekly administration for 3 consecutive weeks, within a 28-day cycle. Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases: an initial accelerated phase of cohorts of 1 patient at doubling doses and a modified Fibonacci phase of cohorts of 3 pts at 25–33% dose increments. The maximum tolerated dose (MTD) was defined as the dose at which 2/3 or 2/6 pts experienced a dose-limiting toxicity (DLT). The recommended dose (RD) was defined as the dose level below the MTD, confirmed by expansion of the cohort to 9 pts. Results: 16 pts received doses of 15, 30, 60, 120, 240, 480 and 640 mg/m 2 /wk. The 2 pts treated at 640 mg/m 2 experienced a DLT (grade 3 neutropenia preventing the administration of the 2 nd and 3 rd dose of the first cycle respectively). The RD was defined as 480 mg/m 2 /wk (cohort of 9 pts). Six additional pts were treated at the RD in an extension study in which one of the first 2 doses was given orally. Overall, 2 serious adverse events have been reported as possibly drug-related, both consisting of post-infusion fever without evidence of infection, resolving within 24 hours. Transient neutropenia was the only recurring grade 3 or 4 drug-related adverse event (AE). Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. Stable disease was observed in 3 patients with advanced malignancy. One pt had a stable course over &gt; 8 cycles, and two had stable courses over 4 cycles. Plasma drug concentrations were linear and proportional to dose. Conclusions: The recommended phase 2 dose of 480 mg/m 2 , weekly × 3 q 28 days, offers a predictable safety profile and excellent tolerability. [Table: see text]
Sorafenib as a second-line and sequential therapy for patients with metastatic renal cell carcinoma (mRCC): Analysis for safety and activity on sunitinib progressive pts
Authors: J. Sepulveda, P. Maroto, R. Andres, I. Diaz Padilla, C. Coronado, F. DelaRosa, D. E. Castellano
Journal: Journal of Clinical Oncology (2008)

16100 Background: Sorafenib ia an orally active multikinase inhibitor (Raf kinase, VEGFR 1, 2, and 3; and PDGFR inhibitor) recently approved by the FDA for the treatment of mRCC. The purpose of this study was to assess the efficacy and toxicity of Sorafenib in mRCC previously treated with Sunitinib. Methods: pts with RCC histology, confirmed metastatic disease, PS: 0–3, adequate organ function and informed consent were analysed. Pts received Sorafenib 400 mg/bid/continuosly treatment in repeated 4-weeks cycles. (at least complete 1 treatment-cycle for analysis). Efficacy was assessed by RECIST criteria. Results: 23 pts were recorded, and 3 pts are still too early for efficacy assessment. Baseline characteristics: PS 0–1: 74%; PS 2–3: 26%, median age 62 years (35–79); nephrectomy: 91%; clear-cell 84%, papillary-cell 8%, cromophobe-cell 8%. 2 or > mts sites: 82%. MSKCC 0: 51%, 1: 39%, 2: 10%. All pts were refractory to cytokine treatment, or progressed or experienced unacceptable toxicity after sunitinib therapy. Median number of cycles was 4 (1−8+). The most important toxicity (NCIC 3.0, all pts) was g 1–2 thrombocytopenia in 4 pts, g 1–2 neutropenia in 5 ps and g 1–2 anemia in 7 pts. Non- hematological toxicity was g3 astenia in 4 pts, g-3 mucositis in 2 pts, g3 hypertension in 2 pts, g3 hand-foot syndrome in 1 pt. Of 20 assesable pts, the overall response rate was 18% with a 2 PR (9%), 2 minor response (9%) 10 SD and 6 PD. Median duration of response and stable disease was 27 weeks+ and the median OS was 37 weeks. Conclusions: Sorafenib at doses of 400mg/bid/continuosly result in acceptable and well tolerated salvage treatment for pts previously treated with Sunitinib ± cytokines. These results support the use of Sorafenib as a second-line treatment in this setting. Final and madurate data will be presented at ASCO meeting. No significant financial relationships to disclose.
Phospho proteomics and systems reconstruction of signaling networks to identify targets for therapy
Authors: Iadevaia Sergio, Melissa Muller, Prahlad Ram
Journal: Clinical Cancer Research (2008)

B46  Biological signaling networks are complex dynamical systems, the analysis of which is greatly facilitated when mathematical modeling is used in combination with traditional experimental techniques. High throughput genomics and proteomics provide clustering data based on co-expression of different molecules without a clear understanding of relationships and the resulting system properties of these networks. Mathematical modeling enables quantitative understanding of the signaling dynamics, but their use is limited due to an incomplete knowledge of the molecular interactions that define the causal network topology.  In this work, we have reconstructed the signal transduction network through receptor tyrosine kinases (EGFR and IGFR) by overlaying consensus networks onto Reverse Phase Protein Array (RPPA) data. We have also developed a detailed mathematical model that describes the dynamics of the reconstructed network. The model was employed as a predictive tool to: a) determine signaling network response to perturbations of targeted nodes, b) understand the dynamic properties of the de novo regulatory loops and c) indentify optimal combinations of targeted agents that more effectively disrupted the loops responsible for activation of key signaling intermediates. The modeling predictions were experimentally tested in breast cancer cell lines using immunoblotting and found in good agreement with the data.  Therefore, overlying causal networks onto genomics and proteomics data provide a more detailed systems approach to understand the dynamics of complex signaling networks. Moreover, further implementation of our study on the EGFR/IGFR signaling network will lead to the development of new combinations of targeted pharmaceutical agents for cancer treatment and prevention.
A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T).
Authors: K. Miller, L. Gianni, F. Andre, V. Dieras, R. L. Mahtani, N. Harbeck, J. E. Huang, T. Shih, Y. Choi, H. A. Burris
Journal: Journal of Clinical Oncology (2010)

1012 Background: The HER2-targeted antibody-drug conjugate T-DM1 has shown encouraging efficacy and safety in patients (pts) with heavily pretreated HER2-positive (HER2+) BC. P is the first HER2-directed dimerization inhibitor for treatment of HER2+ BC. T-DM1 and P bind different subdomains of HER2. Combination of P with T or T-DM1 has shown synergistic antitumor activity in HER2+ xenograft models. Methods: This international, 3+3 design, single-arm, phase 1b/2 study investigated P (840 mg cycle 1,420 mg cycle 2 and beyond) with T- DM1 (3.0 mg/kg in cohort 1 and, in the absence of dose limiting toxicity [DLT], 3.6 mg/kg in cohort 2), in pts with HER2+ locally advanced or metastatic BC. This was followed by a 60 pt expansion into phase 2 at the established dose. Primary objectives included safety and preliminary responses per RECIST. Results: As of October 1, 2009, 37 pts had enrolled; 23 safety evaluable pts (9 in phase 1b and 14 in phase 2) received ≥1 cycle of T-DM1 and P (median of 2 cycles each, ranges 1-8 and 1-6, respectively). Pts had received a median of 8 (range 4-15) prior agents. There were no DLTs among the 3 pts in cohort 1 (3.0 mg/kg T-DM1). One of 3 pts in cohort 2 (3.6 mg/kg) had a DLT (Gr 4 thrombocytopenia [TCP]), and continued on-study. The cohort was expanded to 6 total pts, with no further DLTs; 3.6 mg/kg was selected as the phase II dose. To date, one grade 5 AE (pneumonia) has been reported, in a pt who died concomitantly due to disease progression. The only grade 4 event was TCP (DLT), resulting in the only T-DM1 dose reduction (to 2.4 mg/kg). Six pts had grade 3 AEs, including 4 with fatigue; the other grade 3 AEs were nausea, vomiting, diarrhea, deafness, and dyspnea, with no grade 3 cardiac or peripheral neuropathy. No AEs led to study discontinuation. With limited follow-up, there were 9 partial responses (7 unconfirmed) among 23 pts. Responses in heavily pretreated pts have been seen. Conclusions: Safety, tolerability, and preliminary efficacy of full dose T-DM1 + P are encouraging, with no substantial increase in toxicity over single agent T-DM1, and no new safety signals. Hepatic and TCP events were infrequent. T-DM1 dosing was established at 3.6 mg/kg. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Roche Genentech, Roche