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Dose escalation

Mark B Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J Purdon, Meier Hsu, Sean M Devlin, Elizabeth Halton, Nicole Lamanna, Jurgen Rademaker, Michel Sadelain, Renier J Brentjens, Jae H Park
Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Henning Willers, Antino Allen, David Grosshans, Stephen J McMahon, Cläre von Neubeck, Claudia Wiese, Bhadrasain Vikram
In the clinic, proton beam therapy (PBT) is based on the use of a generic relative biological effectiveness (RBE) of 1.1 compared to photons in human cancers and normal tissues. However, the experimental basis for this RBE lacks any significant number of representative tumor models and clinically relevant endpoints for dose-limiting organs at risk. It is now increasingly appreciated that much of the variations of treatment responses in cancers are due to inter-tumoral genomic heterogeneity. Indeed, recently it has been shown that defects in certain DNA repair pathways, which are found in subsets of many cancers, are associated with a RBE increase in vitro...
June 14, 2018: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Alejandro Llanos-Cuentas, Martin Casapia, Raúl Chuquiyauri, Juan-Carlos Hinojosa, Nicola Kerr, Maria Rosario, Stephen Toovey, Robert H Arch, Margaret A Phillips, Felix D Rozenberg, Jade Bath, Caroline L Ng, Annie N Cowell, Elizabeth A Winzeler, David A Fidock, Mark Baker, Jörg J Möhrle, Rob Hooft van Huijsduijnen, Nathalie Gobeau, Nada Araeipour, Nicole Andenmatten, Thomas Rückle, Stephan Duparc
BACKGROUND: DSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection. METHODS: This proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru...
June 13, 2018: Lancet Infectious Diseases
Sarah Barrett, Gerard G Hanna, Laure Marignol
Standard of care radiotherapy in LA-NSCLC is 60-66 Gy in 30-33 fractions. However outcomes for these patients are poor with 5-year survival in the range of 10-20%. Randomised controlled trials have shown that dose escalation in a linear fashion does not improve outcomes for all patients, thus there is a need to tailor the prescription to the individual patient. This review assesses the strategies published to personalise the radiation therapy dose prescription in LA-NSCLC. A systematic and scoping search of the literature was performed to identify studies that met the inclusion criteria...
June 13, 2018: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Radka Stoyanova, Felix Chinea, Deukwoo Kwon, Isildinha M Reis, Yohann Tschudi, Nestor A Parra, Adrian L Breto, Kyle R Padgett, Alan Dal Pra, Matthew C Abramowitz, Oleksandr N Kryvenko, Sanoj Punnen, Alan Pollack
PURPOSE: To develop a prostate tumor habitat risk scoring (HRS) system based on multiparametric MRI (mpMRI) referenced to prostatectomy Gleason Score (GS) for automatic delineation of Gross Tumor Volumes (GTVs). A workflow for integration of HRS into radiotherapy (RT) boost volume dose escalation was developed in the framework of a Phase II randomized clinical trial (BLaStM). MATERIALS AND METHODS: An automated quantitative mpMRI based 10 point pixel by pixel method was optimized to prostatectomy GSs and volumes using referenced Dynamic Contrast Enhanced and Apparent Diffusion Coefficient sequences...
June 13, 2018: International Journal of Radiation Oncology, Biology, Physics
Matthew Cardinal, Constantino Kantaridis, Tong Zhu, Pengling Sun, Debra D Pittman, John E Murphy, Steven Arkin
BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of tissue factor-activated coagulation factor VII (TF-FVIIa) complex and activated factor X (FXa). PF-06741086 is a monoclonal antibody that targets TFPI to increase clotting activity. OBJECTIVES: This study was a randomized, double-blind, sponsor-open, placebo-controlled, single intravenous (IV) or subcutaneous (SC) dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06741086...
June 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Parameswaran Hari, Donna E Reece, Jasleen Randhawa, Neal Flomenberg, Dianna S Howard, Ashrof Z Badros, Aaron P Rapoport, Barry R Meisenberg, Joanne Filicko-Ohara, Gordon L Phillips, David H Vesole
The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220-260 mg/m2 , although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose-response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial...
June 15, 2018: Bone Marrow Transplantation
Colin D Weekes, Lee S Rosen, Anna Capasso, Kit Man Wong, Weilan Ye, Maria Anderson, Bruce McCall, Jill Fredrickson, Eric Wakshull, Steve Eppler, Quyen Shon-Nguyen, Rupal Desai, Mahrukh Huseni, Priti S Hegde, Tony Pourmohamad, Ina Rhee, Alberto Bessudo
PURPOSE: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors. METHODS: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage...
June 15, 2018: Cancer Chemotherapy and Pharmacology
Christopher Abraham, Adam Garsa, Shahed N Badiyan, Robert Drzymala, Deshan Yang, Todd DeWees, Christina Tsien, Joshua L Dowling, Keith M Rich, Michael R Chicoine, Albert H Kim, Eric C Leuthardt, Cliff Robinson
Objective: To identify potentially actionable dosimetric predictors of local control (LC) for non-small cell lung cancer (NSCLC) brain metastases treated with single-fraction stereotactic radiosurgery (SRS). Methods and materials: Patients with NSCLC brain metastases treated with single-fraction SRS were identified. Eligible patients had at least 1 follow-up magnetic resonance imaging scan and were without prior metastasectomy or SRS to the same lesion. LC and overall survival (OS) were estimated using the Kaplan-Meier method...
April 2018: Advances in Radiation Oncology
Kaley Woods, Percy Lee, Tania Kaprealian, Isaac Yang, Ke Sheng
Purpose: This study investigates whether 4π noncoplanar radiation therapy can spare the cochleae and consequently potentially improve hearing preservation in patients with acoustic neuroma who are treated with radiation therapy. Methods and materials: Clinical radiation therapy plans for 30 patients with acoustic neuroma were included (14 stereotactic radiation surgery [SRS], 6 stereotactic radiation therapy [SRT], and 10 intensity modulated radiation therapy [IMRT])...
April 2018: Advances in Radiation Oncology
Kristina Drott, Hans Hagberg, Karin Papworth, Thomas Relander, Mats Jerkeman
The aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs)...
June 26, 2018: Blood Advances
Srinivas Raman, Jean-Pierre Bissonnette, Andrew Warner, Lisa Le, Scott Bratman, Natasha Leighl, Andrea Bezjak, David Palma, Devin Schellenberg, Alexander Sun
We explain the rationale for metabolically adaptive radiation dose escalation in stage III non-small-cell lung cancer and describe the design of a Canadian phase II randomized trial investigating this approach. In the trial, patients are randomized to either conventional chemoradiation treatment (60 Gy in 30 fractions) or metabolically adaptive chemoradiation, where fluorodeoxyglucose-avid tumor sub-volumes receive an integrated boost dose to a maximum of 85 Gy in 30 fractions. The trial sample size is 78 patients, and the target population is patients with newly diagnosed, inoperable stage III non-small-cell lung cancer treated with radical intent chemoradiation...
May 16, 2018: Clinical Lung Cancer
Arash Babaei, Ravinder K Mittal
Cholecystokinin (CCK) is known to cause lower esophageal sphincter (LES) relaxation through the activation of inhibitory motor neurons. Recent studies show that the longitudinal muscle contraction (LMC) related axial stretch may play a role in the LES relaxation. The aim of our study was to determine whether the CCK induced LES relaxation and identify the characteristics of associated LMC in humans. Nine healthy volunteers (5F, 40 + 12 years) received escalating doses of CCK-octapeptide (5, 10, 20 and 40 ng/kg)...
June 14, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Amy Cotterill, Thomas Jaki
Dose-escalation trials commonly assume a homogeneous trial population to identify a single recommended dose of the experimental treatment for use in future trials. Wrongly assuming a homogeneous population can lead to a diluted treatment effect. Equally, exclusion of a subgroup that could in fact benefit from the treatment can cause a beneficial treatment effect to be missed. Accounting for a potential subgroup effect (ie, difference in reaction to the treatment between subgroups) in dose-escalation can increase the chance of finding the treatment to be efficacious in a larger patient population...
June 13, 2018: Pharmaceutical Statistics
Juliet Reid, Stefano Zamuner, Ken Edwards, Sally-Anne Rumley, Katherine Nevin, Maria Feeney, Chiara Zecchin, Disala Fernando, Nicolas Wisniacki
BACKGROUND: The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy and is a potential therapeutic target for inflammatory and fibrotic diseases. METHODS: This was a Phase I, randomised, double-blind, placebo-controlled, single-dose escalation, first-time-in-human study of subcutaneously administered GSK2330811, an anti-OSM monoclonal antibody, in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin and potential for anti-drug antibody formation were assessed...
June 13, 2018: British Journal of Clinical Pharmacology
Yao Wang, Meixia Chen, Zhiqiang Wu, Chuan Tong, Hanren Dai, Yelei Guo, Yang Liu, Jianhua Huang, Haiyan Lv, Can Luo, Kai-Chao Feng, Qing-Ming Yang, Xiao-Lei Li, Weidong Han
Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T-cell directed CD133 (CART-133) was first tested in this trial. The anti-tumor specificity and the postulated toxicities of CART-133 were first assessed. Then, we conducted a phase I clinical study in which patients with advanced and CD133-positive tumors received CART-133 cell-infusion. We enrolled 23 patients (14 with hepatocellular carcinoma [HCC], 7 with pancreatic carcinomas, and 2 with colorectal carcinomas)...
2018: Oncoimmunology
Sarah L Hulin-Curtis, James A Davies, Rachel Jones, Emma Hudson, Louise Hanna, John D Chester, Alan L Parker
Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to "hijack" the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited...
May 29, 2018: Oncotarget
Changhoon Yoo, Jihoon Kang, Ho Yeong Lim, Jee Hyun Kim, Myung-Ah Lee, Kyung-Hun Lee, Tae-You Kim, Baek-Yeol Ryoo
Purpose: The signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC). Materials and Methods: This study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration: 50 mg to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 mg to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose (RD) were the primary endpoints...
June 13, 2018: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Jiayu Wang, Yiqun Han, Xiuqing Shi, Qing Li, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ruigang Cai, Ying Fan, Shanshan Chen, Qiao Li, Binghe Xu
BACKGROUND: Cipatinib is a novel tyrosine kinase inhibitor against both EGFR and HER2/neu. This phase I trial was conducted to assess the safety, dose-limiting toxicities (DLTs), and maximum-tolerated dose of cipatinib in HER2-positive patients with advanced breast cancer. METHODS: Eligible adults with advanced breast cancer were administered cipatinib 200 mg/day (n = 3) as an initial dose, with escalating dosages of 400 mg (n = 4), 800 mg (n = 2), 1200 mg (n = 3), 1400 mg (n = 3), 1600 mg (n = 3), and 1800 mg (n = 2) in 21 day cycles...
June 12, 2018: Thoracic Cancer
Birgitte Andersen, Ellen M Straarup, Kristy M Heppner, Diana L Takahashi, Virginia Raffaele, Gregory A Dissen, Katherine Lewandowski, Thóra B Bödvarsdottir, Kirsten Raun, Kevin L Grove, Paul Kievit
OBJECTIVE: Administration of FGF21 and FGF21 analogues reduce body weight; improve insulin sensitivity and dyslipidemia in animal models of obesity and in short term clinical trials. However potential adverse effects identified in mice have raised concerns for the development of FGF21 therapeutics. Therefore, this study was designed to address the actions of FGF21 on body weight, glucose and lipid metabolism and importantly its effects on bone mineral density (BMD), bone markers, and plasma cortisol in high-fat fed obese rhesus macaque monkeys...
June 11, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
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