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Dose escalation

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https://www.readbyqxmd.com/read/29453628/safety-tolerability-and-preliminary-activity-of-imgn529-a-cd37-targeted-antibody-drug-conjugate-in-patients-with-relapsed-or-refractory-b-cell-non-hodgkin-lymphoma-a-dose-escalation-phase-i-study
#1
Anastasios Stathis, Ian W Flinn, Sumit Madan, Kami Maddocks, Arnold Freedman, Steven Weitman, Emanuele Zucca, Mihaela C Munteanu, M Lia Palomba
Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity...
February 17, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29453627/a-phase-i-and-pharmacokinetic-study-of-taladegib-a-smoothened-inhibitor-in-japanese-patients-with-advanced-solid-tumors
#2
Hideki Ueno, Shunsuke Kondo, Shusuke Yoshikawa, Koichi Inoue, Valérie Andre, Masaomi Tajimi, Haruyasu Murakami
Background This phase I dose-escalation study investigated the safety of the Smoothened inhibitor taladegib in Japanese patients with advanced solid tumors. Methods Patients received taladegib orally once daily for 28-day cycles, using a 3 + 3 dose-escalation method. The primary objective was the safety and tolerability of taladegib at doses up to the global recommended dose (400 mg). Secondary objectives included pharmacokinetics, changes in skin glioma-associated oncogene homolog 1 (Gli1) transcript levels, and antitumor activity...
February 17, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29452863/chest-wall-toxicity-after-hypofractionated-proton-beam-therapy-for-liver-malignancies
#3
Rosanna Yeung, Stephen R Bowen, Tobias R Chapman, Grayden T MacLennan, Smith Apisarnthanarax
PURPOSE: Normal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but it may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiation therapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies. METHODS AND MATERIALS: We retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma, and 1 metastasis) treated with hypofractionated PBT...
December 24, 2017: Practical Radiation Oncology
https://www.readbyqxmd.com/read/29452121/an-open-label-pilot-study-to-evaluate-the-efficacy-of-tofacitinib-in-moderate-to-severe-patch-type-alopecia-areata-totalis-and-universalis
#4
A Jabbari, F Sansaricq, J Cerise, J C Chen, A Bitterman, G Ulerio, J Borbon, R Clynes, A M Christiano, J Mackay-Wiggan
Alopecia areata (AA) is a common autoimmune disease, with a lifetime risk of ∼2%. In AA, the immune systems targets the hair follicle, resulting in clinical hair loss. AA prognosis is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Since these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors...
February 13, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29450591/occurrence-of-pneumonitis-following-radiotherapy-of-breast-cancer-a-prospective-study
#5
Danijela Vasiljevic, Christoph Arnold, David Neuman, Katharina Fink, Marina Popovscaia, Irma Kvitsaridze, Meinhard Nevinny-Stickel, Markus Glatzer, Peter Lukas, Thomas Seppi
AIM: of this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma. PATIENTS AND METHODS: A total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17)...
February 15, 2018: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/29440181/a-first-in-human-study-of-the-new-oral-selective-estrogen-receptor-degrader-azd9496-for-hr-her2-advanced-breast-cancer
#6
Erika P Hamilton, Manish R Patel, Anne C Armstrong, Richard D Baird, Komal Jhaveri, Matthias Hoch, Teresa Klinowska, Justin P O Lindemann, Shethah Morgan, Gaia Schiavon, Hazel M Weir, Seock-Ah Im
PURPOSE: AZD9496 is an oral non-steroidal, small-molecule inhibitor of estrogen receptor alpha (ERα), and a potent and selective antagonist and degrader of ERα. This first in human Phase 1 study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity. EXPERIMENTAL DESIGN: Forty-five patients received AZD9496 (20 mg once daily to 600 mg twice daily) in a dose-escalation, dose- expansion 'rolling 6' design...
February 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29438372/a-phase-i-trial-of-the-%C3%AE-secretase-inhibitor-mk-0752-in-combination-with-gemcitabine-in-patients-with-pancreatic-ductal-adenocarcinoma
#7
Natalie Cook, Bristi Basu, Donna-Michelle Smith, Aarthi Gopinathan, Jeffry Evans, William P Steward, Daniel Palmer, David Propper, Balaji Venugopal, Mirela Hategan, D Alan Anthoney, Lisa V Hampson, Michael Nebozhyn, David Tuveson, Hayley Farmer-Hall, Helen Turner, Robert McLeod, Sarah Halford, Duncan Jodrell
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m -2 , was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D)...
February 13, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29438365/strategies-for-clinical-development-of-monoclonal-antibodies-beyond-first-in-human-trials-tested-doses-and-rationale-for-dose-selection
#8
Marie Viala, Marie Vinches, Marie Alexandre, Caroline Mollevi, Anna Durigova, Nadia Hayaoui, Krisztian Homicsko, Alice Cuenant, Céline Gongora, Luca Gianni, Diego Tosi
BACKGROUND: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results...
February 13, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29438361/a-first-in-human-phase-i-study-to-determine-the-maximum-tolerated-dose-of-the-oral-src-abl-inhibitor-azd0424
#9
Victoria K Woodcock, Sally Clive, Richard H Wilson, Vicky M Coyle, Michael R L Stratford, Lisa K Folkes, Richard Eastell, Claire Barton, Paul Jones, Shamim Kazmi-Stokes, Helen Turner, Sarah Halford, Adrian L Harris, Mark R Middleton
BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity...
February 13, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29438091/a-phase-i-dose-escalation-study-of-clofarabine-in-patients-with-relapsed-or-refractory-low-grade-or-intermediate-grade-b-cell-or-t-cell-lymphoma
#10
Francine Marie Foss, Terri Parker
LESSONS LEARNED: Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T-cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas. BACKGROUND: Clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia...
February 7, 2018: Oncologist
https://www.readbyqxmd.com/read/29437535/safety-and-clinical-activity-of-pembrolizumab-and-multisite-stereotactic-body-radiotherapy-in-patients-with-advanced-solid-tumors
#11
Jason J Luke, Jeffrey M Lemons, Theodore G Karrison, Sean P Pitroda, James M Melotek, Yuanyuan Zha, Hania A Al-Hallaq, Ainhoa Arina, Nikolai N Khodarev, Linda Janisch, Paul Chang, Jyoti D Patel, Gini F Fleming, John Moroney, Manish R Sharma, Julia R White, Mark J Ratain, Thomas F Gajewski, Ralph R Weichselbaum, Steven J Chmura
Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases...
February 13, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29434389/outcomes-from-a-pharmacist-led-proton-pump-inhibitor-stewardship-program-at-a-single-institution
#12
Rebekah A Wahking, Randal L Steele, Rachel E Hanners, Sean M Lockwood, Kelly W Davis
Background: Proton pump inhibitors (PPIs) are effective medications for acid-related disorders; however, they are also overused and may be associated with several adverse effects. A PPI stewardship program was implemented at one institution to combat the overuse of PPIs. Objective: The purpose of this study is to evaluate the effectiveness of an inpatient PPI stewardship program in reducing PPI use, both during hospitalization and upon discharge. Methods: This was a retrospective cohort study of all patients admitted to an internal medicine service at a single institution from March 14, 2016, to August 14, 2016, with an intervention by the PPI stewardship team...
February 2018: Hospital Pharmacy
https://www.readbyqxmd.com/read/29432974/similarities-and-changes-between-15-and-24-year-survival-and-retention-rates-of-patients-in-a-large-medical-affiliated-methadone-maintenance-treatment-mmt-center
#13
Einat Peles, Shaul Schreiber, Anat Sason, Miriam Adelson
BACKGROUND: Environmental and social trends and patients' characteristics may affect predictors for methadone maintenance treatment (MMT) outcome. METHODS: We have expanded our previous study of predictors for MMT outcome (from 619 to 890 patients) and the study period (from 15 to 24 years). Survival and retention in MMT since admission to the MMT clinic (6/1993-6/2016) and until death or study closure (6/2017) were compiled and analyzed. RESULTS: Of 890 patients ever admitted (10,146...
February 7, 2018: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/29432282/phase-i-study-of-multiple-epitope-peptide-vaccination-in-patients-with-recurrent-or-persistent-cervical-cancer
#14
Kosei Hasegawa, Yuji Ikeda, Yuko Kunugi, Akira Kurosaki, Yuichi Imai, Shunsuke Kohyama, Shoji Nagao, Eito Kozawa, Koji Yoshida, Takuya Tsunoda, Yusuke Nakamura, Keiichi Fujiwara
Cancer immunotherapy has now been established as a leading standard therapeutic option in a subset of patients with cancer. In this study, we conducted a phase I dose-escalation trial using a mixture of 5 peptides to vaccinate cervical cancer patients with HLA-A*2402. The primary endpoints were safety and determination of a recommended vaccine dose, and the secondary endpoints were evaluations of immunologic responses and clinical efficacy. All patients had recurrent or persistent disease and had failed to respond to or were intolerant to prior standard chemotherapy...
February 9, 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29432077/phase-i-study-of-dnx-2401-delta-24-rgd-oncolytic-adenovirus-replication-and-immunotherapeutic-effects-in-recurrent-malignant-glioma
#15
Frederick F Lang, Charles Conrad, Candelaria Gomez-Manzano, W K Alfred Yung, Raymond Sawaya, Jeffrey S Weinberg, Sujit S Prabhu, Ganesh Rao, Gregory N Fuller, Kenneth D Aldape, Joy Gumin, Luis M Vence, Ignacio Wistuba, Jaime Rodriguez-Canales, Pamela A Villalobos, Clemens M F Dirven, Sonia Tejada, Ricardo D Valle, Marta M Alonso, Brett Ewald, Joanna J Peterkin, Frank Tufaro, Juan Fueyo
Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A)...
February 12, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29431672/erk-inhibition-a-new-front-in-the-war-against-mapk-pathway-driven-cancers
#16
Inna Smalley, Keiran S M Smalley
ERK inhibitors have enormous therapeutic potential against tumors that are BRAF mutant, BRAF-MEK inhibitor resistant, or RAS mutant. In this issue of Cancer Discovery, Sullivan and colleagues report on the first-in-human dose-escalation study of the ERK inhibitor ulixertinib, which they show to be well tolerated with clinical activity against a wide range of tumor types. Cancer Discov; 8(2); 140-2. ©2018 AACR.See related article by Sullivan et al., p. 184.
February 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29427728/intra-arterial-idarubicin_lipiodol-without-embolization-in-hepatocellular-carcinoma-the-lida-b-phase-i-trial
#17
Boris Guiu, Jean-Louis Jouve, Antonin Schmitt, Anne Minello, Franck Bonnetain, Christophe Cassinotto, Lauranne Piron, Jean-Pierre Cercueil, Romaric Loffroy, Marianne Latournerie, Maëva Wendremaire, Côme Lepage, Mathieu Boulin
BACKGROUND & AIMS: Idarubicin has high cytotoxicity on hepatocellular carcinoma (HCC) cells, high hepatic extraction ratio and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolization) was conducted in cirrhotic patients with HCC to estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics, and health-related quality of life. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolization...
February 7, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29426744/improving-dose-delivery-by-adding-interstitial-catheters-to-fixed-geometry-applicators-in-high-dose-rate-brachytherapy-for-cervical-cancer
#18
Sophie Otter, Amanda Coates, Adrian Franklin, Melanie Cunningham, Alexandra Stewart
PURPOSE: Image-guided brachytherapy (IGBT) is an essential component of the treatment of locally advanced cervical cancer. Interstitial (IS) catheters are being increasingly used for bulkier tumors. We have retrospectively assessed the dosimetric impact of IS catheters. METHODS AND MATERIALS: All patients who received IGBT for cervical cancer between August 2014 and February 2017 were identified. Clinical and dosimetric data were collected. Patients were grouped into the intracavitary (IC) cohort or the IC and IS implant (IC/IS) cohort...
February 6, 2018: Brachytherapy
https://www.readbyqxmd.com/read/29426719/safety-and-preliminary-efficacy-of-vorinostat-with%C3%A2-r-epoch-in-high-risk-hiv-associated-non-hodgkin-s-lymphoma-amc-075
#19
Juan C Ramos, Joseph A Sparano, Michelle A Rudek, Page C Moore, Ethel Cesarman, Erin G Reid, David Henry, Lee Ratner, David Aboulafia, Jeanette Y Lee, Richard F Ambinder, Ronald Mitsuyasu, Ariela Noy
INTRODUCTION: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). PATIENTS AND METHODS: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule...
February 2, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29426358/optimizing-the-prescription-isodose-level-in-stereotactic-volumetric-modulated-arc-radiotherapy-of-lung-lesions-as-a-potential-for-dose-de-escalation
#20
Mark Chan, Matthew Wong, Ronnie Leung, Steven Cheung, Oliver Blanck
BACKGROUND: To derive and exploit the optimal prescription isodose level (PIL) in inverse optimization of volumetric modulated arc radiotherapy (VMAT) as a potential approach to dose de-escalation in stereotactic body radiotherapy for non-small cell lung carcinomas (NSCLC). METHODS: For ten patients, inverse Monte Carlo dose optimization was performed to cover 95% PTV by varying prescription isodose lines (PIL) at 60 to 80% and reference 85%. Subsequently, these were re-normalized to the median gross tumor volume dose (GTV-based prescription) to assess the impacts of PTV and normal tissue dose reduction...
February 9, 2018: Radiation Oncology
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