tbuckley/cabot-search huggingface dataset:
Application of mechanism-based PKPD model to identify optimal dosing regimens for future development of oraxol.
Authors: Gerald J. Fetterly, Allison Gaudy, Biao Liu, Patricia D. Meholick, Min-Fun Rudolf Kwan, David G. Hangauer, Kyung-Mi Park, Jeewoong Son, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

e13505 Background: Paclitaxel (PTX) is a widely used potent anticancer drug that blocks mitosis by stabilization of microtubules. Previous attempts for oral administration of PTX have been unsuccessful at least partly due to its affinity for the efflux pump, P-gp. Oraxol is an oral formulation of PTX combined with a novel potent P-gp inhibitor, HM30181A, to maximize absorption of paclitaxel without itself being systemically absorbed. A population PK/PD model was developed to characterize the temporal relationship between PTX exposure and neutropenia, and subsequently model-based simulations were utilized to determine the optimal dosing strategy for oraxol. Methods: Oraxol was administered to 68 (51M/17F) patients with various malignancies. Oraxol dose levels ranged from 60 to 420 mg/m 2 QW, and 90-150 QWx2 for 3/4 weeks. Population PKPD modeling was performed with the following patient factors: [BSA (1.29-2.15 m 2 ), ECOG PS scores (97% pts ≤ 1), age (36-81.4 yrs), CrCL (39.6-132.8 ml/min), ALB (2.3-4.8 mg/dL), ALT (6-61 IU/L), TBIL (0.2-1.6 mg/dL), and smoking status (NS:57%)]; followed by model validation. Simulations assessed the influence of dose and schedule on the time course and the extent of neutropenia. Results: A precursor-dependent indirect PKPD response model, including three transit compartments was employed to describe the time course of ANC after oraxol administration. Mean predicted (%SEM) baseline ANC and MTT of neutrophils in plasma were 3.6 (3.9) x10 9 cells/L and 6.3 (4.2) days. The magnitude of the inhibition on marrow cells was 3.3% per 100 ng/mL of PTX. Model validation results showed excellent concordance with the observed and simulated ANC profiles at the 150 mg/m 2 dose level. Simulations showed that severity of neutropenia was dose- and schedule-dependent. The optimal dosing scenarios for oraxol 150 mg/m 2 QDx3 and QDx5 showed the incidence of grade ³3 neutropenia to be 53.8% and 58%, respectively. Simulated grade 4 neutropenia was 25 and 34.6% for the same regimens; similar to IV PTX. Conclusions: A PKPD model quantifying the neutropenic effect of oraxol has been developed. The model predicts that the QDx3 or QDx5 oraxol dosing 3/4 weeks may optimize efficacy with manageable toxicity.
Results of a Phase I/II Trial of Pixantrone in Combination with Fludarabine, Dexamethasone, and Rituximab in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).
Authors: Luis Fayad, James Liebmann, Manuel Modiano, Gary Cohen, Barbara Pro, Jorge Romaguera, Scott Stromatt
Journal: Blood (2006)
The role and significance of FoxM1 in invasive breast cancer.
Authors: Cha Kyong Yom, Kyung-Min Lee, Wonshik Han, Sung-Won Kim, Hyeong-Gon Moon, Hee-Chul Shin, Eunyoung Kang, Dong-Young Noh
Journal: Journal of Clinical Oncology (2012)

1056 Background: The Forkhead Box protein M1 (FoxM1) is known to regulate a variety of biologic processes in mammalian cells including cell growth and survival, angiogenesis, DNA damage response, chemotherapeutic drug resistance, and cancer cell migration and invasion. We evaluate the role and significance of Fox M1 in primary breast cancer in vitro and analyzed the relation with FoxM1 expression and clinicopathologic features. Methods: Immunohistochemical staining was used for evaluation of cytoplasmic expression of FoxM1 with TMA of invasive breast cancer. In various breast cancer cell lines, we evaluated FoxM1 expression and treated docetaxel/cisplatin in combination with Siomycin A (FoxM1 inhibitor) for BT20 cell line. Results: From Nov 1995 to Jul 2007, in 84 patients with stage 1-3 invasive breast cancer, FoxM1 expression was noted in 58.7%. Median follow-up duration was 85.1 months. Lymphovascular invasion was positively correlated with FoxM1 expression (p=0.040). In multivariate analysis, FoxM1 expression (p=0.005), HR negativity (p=0.002), high histologic grade (p=0.023), hign nuclear grade (p=0.045), lymphovascular invasiveness (p=0.017), and stage 3 cancer (p=0.015) matched poor disease-free survival. In vitro study, FoxM1 was expressed BT474, JIMT-1, BT20, HCC-1937, and MDA-MB-231 cell lines. The inhibition of FoxM1 had synergistic effect on cisplatin treatment, not docetaxel in BT20 cell. Conclusions: FoxM1 expression was noted in triple negative breast cancer cell lines and its inhibition had synergistically cytotoxic effect on BT20 cell line in combination with cisplatin. Although the further in vivo and clinical study should be needed to draw the solid conclusions, FoxM1 could be both a promising target of treatment for triple negative breast cancer and a independent prognostic factor.
A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial.
Authors: John Sarantopoulos, Long H. Dang, Richard C. Lauer, Alexander Starodub, Ralph J. Hauke, Matt D. Galsky, Kathryn A. Bylow, Charles Lance Cowey, David C. Bibby, Gabriel Kremmidiotis, Elizabeth E. Doolin, Tina C. Lavranos, Jose Luis Iglesias, Guru Sonpavde, Theodore Logan, Noah M. Hahn, Christopher Sweeney, Thomas E. Hutson
Journal: Journal of Clinical Oncology (2013)

4563 Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m 2 ; IV infusion Days 1 &amp; 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Biomarker samples (pre- and post-dose during Cycle 1) were analyzed for 70 plasma analytes including VEGF, PDGF and other markers associated with angiogenesis and vascular responses. Results: Updated results from the completed phase I component confirm the BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single Grade 3 events of anemia and pericardial effusion. Grade 2 events of fatigue, anemia and oral mucositis were also observed. Eight of the 12 phase I subjects achieved disease stabilization. Across all subjects a median of 6 cycles (range: 1-24) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: Full dose BNC105P (16 mg/m 2 ) can be combined with full dose everolimus (10 mg) and is being further evaluated in a randomized phase II study. Clinical trial information: NCT01034631.
Phase I, dose-escalation study of the investigational drug D07001-F4, an oral formulation of gemcitabine HCl, in patients (pts) with advanced solid tumors.
Authors: Chia-Chi Lin, Wu-Chou Su, Jih-hsiang Lee, Chih-Hung Hsu, Ann-Lii Cheng, Chia-Li Lin, Hsiang-Ling Ho, Chia-Tsung Huang, Shu-Ping Hsueh, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2014)

TPS2631^ Background: Gemcitabine HCl is a nucleoside analogue that exhibits antitumor activity and is approved for IV use in the world. Oral dosing of gemcitabine HCl would simplify administration and extend the systemic exposure time after a dose relative to an intravenous exposure profile, which has been correlated with increased activity of gemcitabine in both pre-clinical and clinical studies. Nonetheless, in a reported clinical study, the systemic exposure to oral gemcitabine was low due to extensive first-pass metabolism to dFdU. D07001-F4 is a unique oral formulation of gemcitabine HCl that is expected to enhance the systemic exposure to difluorodeoxycytidine (dFdC) and ultimately dFdCTP, intracellularly. Methods: D07001-F4 is being evaluated of in an open-label, dose escalation study in patients with advanced solid tumors or lymphoma. Eligibility: pts with evaluable tumors, age ³a 20 yrs, PS 0–2 and with adequate oral therapy absorption. Primary objects includes determination of maximum tolerated dose, dose-limiting toxicity(ies) and the recommended phase 2 dose of D07001-F4. Secondary objectives include characterization of pharmacokinetic (PK) and assessment of safety, tolerability and anti-tumor activity. Sequential cohorts of 3 to 6 patients receive doses ranging from 2 mg to 80 mg oral D07001-F4 on Days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. MTD is determined based on DLTs in cycle 1. Tumor response is determined according to RECIST or Cheson criteria. Plasma and peripheral blood samples were obtained for PK analysis in cycle 1. Accrual has completed in Cohorts 1 (2 mg) to 4 (20mg). Accrual is underway for Cohort 5 (30 mg). Clinical trial information: NCT01800630.
A simple but effective model to decrease early deaths in acute promyelocytic leukemia (APL).
Authors: Anand P. Jillella, Ibrahim Sadek, Devi Morrison, Kavita Natrajan, Farrukh Tauseef Awan, Ravindra Kolhe, Vamsi Kota
Journal: Journal of Clinical Oncology (2012)

6573 Background: Recent reports suggest that approximately 30% of patients with APL die during induction. This has been confirmed in large population-based studies in Sweden and the US. A recent analysis of SEER data from 13 population-based cancer registries with 1400 APL patients in the US showed that 17% of all patients and 24% of patients greater than 55 years of age die within one month of diagnosis. The most common causes of death are bleeding, infection, differentiation syndrome and multi-organ failure. Patients who survive induction have an excellent cure rate with few late relapses. Hence, decreasing early deaths is a high priority both at experienced as well as smaller centers with limited leukemia treatment experience in this highly curable disease. Methods: At Georgia Health Sciences University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. Seven patients (5 high-risk and 2 low-risk) died during induction resulting in an unusually high mortality rate of 37%. All patients who survived induction are still in remission at present. The high early death rate prompted us to develop a simple, 2 page treatment algorithm that focuses on quick diagnosis, prompt initiation of therapy, and proactive and aggressive management of all the major causes of death during induction. We also made our treatment protocol available to smaller treatment centers and helped the treating oncologists manage the patient during the first few days after diagnosis. Results: From 11/2010 to 12/2011, we treated 4 patients at GHSU and helped manage 4 patients at 2 outreach sites. The age range was 30 to 60; two patients were high-risk, 5 intermediate- and one low-risk. There were no deaths during induction and all eight patients proceeded to consolidation treatment. Conclusions: While we recognize that this is a small cohort, our own experience and a similar approach pioneered by investigators in Brazil clearly shows this to be an effective intervention to decrease early deaths in APL. We believe our experience warrants large scale implementation of our protocol in an attempt to reduce early APL mortality.
Factors of early recurrence (&lt;24 months) in relapsed node negative early stage breast cancer (the study of Anatolian Society of Medical Oncology).
Authors: Abdurrahman Isikdogan, Zuhat Urakci, Havva Yesil Cinkir, Faysal Dane, Tulay Akman, Ibrahim Vedat Bayoglu, Yusuf Gunaydin, Meltem Baykara, Dogan Yazilitas, Erdem Cubukcu, Ali Suner, Mehmet Bilici, Ugur Ersoy, Ozan Yazici, Muhammet Ali Kaplan
Journal: Journal of Clinical Oncology (2015)

e12066 Background: Recurrence is a important cause of morbidity and mortality in the early stage of breast cancer. Although the node positivity more tightly associated with recurrence, it can be observed in node negative patients. In this study, we evaluated determining factors for early recurrence in node negative operated breast cancer patients. Methods: Between 1998 to 2012, relapsed node negative operated breast cancer patients were included in the study from referral centers. Patients divided into two groups; early recurrence ( ≤ 24 months) and late recurrence ( > 24 months) group. Results: A total of 290 patients were included in the study. While 108 of the 290 patients (37.2%) were in the early recurrence group, 182 (62.8%) were in the late recurrence group. The median age was 51 (21-87), invasive ductal carcinoma histology, the proportion of grade 3 patients, and lymphovascular invasion (LVI) ratio were 83.8%, 33.7%, and 41.3%, respectively. Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Receptor 2 (HER2) positivity were 60.4%, 61.8% and 30%, respectively. Although, there were no statistical differences between early and late recurrence groups in terms of age (median 52 (21-82) vs. 50 (21-87), p = 0.503), histological subtypes (invasive ductal carcinoma ratio, 80.6 % and 85.7 %, respectively, p = 0.417) , tumor stage (T3,4 patients ratio 18.3% and 10.6 %, p = 0.102 ) and LVI (43.9 % and 39.6 %, p = 0.634 ), significant differences were observed in terms of grade (grade 3 patients ratio; 47.0 % vs 25.2 % , p < 0.001), ER positivity (41.1 % vs. 71.8 %, p < 0.001), PR positivity (50.0% vs. 68.9%, p = 0.001 ] and HER2 positivity (36.1% vs. 25.8%, p = 0.064). Statistically significant parameters in the univariate analyze were evaluated in multivariate analysis and ER negativity [ Odds Ratio (OR) : 2.68 , 95% CI ; 1.40 to 5.12 , p = 0.003 ], and the presence of grade 3 disease (OR: 2.27 , 95% CI , 1.28 to 4.02 , p = 0.005) were found as independent prognostic factors. Conclusions: In this study, ER negativity and grade 3 disease were found as independent prognostic factor and these parameters can be used in order to predict recurrence in early stage node negative breast cancer patients.
A phase 1-2 study of the type I progesterone receptor (PR) antagonist onapristone (ONA) in patients (pts) with advanced castration-resistant prostate cancer (CRPC).
Authors: Joaquin Mateo, Daniel Nava Rodrigues, Raquel Perez Lopez, Penelope Flohr, Ruth Riisnaes, Francois Marc Lokiec, Alexander Zukiwski, Stefan Proniuk, Alice Susannah Bexon, Andre Paquin, Joseph Bisaha, Nina Tunariu, Johann Sebastian De Bono, Gerhardt Attard
Journal: Journal of Clinical Oncology (2014)

TPS5097 Background: PR expression in prostate cancer increases with resistance to castration [Bonkhoff 2001]. The transcriptional, activated PR (APR), offers a potential target in advanced CRPC. ONA stops PR dimerization, inhibits ligand-induced PR phosphorylation and prevents PR association with co-activators, blocking PR-induced DNA transcription. ONA was active in preclinical models, with responses reported in pts with other PR+ cancers. An extended-release (ER) tablet formulation of ONA has been developed to achieve continuous exposure and to address the liver function abnormalities seen with an earlier formulation. Parallel development of an APR companion diagnostic allows for stratification of advanced CRPC pts. Methods: This is an open-label, phase 1-2 study with 2 stages: dose-selection and expansion (n~60). Main inclusion criteria are: metastatic/recurrent CRPC, good organ function, prior progression on abiraterone (AA) or enzalutamide (ENZ) and 1-2 lines of chemotherapy. Tumor biopsies are acquired from all pts at baseline to determine PR status. Paired biopsies at day 8-28 and upon progression are collected if possible. Primary endpoints are: determination of recommended phase 2 dose (RP2D) and response rate based on RECIST, circulating tumor cell (CTC) count conversion and/or >50% PSA decline. Secondary endpoints include safety and PK. Exploratory analyses of multiparametric MRI as a response biomarker in bone, circulating nucleic acids and hormone metabolism are included. Stage 1: Pts are randomized to 10 or 20 mg of ONA ER tablets BID (3-6 pts/cohort). Upon confirmation of safety, based on a dose-limiting toxicity (DLT) observation period of 8 weeks, a data review committee (DRC) will open randomization in parallel to the 30-40-50 mg cohorts (6pts/cohort). RP2D will be selected based on tolerability and PK. Stage 2: 36 pts will be treated at RP2D with an interim analysis after 21 pts. The DRC can permit continued AA/ENZ during ONA treatment at this stage. The adaptive design for biomarker-driven pt selection guarantees that >75% pts at RP2D will be APR+. The dose-selection stage of the study is open for accrual. Clinical trial information: NCT02049190.
Phase 1 Evaluation of Oral Tetrahydrouridine-Decitabine As Non-Cytotoxic Epigenetic Disease Modification for Sickle Cell Disease
Authors: Robert E Molokie, Donald Lavelle, Michel Gowhari, Michael Pacini, Lani Krauz, Johara Hassan, Vinzon Ibanez, Maria A Ruiz, Daisy Pacelli, Sherry Fada, Mitch A. Phelps, Santosh L. Saraf, Lewis L. Hsu, Victor R. Gordeuk, Joseph DeSimone, Yogenthiran Saunthararajah
Journal: Blood (2016)
Developing a molecular imaging agent for Met using onartuzumab (MetMAb).
Authors: Cara Elizabeth Wright, Elaine Jagoda, Fabiola Cecchi, Veerendra Bhadrasetty, Stephanie Histed, Mark Williams, Gabriela Kramer-Marek, Esther Mena, Lauren Rosenblum, Lixin Lang, Lawrence Szajek, Chang Paik, Peter L. Choyke, Jan Marik, Jeffrey Tinianow, Mark Merchant, Donald P. Bottaro
Journal: Journal of Clinical Oncology (2013)

11083 Background: Developing an imaging agent to assess Met expression would aid in diagnosis and monitoring tumor response to Met-targeted therapies. Onartuzumab (MetMAb), a Met selective humanized one-armed monoclonal antibody, has been studied in Phase I-II clinical trials in which it was generally well tolerated and has shown the most benefit in patients with MET positive tumors. Methods: Studies to assess Met-binding were executed using the human gastric carcinoma cell line MKN-45 which exhibits a high level of Met expression. Murine PET studies and biodistribution assays were performed using MKN-45 xenografts. Results: Plasma shed Met concentration is directly related to total tumor burden (p &lt; 0.001). The absence of a positive correlation between shed Met and %ID in blood indicates that binding of tracer to shed Met present in plasma is unlikely. There are positive correlations between tumor mass, Met abundance, and phosphoMet content and uptake of 89 Zr-df-onartuzumab in MKN-45 mouse xenografts. Lastly, tumor mass, Met, pMet and 89 Zr-df-onartuzumab uptake were all significantly decreased by drug treatment. Conclusions: MKN-45 tumor uptake of 89 Zr-df-onartuzumab correlated significantly with tumor mass and Met abundance. Blood tracer uptake did not positively correlate with the presence of plasma shed Met. The amounts of Met, pMet, as well as 89 Zr-df-onartuzumab image intensity correlated significantly with tumor size (all Spearman p values &lt; 0.001).Tumor volumes and Met content were significantly decreased in TKI treated versus control mice, which correlated with imaging results. 89 Zr-df-onartuzumab has potential utility for imaging Met to identify patients for treatment with Met-targeted therapeutics and to identify the emergence of Met-driven acquired resistance to other molecularly targeted cancer therapies.
CDK4 phosphorylation status and corresponding gene expression profile predict sensitivity to Palbociclib
Authors: E. Raspé, K. Coulonval, J. Pita, S. Paternot, F. Rothé, L. Twijffels, S. Van Laere, M. Ignatiadis, C. Sotiriou, P. Roger
Journal: Annals of Oncology (2017)
High SLFN11 expression to predict sensitivity of FOLFOX regimen in stage 2-3 colon cancer patients with <i>KRAS</i> wildtype.
Authors: Yanhong Deng, Yue Cai, Yan Huang, Zihuan Yang, Yang Bai, Yanlu Liu, Xiuping Deng, Jianping Wang
Journal: Journal of Clinical Oncology (2014)

e14618 Background: Range of SLFN11 expression in colorectal cancer was observed, high SLFN11 expression might indicate sensitive to DNA Damage Agents (DDA). We aimed to investigate whether it predicts the sensitivity of oxaliplatin (one kind of DDA) in FOLFOX regimen. Methods: Tissue microarray(TMA) was made with 261 sporadic patients who received 5-FU based adjuvant chemotherapy. TMA was stained with anti-SLFN11 antibody (Abcam). The intensity and proportion was classified to 0-3, the final score was calculated by intensity plus proportion. The score higher than five was defined as strong expression. Results: There were 15.3% patients who showed high SLFN11 expression, 32.2% patients had KRAS mutation. SLFN11 was not correlated to stage, KRAS status and carcinoembryonic antigen (CEA). In all patients, SLFN11 was not related to overall survival (P=0.236, HR=2.12). However, in KRAS wildtype patients, all 23 high SLFN11 expression patients survived after 36 month follow up. They had significant better survival than low expression ones (log rank P=0.048). Conclusions: High SLFN11 expression predicts predicts sensitivity of FOLFOX regimen in stage = 2 * ROMAN II- = 3 * ROMAN III colon cancer patients with KRAS wildtype. KRAS wildtype and high SLFN11 expression patients have very good outcome.