phase ii
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ESMO Open ◽  
2022 ◽  
Vol 7 (1) ◽  
pp. 100314
M.M. Javle ◽  
D.-Y. Oh ◽  
M. Ikeda ◽  
W.-P. Yong ◽  
K. Hsu ◽  

2022 ◽  
Vol 162 ◽  
pp. 161-169
Sophie Cousin ◽  
Coralie Cantarel ◽  
Jean-Philippe Guegan ◽  
Thibault Mazard ◽  
Carlos Gomez-Roca ◽  

Eva Giné ◽  
Fátima de la Cruz ◽  
Ana Jiménez Ubieto ◽  
Javier López Jimenez ◽  
Alejandro Martín García-Sancho ◽  

PURPOSE The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients. METHODS This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites ( identifier: NCT02682641 ). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m2. Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria. RESULTS Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia. CONCLUSION Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.

2022 ◽  
pp. 1-9
Joseph Stavas ◽  
David Gerber ◽  
Steven G. Coca ◽  
Arnold L. Silva ◽  
Ashley Johns ◽  

<b><i>Background:</i></b> Cell therapies explore unmet clinical needs of patients with chronic kidney disease with the potential to alter the pathway toward end-stage kidney disease. We describe the design and baseline patient characteristics of a phase II multicenter clinical trial utilizing the novel renal autologous cell therapy (REACT), by direct kidney parenchymal injection via the percutaneous approach in adults with type 2 diabetic kidney disease (T2DKD), to delay or potentially avoid renal replacement therapy. <b><i>Design:</i></b> The study conducted a prospective, multicenter, randomized control, open-label, phase II clinical trial between an active treatment group (ATG) receiving REACT from the beginning of the trial and a contemporaneous deferred treatment group (DTG) receiving standard of care for 12 months before crossing over to receive REACT. <b><i>Objectives:</i></b> The objective of this study was to establish the safety and efficacy of 2 REACT injections with computed tomography guidance, into the renal cortex of patients with T2DKD administered 6 months apart, and to compare the longitudinal change in renal function between the ATG and the DTG. <b><i>Setting:</i></b> This was a multicenter study conducted in major US hospitals. <b><i>Patients:</i></b> We enrolled eighty-three adult patients with T2DKD, who have estimated glomerular filtration rates (eGFRs) between 20 and 50 mL/min/1.73 m<sup>2</sup>. <b><i>Methods:</i></b> All patients undergo an image-guided percutaneous kidney biopsy to obtain epithelial phenotype selective renal cells isolated from the kidney tissue that is then expanded ex vivo over 4–6 weeks, resulting in the REACT biologic product. Patients are randomized 1:1 into the ATG or the DTG. Primary efficacy endpoints for both study groups include eGFR measurements at baseline and at 3-month intervals, through 24 months after the last REACT injection. Safety analyses include biopsy-related complications, REACT injection, and cellular-related adverse events. The study utilizes Good Clinical and Manufacturing Practices and a Data and Safety Monitoring Board. The sample size confers a statistical power of 80% to detect an eGFR change in the ATG compared to the DTG at 24 months with an α = 0.05. <b><i>Limitations:</i></b> Blinding cannot occur due to the intent to treat procedure, biopsy in both groups, and open trial design. <b><i>Conclusion:</i></b> This multicenter phase II randomized clinical trial is designed to determine the efficacy and safety of REACT in improving or stabilizing renal function among patients with T2DKD stages 3a–4.

2022 ◽  
Asad Ali Usman ◽  
Samantha Stein ◽  
Audrey Spelde ◽  
Felipe Teran-merino ◽  
John Augoustides ◽  

Abstract This trial is aimed at studying the utility and interventional outcomes of rescue transesophageal echocardiography (RescueTEE) to aid in diagnosis, change in management, and outcomes during CPR by using a point of care RescueTEE protocol in the evaluation of in-hospital cardiac arrest (IHCA). This is an interventional prospective convenience sampled partially blinded phase II clinical trial with primary outcomes of survival to hospital discharge (SHD) with RescueTEE image guided ACLS versus conventional ACLS.

2022 ◽  
Vol 12 ◽  
Erkka Järvinen ◽  
Feng Deng ◽  
Wilma Kiander ◽  
Alli Sinokki ◽  
Heidi Kidron ◽  

Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

Bingyi Wu ◽  
Zhenkun Li ◽  
Jennifer A. Francis ◽  
Shuoyi Ding

Abstract Arctic warming and its association with the mid-latitudes have been hot topic over the past two decades. Although many studies have explored these issues it is not clear that how their linkage has changed over time. The results show that winter low tropospheric temperatures in Asia experienced two phases over the past two decades. Phase I (2007/2008 to 2012/2013) was characterized by a warm Arctic and cold Eurasia, and phase II by a warm Arctic and warm Eurasia (2013/2014 to 2018/2019). A strengthened association in winter temperature between the Arctic and Asia occurred during phase I, followed by a weakened linkage during phase II. Simulation experiments forced by observed Arctic sea ice variability largely reproduce observed patterns, suggesting that Arctic sea ice loss contributes to phasic (or low-frequency) variations in winter atmosphere and make the Arctic-Asia temperature association fluctuate over time. The weakening of the Arctic-Asia linkage post-2012/2013 was associated with amplified and expanded Arctic warming. The corresponding anomalies in SLP resembled a positive phase North Atlantic Oscillation (NAO) during phase II. This study implies that the phasic warm Arctic-cold Eurasia and warm Arctic-warm Eurasia patterns would alternately happen in the context of Arctic sea ice loss, which increase the difficulty to correctly predict Asian winter temperature.

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