tbuckley/cabot-search huggingface dataset:
MILGa-01: A first-in-human study assessing the safety and tolerability of chMIL-38 in metastatic prostate, bladder, and pancreatic cancers.
Authors: Howard Gurney, Dhanusha Sabanathan, David Gillatt, Pirooz Poursoultan, Kevin Ho Shon, Brad Walsh, Vicki Velonas, Kristofer Thurecht, Douglas Campbell
Journal: Journal of Clinical Oncology (2017)

e565 Background: Metastatic or recurrent cancer continues to be a challenge in patients with urogenital and pancreatic cancers despite the development of newer anti-androgen therapies. MIL-38 is an IgG1 murine monoclonal antibody directed against Glypican-1 (GPC-1). The proteoglycan GPC-1 is upregulated in prostate, pancreatic and bladder cancer cell lines. Targeting of tumor xenografts and lack of adverse events in pre-clinical models suggest chimeric MIL-38 (chMIL-38) is a good candidate for both radioimmunotherapy and antibody-drug conjugate development. Methods: Patients with known metastatic prostate and pancreatic cancer were injected with a single dose of MILGa drug (1mg, 250MBq dose) and imaged with whole body gamma camera scans and SPECT/CT at 30 minutes, 6 h, 24 h, 48 h, 72 h (if required) and 144h post infusion. Blood and urine samples for pharmacokinetic, biomarker studies, cancer markers and hematology and biochemistry analysis were collected at each time point. Dosimetry analysis of tumour images was performed to determine the relative accumulation of MILGa in different organs. Results: To date one pancreatic cancer patient and one prostate cancer patient with metastatic disease have been infused with the MILGa drug. The drug was safe and well tolerated in both patients with no infusion reactions or drug-related adverse events. Tracer uptake was observed in the liver, with mild tracer uptake in the spleen, skeletal system and kidneys. Significant MILGa targeting was seen in Patient 2 24 hours post infusion onwards with uptake in the right foot (right calcaneum and cuneiform bones). SPECT/CT at 24 hours confirmed uptake was in the bone, not in the joint space or soft tissue. Conclusions: MILGa has shown a promising safety profile to date with indication of tumour targeting in metastatic prostate cancer. Additional data from this study may permit the selection and evaluation of potentially sensitive tumor types to be studied for further therapeutic and diagnostic studies. Clinical trial information: ACTRN12616000787482.
Effect of decitabine on DNA methylation in human cancers
Authors: David J. Stewart, Razelle Kurzrock, Yasuhiro Oki, Luis H. Camacho, Sanjay Gupta, Ignacio Ivan Wistuba, Susan R. Pilat, Zhong Guo, Issa Pean-Pierre
Journal: Cancer Research (2006)

1616  Background: Decitabine may decrease DNA methylation by inhibiting DNA methyltransferase. Reduction of DNA methylation may turn back on expression of genes down-regulated by hypermethylation, including tumor suppressor genes & genes required for apoptosis. In leukemia patients, DNA hypomethylation and therapeutic efficacy of decitabine appeared to plateau as dose increased. Methods: We initiated a phase I trial of decitabine given IV over 1 hr/day x 5 days/week x 2 weeks in patients with solid tumors & lymphomas (all of whom had received > 1 prior regimen). Planned dose levels are 2.5, 5, 10, 15 & 20 mg/m2/day, with 6 patients per dose level. All patients have tumor biopsies before day 1, cycle 1 and shortly after last decitabine treatment in cycle 1. Peripheral blood mononuclear cells (PBMCs) are collected at the same time. Global DNA methylation (% CpG methylation) was assessed by “LINE” assays. Tumor was compared to PBMCs with respect to decitabine-induced changes in DNA methylation. Results: Thirteen patients were entered from 9/04 to 11/05, (6 at 2.5 mg/m2/day, 6 at 5 mg/m2/day & 1 at 10 mg/m2/day). No dose-limiting toxicity was seen in cycle 1 for cohorts 1 or 2, although grade 1-2 non-hematological toxicity has been seen, and 2 patients in cohort 2 had grade 3 neutropenia. The first patient in cohort 3 developed rapidly reversible grade 4 neutropenia. Nine patients have had stable disease. DNA methylation has been assessed in cohort 1 & 2 patients. Mean DNA methylation decreased by 4.5% in tumor (p = 0.038 by paired t-tests), with decreases seen in tumors of 8 of 12 patients. DNA methylation decreased by a mean of 17% in PBMCs (p = 0.0003). By paired t-tests, change in DNA methylation was greater in PBMCs than in tumors from the same patient (p = 0.0035). Within the same patient, pretreatment DNA methylation in tumor did not correlate with that in PBMCs (R2 = 0.0001, p = 0.98), and change in DNA methylation correlated weakly between tumor and PBMCs (R2 = 0.1175, p = 0.28). DNA demethylation did not vary with decitabine dose: mean decrease in tumor DNA methylation was 4.6% in cohort 1 & 4.4% in cohort 2 (p = 0.97). Mean decrease in PBMCs was 16.1% in cohort 1 & 17.8% in cohort 2 (p = 0.81). Conclusions: Preliminary results indicate: 1) Even low dose decitabine reduces DNA methylation in tumors, but less than in PBMCs. 2) PBMCs may be of limited value as surrogates for tumor. 3) To date, there is no indication that higher doses are more effective than lowest doses tested. Ongoing studies: Assessment of: 1) higher dose levels 2) effect of decitabine on methylation & expression of individual genes 3) correlation of effect with tumor decitabine levels 4) factors affecting tumor decitabine levels. Supported in part by NIH grant UO1 CA062461-10 & R21 CA112895-01A1.
Chemical Biology Strategy Reveals Cell Lineage- and Cell Differentiation-Specific Small Molecule Inhibitors of NF-κB.
Authors: Hideki Goto, Paul Diaz, Shu-ichi Matsuzawa, Eduard Sergienko, Steve Vasile, Thomas Chung, Carina Wimer, Michael Hedrick, Ricardo Correa, Thomas J Kipps, Anthony Pinkerton, John C. Reed
Journal: Blood (2012)
Genome sequencing of multiple primary tumors to reveal underlying germline cancer susceptibility.
Authors: Kasmintan A. Schrader, Kelly Lynn Stratton, Rajmohan Murali, Yael Laitman, Luca Cavallone, Lily Offit, Yong Hannah Wen, Sohela Shah, Rohini Rau-Murthy, Christopher Manschreck, Ebunoluwa Otegbeye, Marina Corines, Noah D. Kauff, Robert J. Klein, Mark E. Robson, Zsofia Kinga Stadler, Eitan Friedman, William Foulkes, Joseph Vijai, Kenneth Offit
Journal: Journal of Clinical Oncology (2013)

1552 Background: Apart from germline mutations in BRCA1 and BRCA2, the basis for genetic susceptibility to breast and ovarian cancer is heterogeneous, and can necessitate sequential or multiplex genetic testing. In addition, examination of germline DNA alone may not be conclusive. Information regarding both primary and secondary genetic events can be obtained from genomic analysis of tumors in conjunction with germline DNA. Methods: To determine the underlying cause of multiple primary malignancies in an Ashkenazi Jewish individual, whole genome sequencing was performed on DNA from the patient’s germline, invasive ductal carcinoma of the breast, and ovarian high-grade serous carcinoma. After identifying a structural variant of interest in this patient, germline DNA of 1846 Ashkenazi Jewish individuals who had a personal history of either breast, pancreatic, or ovarian cancer or a history of both breast and/or ovarian cancer and a similar family history, were screened using a TaqMan copy number assay or a specific PCR breakpoint assay to determine if this structural variant is a founder mutation. Results: A novel germline complex structural variant of PALB2 creating a 3790 base-pair deletion encompassing exon 11 associated with a 68 base-pair insertion was identified and confirmed by Sanger sequencing and a TaqMan copy number assay. The germline deletion was retained in both tumors. In addition, both tumors acquired second hits that led to inactivation of the wild-type allele of PALB2. The germline PALB2 structural variant was not identified in any of the additional 1846 Ashkenazi Jewish individuals genotyped. Conclusions: Whole genome sequencing of multiple primary tumors enabled identification and characterization of a novel germline structural variant in PALB2 as the basis for the individual’s susceptibility to breast and ovarian cancer. The variant does not appear to be a founder mutation in Ashkenazim.
Triple-negative phenotype is a strong predictor of sensitivity to epirubicin-cyclophosphamide (EC) then docetaxel (D) (ECD) primary chemotherapy (PCT) for localized breast cancer
Authors: M. E. Marty, J. Guinebretiere, M. Mathieu, B. Sigal-Zafrani, A. De Roquancourt, M. Spielmann, S. Giacchetti, P. De Cremoux, F. Spyratos, B. Asselain
Journal: Journal of Clinical Oncology (2007)

21128 Background: Molecular markers (GEP, p53 mutations,) could overcome usual predictors (size, pathology, Hormone receptors, HER2) in identifying patients (pts) experiencing complete pathological response (pCR) with anthracyclin based chemotherapy (Clin.Cancer Res., 2004, 10 6789). We aimed at validating and refining these finding in pts treated with ECD. Methods: From 05/2004 to 04/2006 170 pts not amenable to Breast Conserving Therapy and/or with high evolutive potential were randomly allocated to EC (75/750mg/sqm)x4 then D (100 mg/sqm)x 4 (with or without celecoxib in HER2-ve or trastuzumab (T) in HER2+ve. The primary endpoint - absence of residual invasive breast carcinoma and of nodal involvement (pCR)- was to be correlated with usual predictors , phenotype, GEP and p53 mutations assessed from core biopsies. pCR ranged from 13 to 14% in the arms without T thus without suggestion of a difference between these arms. pCR in the 30 HER2+ve pts having received ECD + T was 30% (NS). Results in 135 fully evaluable pts not allocated to T and having undergone secondary surgery are analyzed. Results: Main predictors and related pCR are shown in the table below Results of ongoing molecular analysis will be reported. Conclusions: Expression of ER appears to be the major prognosticator for ECD induced pCR. Triple negative breast cancers experience the highest pCR rate (p&lt; 0.0001) (chi2 test with Yates correction). Molecular studies to be presented will show if GEP and/or p53 mutations could allow to improve such prediction. [Table: see text] No significant financial relationships to disclose.
Authors Index/Index des auteurs
Authors: C. Koupernik, C. Nicolétis, E.E. Rawlings, P. Sivadon, J. Bergeret, S. Black, R. Fried, B. Ecanow, B.H. Gold, P. Tunkunas, G. Pankow, P.E. Sifneos, C. Berlioz, P. Bugard, L. Chertok, O. Bourguignon, Cl. Veil, R. Delasnerie, R. Gelly, Leisla M. Howell, P. Moutin, E. Dervaux, R. Quéro, M. de Senarclens, J.-D. Stucki, G. Besançon, C. Ganry, G. de la Rochefordière, A. Ermentini, G. Mascherpa, Ph. Lemoine, O. Meier, O. Rosowsky, M. Burner, P. Geissmann, P. Aboulker, O. Bourguignon, L. Chertok, L. Bernstein, J.L. Auber, H. Danon-Boileau, M. Laxenaire, L. Bentz, Cl. Chardot, G. Kambourakis, Gisela Heinze, P. Moron, Y. Bruno, N. Morris, A.B. Sclare, B.P. Geraghty, E. Stoopen, Ct. Veil, C. Mertens de Wilmars, J.M. Coyne, M.R. Kaufman, L.J. Roose, P.Ch. van Reeth, M. Souris, M. de Boucaud, P. Freour, P. Chomy, J. Darquey, J.P. Gachie, J.R. Mallet, M. Bernadou, M. Nacef, J. Valencon, Z.J. Lipowski, W. Schüffel, Cornelia Schaumburg, O. Schonecke, W. Wolfert, J. Cor, D. Becker, S. Delons, A. Lepeuple, R. Thibier, J.N. Vivien, J. Pallies, R. Wolfromm, J.M. Alby, B. Delahaye, E. Calas, A. Luyckx, M. van den Bosch de Aguilar, R. Schild, A. Weintraub, M. Fakhr El-Islam, M.R. Salama, K. Kasr-El-Aini, P. Jonckheere, J.L. Jullien, J. Monier, Henri Péquignot, Michael Balint, P.-B. Schneider, J. Caïn, I. Frank, Rosanne K. Frank, G. Gandini, M. Martin, B. Lazare, M. Bankov, Ilona Demcsak-Kelen, F. Szakacs, R. Jarreau, Reine Klotz, J.-M. Quinodoz, A. Bourguignon, R. Fasquelle, E. Galacteros, J. Cosnier, A. Haynal
Journal: Psychotherapy and Psychosomatics (1972)
Ruxolitinib safety experience in the polycythemia vera clinical trial program.
Authors: Srdan Verstovsek, Ruben A. Mesa, Bruno Martino, Jean-Jacques Kiladjian, Mark M. Jones, Shui He, Dany Habr, Iulian Alecu, Alessandro M. Vannucchi
Journal: Journal of Clinical Oncology (2015)

e18082 Background: Polycythemia vera (PV) is associated with over-activation of the JAK/STAT pathway and characterized by erythrocytosis and an increased risk of thrombosis. Some patients (pts) may require chronic therapy to control their blood counts and symptoms. The purpose of this analysis was to evaluate the long-term safety of ruxolitinib (Rux), a JAK1/JAK2 inhibitor, in a PV clinical trial program. Methods: This safety analysis included pts from the following studies: 1) a phase 2, single-arm, open-label study in pts resistant to or intolerant of hydroxyurea (HU) (NCT00726232); 2) the phase 3, randomized, open-label RESPONSE trial (NCT01243944) comparing Rux with best available therapy (BAT) in HU resistant/intolerant pts; and 3) the phase 3b, randomized, blinded RELIEF study (NCT01632904) comparing Rux with HU in pts generally well controlled on HU but reporting symptoms. Safety data were pooled for Rux across the two studies in HU resistant/intolerant pts (phase 2 study and RESPONSE), including pts in RESPONSE receiving Rux after crossover from BAT. Results: Median Rux exposure was 19.5 months (range, 0.3–66.7 months) in the HU resistant/intolerant group (N = 241), representing 457 pt-yrs of exposure. The most common adverse events (reported as rate per 100 pt-yrs of exposure) in this group were diarrhea (8.7), headache (8.5), and pruritus (7.4); most were grade 1 or 2. Anemia and thrombocytopenia of grade 3 or 4 occurred in 3.7% and 3.7% of pts, respectively, over the duration of follow-up. The rate of non-melanoma skin cancer was 2.8 per 100 pt-yrs. Herpes zoster occurred at a rate of 5.0 per 100 pt-yrs. The rate of thromboembolic events was 2.2 per 100 pt-yrs (vs 8.2 per 100 pt-yrs in the RESPONSE BAT group). In RELIEF, median exposure was 21.6 weeks in the Rux arm (N = 54). During the blinded phase, the adverse event profile was generally consistent with that observed in studies of HU resistant/intolerant pts. Conclusions: Overall, this long-term follow-up of the PV clinical trial program provides evidence supporting the safety and tolerability of Rux in pts who have an inadequate response to or are intolerant of HU. Clinical trial information: NCT00726232, NCT01243944, and NCT01632904.
Comparative effectiveness assessment of a lung cancer multidisciplinary practice to improve patient care.
Authors: Hamid R. Mirshahidi, Elvin Hernandez, Matthew Ta, Sheley M Baylon, Minh Thy Pham, Bonnie Lee, Patrick Jahng, Ling Kung, Siu-Fun Wong
Journal: Journal of Clinical Oncology (2012)

e16523 Background: Multidisciplinary focused-care teams have shown beneficial outcomes in diagnosis and treatment in cancer patients as well as assist in providing accessible, cohesive and continuous care. The multidisciplinary team specializing in thoracic cancer at our institution includes thoracic surgeons, pulmonologists, medical oncologists, radiation oncologists, pathologists, radiologists and a weekly tumor board with the inclusion of a dietician, a pharmacist, and a psych/social worker. This study examined the effectiveness of a multidisciplinary focused program in improving overall care in lung cancer patients. Methods: Lung cancer patient data between January 2000-December 2009 were abstracted from the institutional cancer registry. Patient demographics, treatment received, and survival (1-year and 2-year) were compared between Group A (January 2000-July 2005) and Group B (August 2005-December 2009) using Fisher’s exact test. Results: 1202 patients (Group A = 760; Group B = 442) were evaluated. Majority of patients were &gt; 60 years old, male, and has stage IV adenocarcinoma. Missing stage was less in Group B (13.8% vs 17.4%). Early stage patients in Group B received more surgeries and less inappropriate treatments. More palliative chemotherapy/radiation treatments were given in Group B late stage disease. More stage II (21.1% vs 2.3%) and IIIA (12% vs 1.5%) patients in Group B were treated with wedge resection and chemotherapy. One-year survival differences were seen between 2 groups in stage I, IIIA, and IV (P &lt;0.05). 2-year survival difference was seen in stage IV disease (P&lt;0.05). Conclusions: Introduction of multidisciplinary lung care team between 2005-2009 was associated with an increased patients being staged and more appropriate treatments. One year survival almost doubled in stage I patients where stage IV pts experienced up to 4 times improvement in 1- and 2-year survival. The results of the present evaluation appear to confirm the value of a multidisciplinary approach to the management of patients with lung cancer.
AvaALL: Open-label randomized phase IIIb trial evaluating the efficacy and safety of standard of care with or without continuous bevacizumab (BV) treatment beyond disease progression in patients (pts) with advanced nonsquamous non-small cell lung cancer (NSCLC) after first-line (1L) treatment with BV plus platinum-doublet chemotherapy (CT).
Authors: Cesare Gridelli, Jaafar Bennouna, Javier De Castro, Anne-Marie C. Dingemans, Frank Griesinger, Francesco Grossi, Nick Thatcher, Yuichiro Ohe, Pablo Diego Perez-Moreno, Corey J. Langer
Journal: Journal of Clinical Oncology (2012)

TPS7612 Background: Pts with NSCLC have a poor prognosis upon progression following 1L CT. Although the disease may have progressed on 1L CT, it is likely still dependent on VEGF-mediated pathways. Thus, persistent VEGF suppression along with second- and third-line cytotoxic regimens may yield clinical benefit. Analyses have associated this strategy with improved survival in NSCLC (Nadler et al, Oncologist 2011) and mCRC (Grothey et al JCO 2008). Methods: AvaALL (MO22097; NCT01351415), a multicenter (144 centers, 20 countries) open-label randomized (1:1) 2-arm phase IIIb study, recruits pts with advanced non-squamous NSCLC that has progressed after 1L treatment with BV plus a platinum-doublet and at least 2 cycles of BV maintenance monotherapy. Pts in the experimental arm receive BV at the same dose from induction (7.5 or 15 mg/kg IV on D1 of every 21-day cycle) continuously along subsequent lines, plus investigator’s choice of second-line agent (limited to pemetrexed, docetaxel, or erlotinib) and subsequent lines of treatment. Pts in the control arm receive investigator’s choice of agent alone in second and subsequent lines of treatment, but no further BV treatment. Stratifications include nature of second-line standard treatment, number of cycles of BV maintenance (≤6 vs. &gt;6) and smoking status. The primary endpoint is overall survival (OS). Secondary endpoints include 6-, 12-, and 18-month OS rates, progression-free survival, time to progression at second and third progressive disease (PD), response rate, disease control rate, duration of response at second and third PD, and safety of BV across multiple lines of treatment. Exploratory objectives include quality of life assessment through multiple treatment lines, and biomarker analysis. Assuming a median OS beyond PD of 7.9 months in the control group and 10.1 months in the treatment arm (HR 0.78), 528 events are required to achieve 80% power for the log-rank test at a 2-sided significance level of 5%. Enrollment began in June 2011.
First-line cisplatin (P) with docetaxel (TXT) or vinorelbine (VNR) in patients with advanced non-small cell lung cancer: A randomized phase II trial of the Gruppo Oncologico Italia Meridionale
Authors: V. Gebbia, D. Galetta, V. Lorusso, M. Caruso, F. Riccardi, E. Maiello, N. Borsellino, F. Ferraù, G. Colucci, S. Cinieri
Journal: Journal of Clinical Oncology (2009)

e19042 Background: P-based doublets are considered standard therapy for advanced NSCLC. The GOIM consider P/VNR as a reference treatment. P/TXT doublet has been reported to be active but it's not well known its real impact on QoL in comparison to P/VNR. Methods: Pts received either 6 courses of P/TXT or P/VNR with QoL and safety being the primary endpoints. Secondary endpoint included response rate, TTP, OS, and tolerability. Patients with stage IV/IIIB, age ≤70, and ECOG PS 0–1, were eligible. Sample size was calculated according to Fleming's single-stage procedure. QoL was analysed using the EORTC questionnaire, responses and toxicity according to the RECIST and NCI-CTC criteria. Pts were randomized to: TXT 75 mg/m2 over 60 min followed by P 75 mg/m2 on d1 every 21 d, or VNR 30 mg/m2 on d 1,8 and P 80 mg/m2 on d1 every 21 d. Results: From 12/06 to 3/08 86 pts were enrolled: P/TXT 42pts, M/F 32/10, IIIB/IV 8/34, squamous/not-squamous:13/29, median age 61 (r 41–70); P/VNR 44 pts, M/F 35/9, IIIB/IV 10/33, squamous/not-squamous 14/30, median age 62 (r 44/70). No statistically significant differences were observed in QoL among the two arms. Detailed analysis of side-effects showed no difference among the two regimens with the exception of G3–4 neutropenia and leukopenia with were slightly higher in the P/VNR arm (p=0.02 and p=0.0005 respectively). The use of G- CSF/darbopoietin was more frequent in pts treated with P/VNR than in the P/TXT arm (p=0019). Conclusions: Final data show an equivalence among the two arms regarding QoL and activity but with a slightly more hematological toxicity in the P/VNR arm. Both regimens are to be considered as standards in the treated of advanced NSCLC. [Table: see text]
The role of salvage induction chemotherapy after azacitidine (AZA) treatment failure.
Authors: Karen W. L. Yee, Joseph Brandwein, Aaron D. Schimmer, Vikas Gupta, Mark D. Minden, Andre C. Schuh
Journal: Journal of Clinical Oncology (2013)

7078 Background: Hypomethylating agents (HMA) such as AZA, are considered standard of care for patients (pts) with IPSS Int-2 or High-risk MDS. These agents are not curative. Many centers have used HMAs as a bridge to alloSCT in pts with MDS in an attempt to reduce tumor burden and prolong time to progression to AML. However, pts are at risk of AZA treatment failure, which may delay or prevent subsequent alloSCT. Recent data have demonstrated poor responses to intensive chemotherapy after AZA failure [ORR of 0% (0 of 4 pts) to 14% (3 of 22 pts) (J Clin Oncol 2011; Br J Haematol 2012)]. Methods: This retrospective analysis evaluates the outcomes of 18 pts with MDS, CMML and AML, who failed AZA therapy, and subsequently received induction chemotherapy at the Princess Margaret between July 2009 and December 2012. Results: Median age was 57.7 y (range, 19 - 75 y); only 1 pt was &gt; 70 y. 56% were male. Of the 18 pts, 83% were treated for MDS, 6% CMML-2, and 11% AML. IPSS was Int-2/High-risk in 16 pts and Int-1 risk in 2 pts. 83% of pts had been treated with AZA as first-line therapy. Two pts had received growth factors &amp; 1 pt hydroxyurea prior to AZA. Median number of AZA cycles administered was 5.5 (range, 1 - 18) with 72% of pts receiving &lt; 6 cycles. Eleven (61%) pts had primary AZA failure, 5 (28%) secondary AZA failure, and 2 (11%) were taken off AZA to receive induction chemotherapy as an HLA-identical donor was found. At the time of induction chemotherapy, 15 pts had s/tAML, 2 RAEB-2 and 1 CMML-2. Cytogenetic risk was intermediate in 4 and poor in 11 pts, respectively. Karyotype analysis was not done or inconclusive in 3 pts. ORR was 44% and 37.5% in all pts and in AZA failures only, respectively. CR rate was 22% and 25%, CRi 27% and 12.5%, and MLFS 6% and 0% in all pts and in AZA failures only, respectively. Four pts died during induction. Four of 8 responders received an alloSCT, with the remaining 4 pts relapsing (3 while awaiting an alloSCT). Median F/U of all pts was 12.6 mos, with a median OS of 8.3 mos. Conclusions: Contrary to prior reports, salvage induction chemotherapy can yield responses in a significant number of pts who have failed AZA therapy. However, response duration and OS remain poor for AZA treatment failures. There is an unmet need for novel therapeutic agents in this group of patients.