tbuckley/cabot-search huggingface dataset:
A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC)
Authors: M. Beeram, H. A. Burris, S. Modi, M. Birkner, S. Girish, J. Tibbitts, S. N. Holden, S. G. Lutzker, I. E. Krop
Journal: Journal of Clinical Oncology (2008)

1028 Background: T-DM1 is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20–100 times more potently than vincristine. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials.T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T- DM1 given IV q3 wks to pts with advanced HER2+ BC who have progressed on a T-containing regimen. Dose levels for successive cohorts were doubled until a related gr 2 AE was observed. Further escalation utilized a 3+3 modified Fibonacci design. Results: Twenty-four pts (median age 50.5 [range 35–70]; all PS 0–1; median number prior metastatic chemo regimens 3 [range 1–7]) have received 156 doses of T- DM1 at 6 dose levels (0.3 mg/kg, 3 pts; 0.6 mg/kg, 1 pt; 1.2 mg/kg, 1 pt; 2.4 mg/kg, 1 pt; 3.6 mg/kg, 15 pts; 4.8 mg/kg, 3 pts). Related grade (gr) 1–2 AEs include TA elevations (gr 1, 5 pts; gr 2, 2 pts), thrombocytopenia (TCP; gr 1, 6 pts; gr 2, 3 pts), fatigue (gr 1, 5 pts; gr 2, 2 pts), anemia (gr 1, 4 pts; gr 2, 3 pts), and neuropathy (gr 1; 2 pts). Related gr 3–4 AEs include rapidly reversible TCP (gr 3, 1 pt; gr 4 [DLT], 2 pts both at 4.8 mg/kg) and neutropenia (gr 3, 1 pt). No cardiac-specific toxicity has been observed. T-DM1 clearance decreased with increasing dose as predicted preclinically. Six of 16 pts at 2.4 or 3.6 mg/kg have had partial responses (5 confirmed); 5 more have stable disease ongoing after 130 to 260 days. Conclusions: The MTD and recommended phase II dose of T-DM1 given IV q3 wks is 3.6 mg/kg. At the MTD, gr ≥2 AEs related to T-DM1 have been infrequent and manageable. T-DM1 PK is compatible with q3-week dosing. Objective tumor responses have been observed at doses at or below the MTD. A phase II trial in advanced HER2+ BC pts who have progressed on a T-containing regimen is underway; weekly dosing is also being explored. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.
An international comparison of barriers in opening oncology clinical trials
Authors: A. Wang-Gillam, S. Novello, K. Williams, F. Gao, G. V. Scagliotti, R. Govindan
Journal: Journal of Clinical Oncology (2009)

6580 Background: Well designed clinical trials are critical to improve the outcomes of patients with cancer. There are significant barriers to accrue patients to clinical trials beginning with processes required to “open” a trial. This study aims to compare the procedures and time required to open thoracic oncology trials at a United States academic center to a similar center in Europe. Methods: A retrospective review was performed of all thoracic oncology therapeutic trials submitted for regulatory review between 2001–2008 at Washington University School of Medicine (WUSM) and the University of Torino, Italy (UT). A process map was drafted by both institutions to establish the order of required events. The timing data for each step was collected and analyzed for comparison. Results: A total of 137 therapeutic thoracic oncology trials were reviewed, 83 from WUSM and 54 from UT. Five major regulatory steps are required to open a trial in WUSM compared to three at UT. The median times to open a trial are 163 days (with inter-quartile range of 91 to 257 days) for WUSM and 122 days for UT (with inter-quartile range of 96 to 159 days) (p = 0.048). The median times for regulatory approval are 75 days (inter-quartile range, 26 to 131 days) for WUSC and 31 days (inter-quartile range, 10 to 67 days) for UT (p&lt;0.0001), attributed to the additional requirement of Scientific Review Committee approval at WUSM prior to consideration by the Institutional Review Board (IRB), while regulatory approval is a single process at UT. However, the median time for contact approval process identified as the limiting step requiring a median of 115.1 (WUSM, inter-quartile range of 78 to 187) or 84 (UT, inter-quartile range of 44 to 124) days (p = 0.011). Conclusions: It takes additional steps and significantly longer time to open a therapeutic thoracic clinical trial at a representative U.S. site (WUSM) compared with a site in Europe (UT). As global trial collaboration increases, uniform strategies must be developed to shorten the administrative process, encouraging the creation of streamlined systems that enable centers to increase the number of agents under investigation. No significant financial relationships to disclose.
Analysis of the mutation rate in lymphocytes derived from patients with cutaneous T-cell neoplasms using the <i>PIG-a</i> gene.
Authors: Behzad Doratotaj, Leah B. Zamechek, Kenneth B. Hymes, David J. Araten
Journal: Journal of Clinical Oncology (2012)

e21082 Background: It has been proposed that genomic instability may account for the high number of mutations observed in cancer. Inherited mutations in repair genes might play a role; alternatively, hypermutability may be the result of mutagens, or may be limited to a specific pre-malignant population. Here we have investigated the hypothesis that cutaneous T cell neoplasms might be associated with constitutional hypermutability, using an assay based on the PIG-A gene. A broad spectrum of mutations can inactivate PIG-A, which is X-linked; thus, only one mutation is required to produce the PIG-A-null phenotype, which entails a loss of all GPI-linked membrane proteins (e.g. CD48, CD55, CD59, CD52). Methods: We have isolated peripheral blood lymphocytes from normal donors and patients with cutaneous T cell neoplasms, which are initially stimulated with phytohemagglutinin. After 1 week, cells are stained with an anti-CD59 antibody and sorted to eliminate pre-existing mutants. The collected GPI (+) cells are then counted, returned to culture with IL-2 and IL-15, and re-stimulated with beads bearing anti-CD2, anti-CD3, and anti-CD28. After 3 weeks in culture the cells are re-counted, and the frequency (f) of new mutants arising in vitro is determined by flow cytometry, by staining sequentially with a mixture of mouse antibodies specific for 4 GPI-linked proteins, followed by a secondary PE-conjugate, followed by a FITC conjugated antibody specific for a non-GPI linked protein, e.g., CD4, CD8, or CD45. The number of cell divisions (d) in culture is determined by live cell counts before and after expansion, and the mutation rate (μ) is calculated as μ = f / d. Results: Amongst 15 normal donors (mean age 54), μ in proliferating CD45 + T cells ranged from 10 to 183 x 10 -7 mutations per cell division (median 35 x 10 -7 ). Amongst 10 patients with cutaneous T cell neoplasms (mean age 60) μ ranged from 7 to 116 x 10 -7 (median 23 x 10 -7 ) in proliferating CD4+ cells, and μ ranged from 10 to 363 x 10 -7 (median 26 x 10 -7 ) in proliferating CD8 + cells. Conclusions: We conclude that a constitutional increase in the mutation rate, as detected by this assay, is not a common feature of cutaneous T cell malignancies.
Abstract 14944: Improved Assessment of Coronary Artery Stenosis Severity Using Combined Anatomical and Functional Endpoints: A Clinical Study
Authors: Srikara Viswanath Peelukhana, Kranthi K Kolli, Mohamed Effat, Tarek Helmy, Imran Arif, Massoud Leesar, Back Llyod, Rupak K Banerjee
Journal: Circulation (2012)

Introduction: During cardiac catheterization, functional severity of blockages is assessed using diagnostic parameters, like Fractional Flow Reserve (FFR, pressure based) and Coronary Flow Reserve ...
The prevalence of vasomotor and psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a single-institution experience.
Authors: Amarnath Challapalli, Waqar Saleem, Ernese Gjafa, Marc Laniado, Bente Stanbridge, Giles Hellawell, Stephen Mangar
Journal: Journal of Clinical Oncology (2014)

283 Background: Hormonal therapy is an important therapeutic modality in both early and metastatic prostate cancer. Whilst the long term effects of androgen deprivation (AD) have been extensively studied, little attention has focussed on assessing short-term vasomotor and psychological effects and the resulting impact of quality of life (QoL) in prostate cancer, relying on data mainly extrapolated from breast cancer patients. This prospective study sought to assess these effects and identify any predictive factors. Methods: Data from 200 consecutive prostate cancer patients were collected from January 2010 to August 2013. A self-reported questionnaire was employed to objectively assess a variety of vasomotor and psychological symptoms, graded from 1 no toxicity, 2 mild, 3 moderate to 4 severe toxicity. Other parameters including height, weight, Body Surface Area (BSA), Body Mass Index (BMI), duration and type of hormonal therapy were also recorded. Results: 181 patients were fully evaluable, with a median age of 75 (IQR 70.5-80). 166 received an LHRH analogue,11 maximum androgen blockade, and 4 received anti-androgens only. 33 (18.2%) of patients reported no toxicity, with 76 (42%), 55 (30%) and 17 (9.4%) experiencing mild, moderate and severe (debilitating) symptoms respectively. The commonest debilitating symptoms were vasomotor: drenching sweats (82%), and hot flashes (82%), which usually coexisted, and less commonly psychological: sleep disturbances (18%) and tiredness (12%). Age (median: 77 vs. 74 yrs), weight (median: 79.8 vs. 84.4), and BMI (median: 26.6 vs. 28.3) significantly predicted between those with grade 1/2 and grade 3/4 symptoms, (p=0.0007, 0.02, 0.02). A non-significant trend was observed with increasing duration of hormonal treatment and toxicity (median: 5, 7, 9.5 and 12 months for Grade 1-4, respectively, p=0.07). Conclusions: The short term side-effect profile of hormonal therapy for prostate cancer is generally favourable, though debilitating predominantly vasomotor symptoms can occur in a significant minority of cases. Increasing age, weight, and BMI may be predictive of toxicity.
Phase II trial of gemcitabine and cisplatin as first-line treatment of advanced non-small cell lung cancer (NSCLC)
Authors: N.-S. Lee, J.-H. Byun, S.-B. Bae, C.-K. Kim, K.-T. Lee, S.-K. Park, K.-K. Park, J.-H. Won, D.-S. Hong, H.-S. Park
Journal: Journal of Clinical Oncology (2005)

7326 Background: The prognosis of patients with advanced non-small-cell lung cancer (NSCLC) is extremely poor. Many prospective randomized trials on patients with advanced NSCLC suggested systemic chemotherapy improves both the survival and quality of life. A phase II trial was conducted to evaluate the efficacy and safety profile of the combination chemotherapy of gemcitabine and cisplatin in advanced NSCLC. Methods: Forty-four patients with locally advanced or metastatic NSCLC were enrolled. The patients received a cisplatin, 75 mg/m2, infusion over 30 minutes on days 1, followed by a gemcitabine, 1,250 mg/m2, infusion over 30 minutes on days 1 and 8 every 3 weeks. Results: The median age of the patients was 64 years (range: 27∼75). Forty-one patients were assessable for response and toxicity analyses. The overall response rate was 53.6%, but with no complete remissions. The median time to progression was 5.6 months (range: 1∼15.4). The median survival was 14.2 months (95% confidence interval (CI), 13.8∼22.5). A total of 179 cycles were administered, with a median of 4 cycles of chemotherapy, ranging from 2 to 9 cycles. The most common hematological toxicities were NCI grades 3/4 neutropenia (24%) and thrombocytopenia (7.8%). The most common non-hematological toxicity was fatigue (42.4%). There were no life-threatening toxicity or treatment related mortalities. The median duration of follow up was 9.4 months, ranging from 1.6 to 30.3 months. Conclusions: In this trial, the combination of gemcitabine and cisplatin showed significant activity, with acceptable and manageable toxicities as a first-line regimen for patients with advanced NSCLC. No significant financial relationships to disclose.
Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension.
Authors: M Gasparini, F Lombardi, M C Gianni, M Massimino, L Gandola, F Fossati-Bellani
Journal: Journal of Clinical Oncology (1990)

A series of 15 consecutive children with head and neck nonorbital rhabdomyosarcoma (RMSA) with meningeal extension were prospectively treated with chemotherapy consisting of Adriamycin (doxorubicin; Adria Laboratory, Columbus, OH) (ADM), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) followed by radiotherapy (60 Gy) to the primary tumor volume, along with intrathecal methotrexate (IT MTX). Thirteen of 15 responded to preradiation chemotherapy. Four of 13 relapsed. Relapse occurred at the level of the primary tumor in three of four. The 3-year progression-free survival (PFS) was 59%, similar to that achieved in a previous series treated with a comparable therapeutic approach that also included whole-brain radiotherapy as a prophylaxis of possible occult meningeal seeding. It is concluded that CNS prophylaxis with radiotherapy is questionable in the management of childhood RMSA with meningeal extension.
A chimeric humanized anti-CD40 antibody renders human multiple myeloma (MM) cells refractory to the mitogenic and protective effects of IL-6
Authors: YT Tai, CS Mitsiades, LP Catley, R Burger, K Podar, R Shringarpure, T Hideshima, D Chauhan, M Hamasaki, K Ishitsuka, P Richardson, N Munshi, S Treon, K Anderson
Journal: Blood (2003)
Initial results of a phase II trial of patients with extensive stage small cell lung cancer (SCLC) immunized with dendritic cells (DC) transduced with wild-type p53
Authors: D. I. Gabrilovich, N. Mirza, A. Chiappori, M. Dunn, M. Willis, W. Janssen, R. Smilee, K. Menander, S. Chada, S. Antonia
Journal: Journal of Clinical Oncology (2005)

2543 Background: Many types of cancer are associated with mutations in the p53 gene. Patients with SCLC exhibit a very high frequency of p53 mutations, which result in overexpression of p53 protein in tumor cells. In preclinical studies we and others have demonstrated that tumor cells can be recognized by p53-specific cytotoxic T cells. Here, we tested this concept in clinical trial. Methods: Twenty-two patients with extensive stage SCLC were treated to date in an on-going phase II trial. Patients received first-line chemotherapy to best response, and those patients with stable disease or minor progression underwent leukapheresis 8 weeks after the last dose of chemotherapy. DC were generated from peripheral blood precursors and then infected with adenoviral construct containing wild-type p53 (ADVEXIN). Patients received 3 doses of vaccine i.d. (2–5x106 p53+ DCs per dose). p53 specific immune response was evaluated using ELISPOT and staining with tetramers. Results: The vaccine was well tolerated, and no appreciable toxicity was detected in any of the treated patients. Statistically significant immunological response to vaccination was detected in 11 out of 20 tested patients (55%). Five patients had stable disease after 3 doses of the vaccine and were given 3 more doses. Seventeen patients had progressive disease (almost all within 3 months after completing first-line chemotherapy) and were treated with second-line chemotherapy. To date, clinical response to chemotherapy was evaluated in 13 of those patients. Surprisingly, a substantial proportion of patients responded to chemotherapy: 2 patients had stable disease, 7 (53.8%) had objective partial response and 4 had progressive diseases. Conclusions: Novel vaccine utilizing DC genetically engineered to express wild-type p53 demonstrated safety and substantial specific immune response in patients with extensive stage SCLC. Initial evaluation of clinical response demonstrates promising results. The DC-p53 vaccine appears to sensitize SCLC tumors to subsequent chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Introgen Therapeutics Introgen Therapeutics American Cancer Society
Phase I study (A8471004) in Asian patients of PF-03446962, a fully human mab against ALK-1 receptor involved in tumor angiogenesis: Safety, pharmacokinetics (PK), and pharmacodynamics (PD).
Authors: Kyung-Hun Lee, Toshihiko Doi, Tae Min Kim, Atsushi Ohtsu, Tae Yong Kim, Masafumi Ikeda, Kiyotaka Yoh, Corrado Gallo-Stampino, Tomoko Hirohashi, Akiyuki Suzuki, Fujii Yosuke, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

11031 Background: Activin receptor like kinase 1 (ALK-1) is a member of the TGF-βRI family selectively expressed in proliferating endothelial cells, and plays an important role in regulating tumor initiation and metastasis. PF-03446962 is a fully human IgG2 mAb anti ALK-1 evaluated within two phase 1 studies in Western and Asian pts. Herein we report the preliminary safety, PK and PD data of the Phase I study. Methods: Primary objective is to identify the maximum tolerated dose (MTD) in Asian cancer pts; secondary objectives include the safety profile, PK, antitumor activity, and potential PD markers in blood and tumor samples. PF-03446962 is administered IV on Day 1, 29 and then q 2 weeks. Results: Study A8471004 consists of two parts: a 3+3 dose escalation (Part 1) and a dose expansion (Part 2) at 2 dose levels. In Part 1, 16 pts have been enrolled at 3 dose levels (4 pts at 4.5 mg/kg, 3 pts at 7.0 mg/kg, and 9 pts at 10 mg/kg). No DLTs occurred in Part 1 and 10 mg/kg was confirmed as MTD in the Asian population. The observed AUC 0-28day for the 4.5, 7 and 10 mg/kg doses, were 12960, 22190 and 28030 μg·h/mL and Cmax were 97.1, 131.5 and 179.8 μg/mL, respectively. Drug exposure (mean Cmax and AUC) increased in a nearly dose proportional manner in Asians. In Part 2, expansion cohorts at doses of 7.0 mg/kg (10pts) and 10.0 mg/kg (8pts) of pts previously treated with VEGF inhibitors (VEGFi) have been enrolled, and the most common drug related adverse events observed (&gt;10%) being thrombocytopenia, pyrexia, epistaxis, and telangiectasia (an anti-ALK-1 mediated toxicity) similarly in the 2 dose levels. Telangiectasia was observed in 1 CRC and 3 HCC patients. 4 patients who progressed after VEGFi treatment (RCC, sarcoma, 2 HCC patients) presented a SD lasting for 290, 248, 247 and 208 days, respectively, suggesting the ALK-1 could serve as mechanism of escape for VEGF. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 is well tolerated in the Asian pts and preliminary observation of clinical activity supports ALK-1 as a viable target. Update of study results and potential PD effects obtained on blood and tumor samples will be presented. Clinical trial information: NCT01337050.
90y-Ibritumumab Tiuxetan (Zevalin ®)-BEAM/C with Autologous Stem Cell Support as Frontline Therapy for Advanced Mantle Cell Lymphoma. – Preliminary Results From the Third Nordic MCL Phase II Study (MCL3).
Authors: Arne Kolstad, Anna Laurell, Niels S Andersen, Erkki Elonen, Riikka Raty, Lone Bredo Pedersen, Annika Loft, Trond Velde Bogsrud, Marie Nordstrom, Dorte Gillstrom, Per Boye Hansen, Hans Bentzen, Unn-Merete Fagerli, Peter Meyer, Herman Nilsson-Ehle, Mats Jerkeman, Anne Kristine Lehmann, Grete F Lauritzsen, Christer Sundstrom, Jan Delabie, Marja-Liisa Karjalainen-Lindsberg, Elisabeth Ralfkiaer, Mats Ehinger, Christian H. Geisler
Journal: Blood (2009)
Skipping of ATP-Binding Cassette Transporter A3 Exon 19 in AML Cells Is an Independent Prognostic Factor in Patients with Normal Cytogenetics
Authors: Aminetou Mint Mohamed, Morgan Thenoz, Lea Payen-Gay, Delphine Maucort-Boulch, Hussein Mortada, Didier Auboeuf, Catherine Koering, Meyling Cheok, Olivier Nibourel, Claude Preudhomme, Mohamed El-Hamri, Xavier Thomas, Franck E. Nicolini, Isabelle Tigaud, Emeline Cros, Charles Dumontet, Lydia Campos, Francoise Solly, Denis Guyotat, Pascale Flandrin-Gresta, Franck Mortreux, Eric Wattel
Journal: Blood (2014)
Phase II trial of the poly(ADP-ribose) polymerase (PARP) inhibitor AG-014699 in <i>BRCA</i> 1 and 2–mutated, advanced ovarian and/or locally advanced or metastatic breast cancer.
Authors: Y. Drew, J. A. Ledermann, A. Jones, G. Hall, G. C. Jayson, M. Highley, D. Rea, R. M. Glasspool, S. E. R. Halford, G. Crosswell, S. Colebrook, A. V. Boddy, N. J. Curtin, E. R. Plummer
Journal: Journal of Clinical Oncology (2011)

3104 Background: AG-014699 (PF-01367338) is an intravenous, potent, selective PARP-1 and 2 inhibitor (Ki = 1.4 nM). In pre-clinical studies AG-014699 induces selective cytotoxicity in tumour cells defective in homologous recombination repair (HRR) through BRCA 1 and 2 deficiency and non-BRCA mutated HRR defects. The aim of this study was to determine the efficacy of AG-014699 in confirmed BRCA 1 or 2 mutation carriers with advanced ovarian and/or advanced breast cancer. Methods: Multi-centre, single arm phase II trial of AG-014699 18mg/m2 given days 1 to 5 of a 21 day cycle. Study included 2 sequential 6 patient safety cohorts in which cycle 1 was given at 4mg/m2 or 12mg/m2. Patients were dose escalated to 18mg/m2 for subsequent cycles if no dose limiting toxicity (DLT) was observed. Primary endpoint was best objective response rate (ORR) by RECIST and toxicity of AG-014699. Secondary aims included progression-free survival, pharmacokinetic and pharmacodynamic endpoints. Results: On December 1, 2010, 41 patients (17 breast, 24 ovary; 22 BRCA1 deficient, 19 BRCA2 deficient) exposed to a mean of 2 prior chemotherapy regimens had been enrolled. Mean age was 52 years (range 28-72). 38 had RECIST assessments. ORR was 5% (2/38) however 26% (10/38) achieved stable disease for ≥ 4 months with 3 patients remaining on study for > 54 weeks. No DLT occurred at any dose level. AG-014699 had an acceptable safety profile with drug-related toxicity mainly grade 1 and 2; the most common being: fatigue (39%), nausea (26.8%), diarrhoea (19.5%) and dizziness (17.1%). PARP activity assessed in surrogate peripheral blood lymphocytes demonstrated mean inhibition of 84% over baseline levels at 24 hours after a single dose of 18mg/m2 AG-014699. Conclusions: AG-014699 (18mg/m2) resulted in significant PARP inhibition, was well tolerated and resulted in a clinical benefit rate (CR+PR+SD ≥ 4 months) of 32%. ORR was lower than reported in other studies and this may be secondary to the intermittent dosing schedule allowing time for recovery of PARP activity and loss of synthetic lethality. A more frequent dosing schedule of oral AG-014699 is planned in this patient population.