Despite widely adopted, rule-based dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and t … Dec 12, 2020 · The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Standard – 3+3. 3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose Aug 5, 2022 · The historically most widely used dose‐escalation design is the 3 + 3 design. This document has been prepared by the Office of New Drugs in the Center for Drug May 20, 2013 · Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. Aug 23, 2022 · In a phase I dose-escalation study, 31 patients with advanced hematologic malignancies were treated with 8, 15, 25, 35, 50, 60, 75, or 100 mg duvelisib BID (Table 1) . Food did not have a significant effect F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e. The MTD or recommended phase II dose is the dose below the level that is too toxic. Rule based Model based Oct 14, 2021 · Rule-based designs such as 3 + 3 and accelerated titration (ATD) are by far the most commonly used methods for dose escalation in early phase clinical trials Jul 19, 2022 · By leveraging pharmacokinetics, dose escalation considers exposure and interindividual variability on a continuous rather than discrete domain, offering additional information for dose-escalation decisions. Dec 19, 2019 · The primary aim of many phase I dose-escalation studies is to estimate the maximum tolerated dose of a novel drug or treatment. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of clinica … Jun 16, 2023 · PURPOSE This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate in solid tumors, including advanced non–small-cell lung cancer (NSCLC). Lokhorst, Ajai Chari, Jonathan L. Data for the dose escalation A survey of Phase I dose escalation trials published since 1995 shows that there is great disparity in all aspects of the design of the studies, and the cohort sizes range from 2 to 16 subjects with a great variety in the distribution between active and placebo-treated subjects. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. . The landscape of early phase clinical trials has changed rapidly in the last few years [1], [2]. We assessed the safety and immunogenicity of the ChAdOx1 MERS vaccine in a phase 1b trial in healthy Middle Eastern adults. Oct 10, 2023 · Purpose: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC). Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy. May 28, 2024 · Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week Methods: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Four designs were evaluated. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. We report the results of patients with acute leukaemia (leukaemia cohort). modern phase 1 trials. Results: No dose-limiting toxicities were observed. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, Lotfi Benboubker, Peter Hellemans, Tara Masterson, Pamela L Clemens, Tahamtan Ahmadi, Kevin Liu, Jesús San-Miguel; Open-Label, Multicenter, Dose Escalation Phase 1b Study to Assess the Mar 29, 2014 · Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial Lancet . 36 Dose-finding trials (e. During dose-escalation, patients were treated with SHR-1210 at a fixed dose of 60 mg every 2 weeks, with escalation to 200 and 400 mg. Key eligibility criteria Nov 1, 2021 · Fictional examples of how the dose-escalation method chosen can alter the outcomes of a phase 1 study are described, including the number of patients enrolled, the trial’s timeframe, and the dose level chosen as MTD. Dose-Escalation Designs Phase 1 trials must prioritize safety while attempting to maintain efficiency. May 20, 2009 · Several strategies for dose escalation in phase I trials of two drugs are illustrated in Figure 3: 1) alternate escalation of the agents in the series of dose levels; 2) simultaneous escalation of both agents; 3) escalation of one agent to the recommended dose for phase II trials while holding the other agent at a fixed (generally high) dose Jan 13, 2021 · Only two articles relied on an adaptive dose escalation design. 33 in cancer trials. The guiding principle for dose escalation in phase I trials is to avoid exp … Feb 6, 2024 · The Phase I, open-label, interventional dose-escalation trial is enrolling patients with locally advanced unresectable or metastatic soft tissue sarcomas at two German clinical sites: Helios Jun 28, 2019 · This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Jun 26, 2019 · A key principle for dose escalation in phase I trials is maintaining rapid dose-escalation in order to avoid exposing too many patients to sub-therapeutic doses while preserving safety by limiting the frequency of toxic events (dose limiting toxicities or DLTs). The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Initially, 10 patients were treated as part of the dose-escalation phase at the MTD of 6 mg/kg. Here we present an innovative trial design for immune-modulating agents. Research output: Contribution to journal › Article › peer-review Dose-Escalation and Determination of the MTD In the dose-escalation stage of a phase 1 trial, we monitor subjects for dose-limiting toxicities (DLTs), which are treatment-related adverse events defined a priori to satisfy criteria of type, severity, and time of occurrence. Dose escalation designs influence the number of patients enrolled, the fraction of patients treated at sub‐therapeutic doses and the efficiency of the study. Epub 2014 Jan 10. The MTD was 1. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer. These additional data will inform discussions with CytomX partner, Amgen, towards initiation of Phase 1b expansion cohorts in specific EGFR positive tumor types. Successive cohorts will be given doses of 125 and 150 mg/m^2 twice a day. 20 and 0. 1016/S0140-6736(13)61939-X. This is the first multimodal exercise dose escalation study in stroke. In recent reviews, more than 95% of phase I trials have been based on the 3 + 3 design A phase I dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors. All the reported AEs were mild or moderate, and no SAE occurred during the trial. Graphical depiction of dose escalation methods for phase I cancer clinical trials. Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and Oct 20, 2021 · It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity. The aim is to identify the MTD, if one exists among the proposed doses. 9% male: median age 58 years) with advanced solid tumors. Jun 17, 2024 · In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti For dose determination, the following stopping rules will be implemented for the dose escalation phase: (a) at least 6 evaluable subjects have been enrolled at the MTD/RP2D level with at least 18 evaluable subjects in total enrolled in the dose escalation part, or (b) at least 9 evaluable subjects have been May 12, 2023 · Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. In phase 2, patients were randomly assigned centrally and stratified by previous chemotherapy and treatment with CPY17 inhibitors, to receive one of three daily doses of ODM Dec 2, 2016 · Saad Z Usmani, Hareth Nahi, Maria-Victoria Mateos, Henk M. 2012]. Feb 1, 2024 · Phase II studies are required to confirm these results. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. During the dose escalation phase, the MTD is estimated; during the expansion phase, an additional number of patients (6, 10 or more) are treated at the estimated MTD [Topalian et al. 18, 15. We now plan to confirm safety and feasibility of this program in a larger Phase II trial. Methods: This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. arXiv preprint arXiv:2104. Mar 20, 2018 · PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Dec 19, 2019 · Dose-escalation studies are essential in the early stages of developing novel treatments, when the aim is to find a safe dose for administration in humans. These studies involve exposure of a Aug 25, 2020 · Patient selection. gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. The classic Phase 1 dose escalation design has become more rare and has been almost entirely replaced by a different set-up involving an initial dose finding algorithm followed by the subsequent addition of dose expansion cohorts (DEC). Pharmacodynamics of dinaciclib May 8, 2024 · The Company expects to provide an additional Phase 1a dose escalation update by the end of 2024. ; Telli, Melinda; Munster, Pamela et al. Dose escalation will continue until the maximum-tolerated dose (MTD), defined as one dose level below Nov 11, 2018 · The 3 + 3 design is the most common choice among clinicians for phase I dose-escalation oncology trials. The study was conducted at 4 centres in France and Belgium (Institut Curie—Paris, Institut Claudius Régaud IUCT Jul 30, 2022 · This was an open-label phase I clinical trial with two-phase design including a dose escalation and an expansion phase in pancreatic cancer. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. 2014 Mar 29;383(9923):1138-46. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling Methods: In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. single protocol with an initial dose-escalation phase followed by three or more additional subject pharmacokinetics unless there is adequate data to determine a recommended phase 2 dose. ” The maximum tolerated dose (MTD) was 300 mg bid. 09. [1, 2] The classic Phase 1 dose escalation design has become more rare and has been almost entirely replaced by a different set-up involving an initial dose finding algorithm followed by the subsequent addition of dose expansion cohorts (DEC). Methods We evaluated the actual efficiency of different dose escalation methods employed in first-in-human phase I clinical 知乎专栏提供随心写作和自由表达的平台,分享端午节的祝福和药物剂量递增爬坡的讨论。 Apr 19, 2024 · Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. , 2009; LoRusso et al. A dose-escalation study may also measure ways that the drug is used by the body and is often done as part of a phase I clinical trial. In practice, this often means identifying a dose for which the probability of a patient developing a dose-limiting toxicity is close to a prespecified target toxicity level, typically between 0. The Methods: We did a single centre, dose-escalation, dose-expansion, phase 1-2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Despite their great importance, many dose-escalation studies use study designs based on heuristic algorithms with well-documented drawbacks. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m 2 /day for six cycles of 1week on and 1week off. These studies allow early exploration of potential drugs in humans, to evaluate, for example, human PK, and therapeutic target relevance to disease. NCT02500407 is an ongoing phase I and Ib multicenter, open-label, dose-escalation, and expansion study of mosunetuzumab. Healthy Middle Eastern adults aged 18-50 years were included in the study. guided dose. Jul 23, 2012 · The actual dose escalation referring to the “modified Fibonacci scheme” is a dose-escalation term close to and intermediate between the genuine and the “modified Fibonacci” schemes (Figure 2). The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. method. A typical dose-escalation phase 1 study selects a safe starting dose based on preclini-cal data from in vitro and in vivo testing of the drug. These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected. The primary endpoints were frequency and Feb 1, 2019 · Patients and methods: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. 27, No. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks). Mar 25, 2024 · This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING (PART I) (CHAPTER 1, 7) NAITEE TING, BOEHRINGER-INGELHEIM 2 DRUG DEVELOPMENT PROCESS Drug Discovery Non-clinical Development Clinical Development • Phase I Clinical pharmacology (PK/PD, MTD) • Phase II Drug efficacy/safety, dose ranging • Phase III Long-term, large scale, confirmatory May 27, 2021 · Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Dec 1, 2022 · Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Data for dose-escalation and interim expansion cohorts using fixed (group A) or cycle 1 step-up dosing (group B) are reported. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. / Harding, James J. A phase II dose escalation study may identify a dose that is both safe and effective. RC48-ADC is an antibody-drug conjugate drug with a novel humanized anti-HER2 antibody conjugated to monomethyl auristatin E (MMAE) through a cleavable linker. Patients and methods: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). Methods: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0. Further enrollment into group A was stopped, and further escalation was conducted with a cycle 1 step-up dosing schedule in group B to expand the therapeutic index by CRS mitigation. Dose escalation … Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. The long-term safety and efficacy of this Jun 5, 2022 · Hutchings M, Mous R, Clausen MR, et al. , trials that include dose-escalation and dose-expansion portions with the 37 primary objective of selecting the recommended phase II dose) for oncology drugs have Jun 2, 2022 · TPS3167 Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. Mar 15, 2024 · Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Mar 26, 2020 · This was a phase I, open-label, nonrandomized, dose-escalation and dose-expansion study. 0 mg/day, with an elimination half-life of 50 hours. Jun 1, 2018 · 1030 Background: There is still urgent medical needs for new therapeutics in the patients with metastatic breast cancer (MBC) and other solid tumors with HER2 overexpression. 4994-5003. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. g. Jun 10, 2021 · Thus, the dose-escalation phase is carried out first (MTD determination; Fig. Despite widely adopted, rule-based dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and tend to treat a significant number of patients at subtherapeutic doses. Both phases are increasingly combined. Establishing the maximum tolerated dose early on in the trial reduces the potential risks to patients as the trial progresses. Feb 10, 2022 · Methods: This first-in-human trial (ClinicalTrials. A total of 54 patients were accrued: 34 patients during the dose-escalation phase, and 20 patients during the expansion phase. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Jun 17, 2021 · Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling Jun 1, 2021 · Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO) Haematologica . 2mg Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Mar 19, 2013 · The core assumption underlying many phase I dose escalation methods that, as the dosage of a drug increases (with all other drugs held constant), the probability of DLTs increases. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. In: Clinical Cancer Research, Vol. Finally, the recent trends in dose-escalation methods applied in phase 1 trials in the immunotherapeutics era are reviewed. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). Lancet 2021 May 25, 2020 · 102 Background: MAGE-A4 is a cancer/testis antigen with expression in many solid tumors promoting cell growth by preventing cell cycle arrest and apoptosis. 6, 7 Dose escalation is based on a set of rules that determine when to escalate to the next dose, in some cases when to de‐escalate, when to stop dose escalation, and how to determine the MTD. Method: MERS002 is an open-label, non-randomised, dose-escalation, phase 1b trial. Oct 16, 2013 · Methods: Dinaciclib was administered starting at a dose of 0. 9 ~ 30. During the escalation stage, patients are recruited into the trial In this video, a Principal Investigator explains what a dose escalating trial is and why it might be necessary. Nov 4, 2017 · The main principle guiding dose escalation in phase I trials is to treat as many patients as possible within the therapeutic dose range, avoiding unnecessary exposure of patients to sub-therapeutic doses of an agent, while preserving safety and maintaining rapid accrual [6]. Conference Call & Webcast mance of alternative phase I designs on this simulated data. Incremental dose increases for assigned patient cohorts Methods: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Jul 1, 2017 · Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. , 2010). Sep 19, 2019 · However, even with the best design of the expansion phase, we still must consider the design of the dose escalation phase, with respect to assignment of doses and eventual assignment of RP2D – having a dose expansion phase to essentially correct for inadequate dose escalation design is something to be avoided. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. EnaV, a novel ADC of anti-Axl human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in xenograft models. During the Q3W schedule of phase 1b, samples were collected pre-infusion on days 1 and 5 of cycles 1 and 3–6, days 1, 3, and 5 of cycle 2, as well as at the end of treatment and follow-up Sep 29, 2020 · We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. A classic 3 + 3 design was used to determine the maximum tolerated dose and Purpose: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. In a dose-escalation study, the dose of the test drug is increased a little at a time in different groups of people until the highest dose that does not cause harmful side effects is found. Good Review Practice: Clinical Review of Investigational New Drug Applications . PATIENTS AND METHODS Adults with locally advanced/metastatic NSCLC Aug 8, 2018 · This study consisted of an initial dose-escalation and subsequent expansion phase. Jun 21, 2021 · Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and Feb 2, 2021 · This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer. May 20, 2009 · Phase I clinical trials are an essential step in the development of anticancer drugs. Patients and methods: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. This first-in-human, open-label, dose-escalation phase 1 clinical trial preliminarily indicated that the candidate E. 3%) had baseline PD-L1-positive tumor expression (combined positive score ≥1). Aug 12, 2023 · Bio-Thera Solutions Announces Positive Phase 1 Clinical Data for BAT8006 (Folate-Receptor-α-ADC) and Presents Phase 1 Dose Escalation Study at the Bethune Obstetrics and Gynecology Forum Jan 18, 2019 · Introduction The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. May 12, 2009 · Dose escalation methods for phase I cancer clinical trials fall into two broad classes: the rule-based designs, which include the traditional 3+3 design and its variations, and the model-based Jan 28, 2019 · During phase 1a, dose escalation and dose expansion stages, samples were collected pre-infusion on day 1 and subsequently on days 8, 15, 22, 61, and 120. The results of this phase I dose-escalation trial suggest that in patients with LA-NPC, nab-paclitaxel combined with cisplatin and capecitabine is a feasible and active regimen for IC, the RP2D of nab-paclitaxel is 200 mg/m 2. Escalation with. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. escalation. Maximum administered dose was not reached. Atrafi F, Boix O, Subbiah V, et al. Preclinical data in various animal models, including breast Mar 2, 2023 · A Comparison of Model-Free Phase I Dose Escalation Designs for Dual-Agent Combination Therapies. 17 The cycle 1, day 1 and day 8 step doses were empirically selected at 1 mg and 2 mg for the majority of the group B escalation because they were safe, enabled Oct 25, 2022 · Methods: An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. While the MTD is Nov 1, 2013 · The trial included a dose-escalation phase using a 3 + 3 design followed by a DEC. 2021, p. In Module 1A, discontinuations were most Jun 10, 2010 · Patients and methods: This phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0. daily or weekly dosing) once the dose escalation with another schedule HLX22 is a novel monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Aug 3, 2020 · Study design and patient population. 243790. design. 2 Protocol Page Dose Escalation Study Phase I/II of Umbilical and Cord Blood-Derived CAR-Engineered NK Cells in Conjunction in Patients with Relapsed/Refractory Apr 14, 2021 · Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. doi: 10. Trials 5, 465–477 (2008). Introduction and objectives. The sample size of the dose-escalation phase was 45 patients, and it was conducted according to the traditional 3+3 model with modified Fibonacci schema (Data Supplement, online only). Fifty-four patients (59. Apr 29, 2023 · The objectives of this first-in-human, Phase 1/2, open-label, dose-escalation study of SRA737 as a single agent were to establish the safety profile, define the maximum tolerated dose (MTD) and The landscape of early phase clinical trials has changed rapidly in the last few years. Dec 15, 2021 · The sample size was based on other dose-escalation phase 1 studies [12,13] to ensure adequate subject safety and robust PK/PD data to achieve the objectives of the study. coli-produced 9vHPV vaccine is well tolerated and immunogenic in healthy males and females aged 18–45 years old. The Japanese phase I recommended dose of 60 mg/m2 of docetaxel (Taxotere) had been ineffective in phase II trials in ovarian carcinoma. In the rapid acceleration phase, patients are treated with different doses of the drug and increments are achieved through single-or double-dose escalations. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. Methods: In a ph1 trial (NCT02988817), patients (pts) with relapsed/refractory cancer May 28, 2021 · Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0. This was an open-label, dose-escalation Phase 1 trial. Apr 14, 2023 · We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. Dose Escalation Study Design Example 2 of 22 September 2019 (With Results) 100 mg/m^2, via intravenous catheter (IV), twice a day for 4 weeks for the first cohort. 1a), followed by a dose-expansion phase, which is randomised to two dose levels (Fig. For our simulations dose escalation steps are constrained such that no dose skipping is allowed and the starting dose without an intra-patient dose escalation stage is the lowest dose. The decision not to enroll the dose expansion phase of the study was made based on the a lack of evidence of antitumor activity seen during the dose escalation but also considered the inadequate immunologic response, which together, suggested that AMG 228 monotherapy was unlikely to provide meaningful clinical benefit. In the phase 1 part of the trial, patients were given oral ODM-201 at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. Furthermore, the CRM has been shown to assign more trial May 5, 2009 · Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. By competing We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. 5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal Mar 18, 2022 · ATDs consist of 3 steps: (1) rapid acceleration phase, (2) intra-patient dose escalation phase and (3) assessment of dose-toxicity relationship. Nov 15, 2022 · Gerhard Ehninger, Sabrina Kraus, Elisa Sala, Stephan K Metzelder, Vladan Vucinic, Walter Fiedler, Maria-Elisabeth Goebeler, Jan Moritz Middeke, Malte von Bonin, Carla Kreissig, Jan Koedam, Marc Cartellieri, Armin Ehninger, Martin Wermke, Jonas A. All the doses were safe, and no serious adverse events were reported. This first-in-human, phase 1 dose-escalation study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of HLX22 in patients with advanced solid tumors who had failed … Dec 12, 2012 · Background Statistical simulations have consistently demonstrated that new dose-escalation designs such as accelerated titration design (ATD) and continual reassessment method (CRM)-type designs outperform the standard “3+3” design in phase I cancer clinical trials. Once the trial is stopped, the RP2D is determined as the dose for which the posterior probability of toxicity is closest to the target toxicity rate. The trial initially used single-patient dose-escalation co-hortsforgroupA(0. Most adverse events were grade 1 or 2. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. reassessment. The complete, rapid, but temporary removal of IgG provides a new potent therapeutic opportunity in IgG-mediated pathogenic conditions. Methods: In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France [five], UK [one], and Canada [one]). Schäfer; Phase 1 Dose Escalation Study of the Rapidly Switchable Universal CAR-T Therapy Unicar-T May 26, 2019 · 2525 Background: Axl, a transmembrane receptor tyrosine kinase, is aberrantly overexpressed in various human cancers and associated with poor prognosis and treatment resistance. Feb 1, 2021 · Commonly, current dose-finding designs involve escalation of more than one agent, identification of an optimal biologic dose or minimum effective dose (MED), on the basis of safety and efficacy, and late-onset toxicities. Treatment-related severe adverse events were found in two patients. 6, 3, 10, 30, 45, and 60 µg/kg. No treatment-related death was reported. Methods: This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57. Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Exclusion criteria included Jan 13, 2024 · NCT03364400 was a phase 1, first-in-human, multicenter, open-label, dose escalation, and expansion study of VT1021 designed and sponsored by Vigeo Therapeutics, Inc. While it Phase I protocols with dose expansions consist of two phases: the dose escalation phase followed by a dose expansion phase (Figure 1). Methods: This Phase I dose-escalation, expansion trial evaluated patients (pt) who were HLA-A*02 Mar 10, 2022 · Dose escalation usually takes place across phase 1 clinical trials, where researchers establish the safest drug dosage level to administer to patients throughout the remaining trial phases. In addition, in order to expose as few subjects as possible to the study medication and procedures, the sample size for each dose group was 6. Yet, the traditional 3+3 design is still the most commonly used. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. 33 mg/m2, as a 2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 28-day cycle), to determine the maximum administered dose (MAD), dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. In practice, however, the modified Fibonacci sequence, the most popular dose-escalation guidance scheme in dose-seeking phase I trials is a term Mar 1, 2021 · We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors. 05-0. Feb 18, 2023 · Methods: This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). 3324/haematol. This study (NCT03132922) evaluated safety and efficacy of SPEAR T-cells directed against the MAGE-A4 peptide expressed in 9 tumor types. Enabling both methodologists and clinicians to understand and apply model-based study designs with ease is a key factor towards their routine use in early-phase studies. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. The dose-limiting toxicities (DLTs) were grade 3 diarrhoea and fatigue at 300 mg bid and grade 3 skin toxicity at 400 mg bid. An intensified dosing regimen was also studied. 2021 Jun 1;106(6):1725-1732. Accelerated titration. Aug 24, 2018 · The dose escalation continues until at least two patients within a cohort of three to six patients experience a DLT. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models Jul 15, 2015 · Importantly, IdeS has the capacity to inactivate Fc-mediated effector function in vivo, was considered safe with no serious adverse events, and without dose limiting toxicity in this study. In the dose escalation phase, a standard 3 + 3 design was used to determine the maximum tolerated dose (MTD) of alisertib in combination with gemcitabine. Clin. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or studies that are performed prior to the traditional Phase I Single-Dose Escalation (also referred to as Single Ascending Dose, or Single Rising Dose). Jan 15, 2021 · Therefore, dose escalation is not an appropriate design to conduct ICI studies. More recently, however, multiple schedules are more frequently investigated in the same trial. In three out of the four scenarios investigated, the six-parameter model has been found to outperform the three-parameter model when the objective is to identify more than one MTD. He explains that the purpose is to determine The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. Other variations of this design have been implemented, including “2+4,” “3+3+3,” and “3+1+1. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. In the dose range of 100 ~ 400 mg, T 1/2 and AUC 0-t after multiple doses were 26. Data from dose escalation are presented. Such rule‐based designs were favored for their simplicity and ease of Mar 12, 2012 · Such escalation strategies are therefore important, especially for Phase I trials with a large number of prespecified dose combinations. Designs 2 through 4 included only one patient per cohort 2016-0641 October 24, 2016 P pg. The maximal dose of exercise identified was dramatically higher than the dose typically delivered to stroke survivors in current trials. overdose control. 14923, 2021. Jul 24, 2023 · In the dose escalation phase of Module 1A, the severity of treatment-emergent adverse events (TEAEs) increased with dose (Supplementary Tables 6 and 7). 2 h and 189 ~ 356 h*μg/mL, respectively. The JQBA study was the first-in-human, non-randomised, open-label, dose-escalation, Phase 1 study of LY3127804 in patients with advanced/metastatic solid Sep 1, 2016 · 1. Up & down design. A phase I study of an MPS1 inhibitor (BAY 1217389) in combination with paclitaxel using a novel randomized continual reassessment method for dose escalation. The primary end point was the recommended phase II dose (RP2D). 3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Eligible Nov 18, 2021 · The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food Aug 14, 2014 · The fundamental elements of a phase I study are well described in several comprehensive reviews (Le Tourneau et al. This Article details the phase 1 results. 2019. Continual. Adults with Nov 1, 2023 · The study is an open-label, dose-escalation phase I clinical trial conducted from January 2019 to December 2020 that investigated the role of human embryonic stem cells-derived mesenchymal stem Feb 12, 2024 · A comprehensive comparison of the continual reassessment method to the standard 3+3 dose escalation scheme in Phase I dose-finding studies. Dose escalations were based on safety, PK, and PD. Jul 14, 2020 · We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 Nov 1, 2021 · Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Methods: Patients with advanced solid tumors were treated with ivonescimab 0. Conclusions. 1b). The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. Pharmacologically. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. simsw ulvi rruznoo mwcka jqjm zrmen wkgph vlss wvj thziyx
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