Dose escalation phase. VT1021 is found to be safe and tolerable, with .
Dose escalation phase Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 STUDY DESIGN AND METHODS: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the United States (Figure). The FDA recently published “Guidance for Industry: Clinical In a typical phase I dose-escalation study, at a given dose-level, small cohorts of patients are treated and DLT outcomes are observed. EPDF trials typically evaluate new interventions that can be given in different doses and can be pharmacological (chemical or biological—eg, drugs, vaccines, cell therapies, gene therapies), Dose expansion trials are clinical trials that evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of a new drug or treatment in a larger group of patients than in the initial dose escalation trial, particularly in oncology studies, where the aim is to further evaluate the safety, efficacy, and optimal dosage of a drug after the initial dose-escalation phase. • Mainly enrolled patients (pts) with metastatic castration resistant In the dose escalation phase, dose escalation, which followed a standard 3+3 design, was guided by assessing all grade toxicities and trends in adverse events seen in current and subsequent dosing cycles. Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate. In the single ascending dose (SAD) study, volunteers were randomized into 0. A traditional 3 + 3 dose‐escalation scheme was used. One patient was excluded from the DDS due to insufficient safety Informed consent was obtained for all patients. This first-in-human, phase 1 dose-escalation study aimed to evaluate the 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. These designs are either rule‐ or We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. 4. Based on the totality of the data, the study was terminated given the lack of activity of PF-06671008. Owing to the early termination, part 2 of the study (dose expansion) was not conducted and no further The dose escalation phase was to enroll three cohorts of three to six subjects each, with each cohort assigned to receive successive increases of a predefined TKM-080301 dose escalation based on prior clinical experience with TKM-80301 in advanced solid tumors. To ensure safety, the dosage of the low-dose group was set at 30,000 mNAU. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in Patients were enrolled using a conventional 3 + 3 dose escalation phase I design, with escalations based on a modified Fibonacci sequence scheme . All The primary aim of many phase I dose-escalation studies is to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of a novel drug or treatment []. Dose escalations The dose increment between two dose levels should be guided by the dose/toxicity or dose/effect relationship defined in non-clinical studies, depending on whichever is steeper where this In the dose escalation phase of Module 1A, the severity of treatment-emergent adverse events (TEAEs) increased with dose (Supplementary Tables 6 and 7). Patients A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Dose escalation queries for both MHRA With increasing numbers of anticancer drugs requiring testing, new adaptive model-based phase I trial designs can improve on current practice by exploring a wider range Patient flow diagram. 3 mg/kg, after which a 3+3+3 design was used in the dose escalation phase, with a minimum of three DLT-evaluable We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). Groups 1 and 2 were open label with CAP256V2LS administered at 5 mg/kg and 10 mg/kg intravenously and 5 mg/kg, 10 HLX22 is a novel monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Four dose levels (DLs 1–4) of alisertib (20, 30, 40, or 50 mg) were A single-subject cohort was enrolled at the starting dose of 0. The design features utilization of Patient demographics, disposition. g. Methods: A total of 35 eligible healthy Chinese adult volunteers were enrolled in this study. They In clinical practice, the traditional ‘3 + 3’ dose-escalation design or a modification thereof are the most frequently used dose-escalation methods in phase I trials [3]. 1,2 This design was favored, in part, because escalation is cautious, and the risk of overdosing the patient is thought to be limited. Dose escalation based on Background In most phase I oncology trials, it is often stated that the dose increments follow a “modified-Fibonacci sequence”. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. Treatment-related adverse events (TRAEs) were reported in 96. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to Given the hypothesis, dose-escalation to the next cohort can only take place once the PK-analysis in the previous cohort is completed and can be taken into account. 50, 0. Early phase dose-finding (EPDF) or dose escalation or de-escalation trials, commonly known as phase 1 or phase 1 or 2 trials, are an integral part of clinical development. 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. The primary objective of parts 1 and 2A was to evaluate the de-escalation, where the next cohort is administered a combination that is one dose level lower in each drug, and also allow for anti-diagonal escalation, meaning the next cohort receives a combination that is one dose level higher in one drug and one dose level lower in the other. The distinguishing feature of trials considered is that the Dose-escalation schedules of trametinib (T) and uprosertib (U). During phase I, three dose levels Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a 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. Introduction (background) The purpose of FIH trials is to evaluate an investigational medicinal product ( IMP) in humans for the first time, to study the human pharmacology , tolerability and safety of the IMP and to compare how effects seen in non 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. The starting dose of TKM‐080301 was 0. increased exposure by 58 % at the 100 mg dose-level with 1/3 of patients having stable disease as their best response. 03 mg/kg followed by an i3+3 design for dose levels (DLs) ≥0. Based on completed global phase I trial results , , ramucirumab was given intravenously at three dosage levels in three cohorts: 6 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 8 mg/kg every 2 weeks. After confirming safety in three cases in the low-dose group, the Purpose This study was conducted to investigate the safety and tolerability of increasing doses of liposomal curcumin in patients with metastatic cancer. 3, 1, 3, 10, 20 or 30 mg/kg A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer. All the DLTs occurred outside the radiation field. If no DLT was identified at a certain dose level, intra-patient escalation was performed in subsequence dosing cycles until the maximum tolerated dose was defined. Patients 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 fre-quency of toxic events (dose limiting toxicities or DLTs). VT1021 is found to be safe and tolerable, with Dose escalation was by an exposure-adjusted, continual reassessment method. For cytotoxic drugs, in general, greater toxicity and efficacy will occur at progressively The dose escalation phase was to enroll three cohorts of three to six subjects each, with each cohort assigned to receive successive increases of a predefined TKM‐080301 dose escalation based on prior clinical experience with TKM‐80301 in advanced solid tumors. ChAdOx1 MERS In this video, a Principal Investigator explains what a dose escalating trial is and why it might be necessary. As Background The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. These are depicted by the ‘’ symbols in Figure 1, where With regard to the dose-escalation design of this clinical study, a traditionally used 3 + 3 design was adopted with reference to the phase I study design in clinical studies for cancer, as described in Clinical Trials in Oncology . The maximum tolerated dose (MTD) is esti- mated limiting the probability of a DLT to a particu-lar level, the HL-085 is a selective, orally administered MEK1/2 inhibitor. There was no evidence of partial or complete response. Methods To MERS002 is an open-label, non-randomised, dose-escalation, phase 1b trial. The phase I dose-escalation trial design has been used in immune checkpoint inhibitor (ICI) development. Trial (design) adaptations. The 3 + 3 design is the simplest to interpret the dose escalation phase of the study, including the 3 and 5 mg dose cohorts, and the dose expansion cohort in patients with solid tumors of any type treated with the conrmed 5 mg dose Background: HP518 is an oral proteolysis targeting chimera (PROTAC) protein degrader that target androgen receptor (AR) mutations for the treatment of mCRPC. 75, 1. This part of the trial is expected to enroll at . Methods In this phase I, single-center, open-label study in patients with metastatic tumors, liposomal Current dose-finding designs for phase I clinical trials can correctly select the MTD in a range of 30–80% depending on various conditions based on a sample of 30 subjects. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. Two types of dose-escalation designs have been proposed: algorithm-based designs, such as the standard 3 + 3 design, and model-based designs. Alisertib was HLX22 is a novel monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). In total, using the EWOC method, we safely and efficiently evaluated seven dose levels with only 16 patients during this study, minimizing time and patient accrual at lower, likely sub-therapeutic, dose levels. Methods: Patients with advanced solid tumors were treated with ivonescimab 0. For the purposes of the dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled With previous pediatric phase I data to guide the initial dose of each agent, this design provided the potential for more rapid dose escalation . Based on the DLT outcomes the dose is escalated, de-escalated or retained at the current level. They offer rapid, but reasonable, dose escalation, with negligible rates of toxic death. Patients were enrolled per protocol in sequential cohorts of three patients based on the occurrence of dose 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. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. Although MTD is no longer set as the dose for further Dose escalation designs influence the number of patients enrolled, the fraction of patients treated at sub‐therapeutic doses and the efficiency of the study. 11, 2024 (GLOBE NEWSWIRE) -- Prelude Therapeutics Incorporated (Nasdaq: PRLD) (“Prelude” or the “Company”), a clinical-stage precision Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors Invest New Drugs. , 2010). Alisertib was One of the objectives of oncology phase I dose-escalation studies has been to determine the maximum tolerated dose (MTD). In Module 1A, open-label phase I study with standard dose escalation and was performed between 2014 and 2016. Dose escalation designs influence The primary aim of many phase I dose-escalation studies is to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of a novel drug or treatment []. 7 %) at MTD having SD as their best response. Toxicity has traditionally One of the objectives of oncology phase I dose‐escalation studies has been to determine the maximum tolerated dose (MTD). The accelerated titration design (ATD) as originally This randomized, double-blind, placebo-controlled, dose-escalation phase I trial evaluated the safety, tolerability, and pharmacokinetics of nebulized GB05. A total of seven In this phase 2 study, an image-guided adaptive strategy enabled radiotherapy dose escalation to over 86% of patients’ bladder tumours without significant increase in toxicity. A typical dose-escalation phase 1 study selects a safe starting dose based on This first-in-human trial (ClinicalTrials. Enrolled The study consists of 2 parts: 1) a dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a conventional 3+3 dose escalation design to identify the recommended phase 2 dose (RP2D) and 2) a dose expansion phase to further characterize the safety and preliminary efficacy of CLN-978 in disease-specific cohorts This randomized, double-blind, placebo-controlled, dose-escalation phase I trial evaluated the safety, tolerability, and pharmacokinetics of nebulized GB05. With approximately 850 agents currently in development for cancer treatment, it is evident that co Dose-escalation models for combination phase I trials in This Phase I dose-escalation study was designed to evaluate the safety and tolerability of atrasentan (ABT-627), estimate the MTD, and characterize the PK of the drug after once-daily oral administration in patients with refractory adenocarcinomas, particularly those with hormone-refractory prostate cancer requiring pain relief with opioids. report findings from a phase 1 dose expansion study of the tumor microenvironment modulator VT1021 in patients with solid tumors. Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e. 1,2 To further elucidate the drug’s properties, investigators may enroll an additional group of subjects, denoted a dose-expansion cohort (DEC), once the Purpose: We reviewed our seven year single institution experience with pulsed dose rate brachytherapy dose escalation study in patients with intermediate and high risk prostate cancer. The cohort receiving the MTD is often small, typically only 6 subjects. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in Background Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. 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 or were intolerant to standard therapies. 4%), and all were Caucasian. This first-in-man study was initiated to identify the Background Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×10 9, 1×10 10, 4×10 10, and 1×10 11 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) Methods: In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France [five], UK [one], and Canada [one]). Therefore, it was difficult to assess the role of concurrent radiotherapy on the DLTs. Once Phase 1b doses are selected for Phase 1b, participants of select advanced or metastatic solid tumors will receive DCSZ11 in below defined cohorts in Phase 1b: Phase 1b cohort 1 NSCLC. Investigations of anti-tumor activity and of the pharmacokinetics of curcumin were secondary objectives. The MTDc will be defined as the highest dose level with biologically proven activity, defined by the pharmacokinetic–pharmacodynamic curve and radiological tumour response, with 33% or less of patients have a DLT. Methods: Healthy subjects are usually recruited for Multiple Ascending Dose studies, although a Phase 1 dose escalation study design can also include patients under certain circumstances (e. doi: We enrolled 22 patients: 12 patients in initial dose escalation and 10 patients in an expansion cohort at the recommended phase 2 dose. The 3 + 3 design is the simplest to interpret Background Statistical simulations have consistently demonstrated that new dose-escalation designs such as accelerated titration design (ATD) and continual reassessment subsequent dose escalations, the criteria for maximum dose and the conduct of the trial inclusive of multiple parts. 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 The dose-escalation part is likely one of the most crucial aspects of early drug development as it determines whether a drug will be further evaluated, and what dose will be used in later phase trials. The starting dose was olaparib 25 mg BID with carboplatin AUC 3 mg*min/mL followed by olaparib monotherapy 300 mg BID. 35 μg/kg. 00, 1. 2 Safe harbor and forward -looking statements This presentation contains forward -looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. Methods: In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic Dose escalation strategy in phase I oncological trials; it is based on the hypothesis that the area under the plasma concentration-time curve (AUC) at the LD-10 in mice and at the MTD in man are similar (patient’s AUCs must be measured and be available rapidly); → see also continuous reassessment method (CRM), dose escalation, fibonacci search scheme, maximum tolerated subsequent dose escalations, the criteria for maximum dose and the conduct of the trial inclusive of multiple parts. Dose escalation based on toxicities (toxicity-adjusted dose escalation) The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated 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. Both phases are increasingly combined. Although well studied for phase II and III clinical trials, early stopping rules for phase I dose escalation trials are not often used outside of the 2-out-of-6 rule of the standard 3+3 algorithm Phase I dose escalation in oncology aims at finding the maximum tolerated dose (MTD) and Recommended Phase 2 dose (RP2D) for further development, based on Methods: The dose-escalation phase enrolled adult patients with advanced solid tumors. Methods Eligible patients received a single dose of donafenib (50 mg, 100 mg, 200 mg, 300 mg, or 400 mg) and were then observed over a 7-day period; thereafter, each patient received the Early phase dose-finding (EPDF) or dose escalation or de-escalation trials, commonly known as phase 1 or phase 1 or 2 trials, are an integral part of clinical development. The primary objectives of this phase 1 study were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RPD2) of IMGN853 administered Objective: A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. All patients enrolled in the dose-expansion phase received the recommended dose of 160 mg BID Study Design and Methods: Patients ≥18 years with previously treated (≤5 lines of systemic treatment) R/R AML or HR-MDS are eligible for this phase 1/1b, multi-center, open Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti Dose escalation was guided by an adaptive Bayesian logistic regression model with pre-defined criteria related to toxicity, pharmacokinetics, and efficacy. Eligible participants were HIV-negative, healthy adults between 18-50 years. Purpose: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. EPDF trials typically evaluate new Dose escalation methods for phase I trials are reviewed, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents and specific methods for drug This phase 1 study included both a dose-escalation and expansion stage. Subjects in the first cohort received, IP, an absolute dose of 60 mg of BC-819 and sequential Methods: CAPRISA 012B, a first-in-human dose-escalation phase 1 trial evaluated the safety, pharmacokinetics, and neutralisation activity of CAP256V2LS alone and in combination with VRC07-523LS in young HIV-negative women in Durban, South Africa. The For the biological dose-guided escalation late phase 1 design, we propose cohorts of six patients. Dose escalation is a major safety decision in a trial so good quality data is vital to ensure the safety of the subjects. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a An open-label, dose-escalation phase I study to evaluate RC48-ADC, a novel antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. 8 million IU of GB05 or We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Treatment with E7820 is safe and tolerable with 2/3 of patients (66. , 2009; LoRusso et al. Despite their This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel Introduction: Bayesian model assisted designs such as Modified Toxicity Probability Interval (mTPI-2) have recently gained popularity in early phase hematology dose escalation If in the intra-patient dose escalation stage no DLT is observed and the patient has completed all doses before the maximum dose is reached, the intra-patient dose escalation stage continues The phase 1 dose-escalation phase determined the MTD and RP2D of SY-5007. 5–18 mg twice daily), followed by The study consists of 2 parts: 1) a dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a conventional 3+3 dose escalation design to identify the recommended phase 2 dose (RP2D) and 2) a dose expansion phase to further characterize the safety and preliminary efficacy of CLN-978 in disease-specific cohorts Background: Small patient numbers in phase I trials may result in a safe but ineffective dose being recommended for phase II trials. 7–109. The enrolled participants will be assigned to one of three groups receiving 1200 mg, 2400 mg and 4800 mg doses of SH003 per day. 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. 7% of patients, with the most common grade ≥ 3 TRAEs being The prolonged dose-escalation phase, due to the low MABEL-derived starting dose, is a known challenge with developing CD3 bispecific molecules (25, 26). 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 Karnofsky (patients ≥16 years) 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 It commonly tests the drug initially in a dose-escalation phase in which cohorts of patients receive increasing doses until reaching a maximum tolerated dose (MTD). The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in One of the objectives of oncology phase I dose-escalation studies has been to determine the maximum tolerated dose (MTD). This term, however, is vague. During the dose-escalation part for the once-weekly schedule, seven dose levels ranging from 2. During phase 1a, 50 patients were screened for study eligibility between September 24, 2012 and March 28, 2014 (Fig. This is a single-blind, dose Dose-Escalation Designs Phase 1 trials must prioritize safety while attempting to maintain efficiency. Owing to the early termination, part 2 of the study (dose expansion) was not conducted and no further Here, we report on a phase one, first-in-patient, open-label, dose-escalation trial testing the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of S48168 (ARM210) in adult men and women affected with RYR1-RM. At each dose level, we compared the outcomes in the patient simulations across different concentrations of both osimertinib and dacomitinib that are predicted to lead to comparable toxicity profiles. 2, 0. 12, 2024 – Avacta Therapeutics (AIM: AVCT), a life sciences company developing next generation peptide drug conjugates (PDC) targeting powerful anti-tumor payloads directly to the tumor, today announces the completion of the enrollment in the AVA6000 Phase 1a Dose Escalation and Recommended Dose for Expansion (RDE) cohort, and We designed this single‐arm, nonrandomized, open‐label, dose‐escalation, phase I study in Chinese patients with advanced solid tumors. To The fundamental elements of a phase I study are well described in several comprehensive reviews (Le Tourneau et al. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously LONDON – Dec. 1a), followed by a dose-expansion phase, which is randomised to two dose levels (Fig. Adult pts (aged ≥18 years) with CML-CP without the T315I mutation who experienced resistance (BCR::ABL1 IS >1% with 6-12 months of first-line [1L] treatment or >10% with >12 months of 1L treatment) or intolerance Methods: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). The trial was designed with 3 parts, 2 dose escalations (phase Ia, parts A1 and A2), and a phase Ib dose expansion; however, the Phase I clinical Trial is an essential step in drug development. Although MTD is no longer set as the dose for further development in contemporary oncology drug development, MTD determination is still important for informing the therapeutic index. A The decision to escalate or de-escalate the dose is typically made by continuously updating the dose–toxicity and dose–efficacy model estimates based on interim data, in a similar fashion as the continual reassessment method. ChAdOx1 MERS The plan is to enroll 18 patients in the first dose-escalation segment (phase I): 9 patients per arm (3 patients in each cohort, for both arms). For Phase I/II trials, two main types of designs are The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, In the dose escalation phase of Module 1A, the severity of treatment-emergent adverse events (TEAEs) increased with dose (Supplementary Tables 6 and 7). a In part 1A, a zone-based dose-escalation model with a modified 3 + 3 cohort design with a continuous QD Dose escalation (Phase Ib) The dose escalation part of the trial will be conducted in adult patients with BRAF V600- dependent advance solid tumors. A phase II dose escalation study may identify a dose that is both safe and effective. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either Following the dose-escalation phase, a dose-expansion cohort of 12 patients was tested with the dose combination that most approximated the AUC of exposure to intravenous decitabine. Phase I Dose Escalation trials in cancer immunotherapy: Modifying the Bayesian Logistic Regression Model for Cytokine Release Syndrome Matt Chapman-Rounds[1]and Miguel Pereira Abstract We extend Bayesian Logistic Regression to model the dose-toxicity re-lationship in the setting of phase I dose-escalation/ dose-finding trials for cancer immunotherapies. OTX015 was given orally at increasing doses from 10 mg/day to 160 mg/day (14 of 21 days), using a The standard design of phase I dose-escalation trials in oncology has been the 3 + 3 design, and its modifications and performance are well understood. As Classic 3+3 phase I trial designs have withstood the test of time. This was a multicenter phase 1 study. The large number of dose levels The trial cohorts consisted of dose escalations using a 3 + 3 design of a phase I study to identify the recommended phase 2 dose. Methods: Patients with The points or parts in a clinical trial when the decision can be made to proceed to the next stage or phase, such as from dose escalation to dose expansion, from phase 1 to phase 2, or from a single ascending dose to multiple ascending dose. 06 mg/kg, Q2W in a 4-week cycle. Materials and methods: We treated a total of 130 patients for intermediate and high risk prostate cancer at our institution between 2000 and 2007 using PDR-brachytherapy as a boost after During dose escalation, AGS15E was administered intravenously at six levels (0. Patients had class II to IV angina on maximally tolerated Methods: CAPRISA 012B, a first-in-human dose-escalation phase 1 trial evaluated the safety, pharmacokinetics, and neutralisation activity of CAP256V2LS alone and in combination with VRC07-523LS in young HIV-negative women in Durban, South Africa. . A classic 3 + 3 design was used to determine the maximum tolerated dose and This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes. (A) In dose escalation phase, one patient each in 10 mg/kg and 20 mg/kg dropped off within the first cycle and thus deemed non-DLT evaluable. 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 The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, 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. This process is repeated until either the maximum dose level is studied or the MTD is reached. Following a screening period of up to 6 weeks, subjects were enrolled in 3 cohorts. Patients were aged between 36 and 79 years, were primarily men (75. Abstract. 3 mg/kg per dose (Cohort 1), and sequential cohorts were Phase 1a DCSZ11 monotherapy Dose Escalation. With regard to the dose-escalation design of this The fundamental elements of a phase I study are well described in several comprehensive reviews (Le Tourneau et al. Classic 3+3 phase I trial designs have withstood the test of time. A phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of SHR-1905, a long-acting anti-thymic stromal lymphopoietin antibody, in healthy subjects. We’re Here to Help. Dose escalation was based on a In this dose escalation phase 1 study, four patients experienced DLTs. Phase 1a DCSZ11 in combination with fixed dose of pembrolizumab Dose Escalation. Groups 1 and 2 were open label with CAP256V2LS administered at 5 mg/kg and 10 mg/kg intravenously and 5 mg/kg, 10 The prolonged dose-escalation phase, due to the low MABEL-derived starting dose, is a known challenge with developing CD3 bispecific molecules (25, 26). Following the dose-escalation phase, a dose-expansion cohort of 12 patients was tested with the dose combination that most approximated the AUC of exposure to intravenous decitabine. These doses represent the measurement of active This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. A clinical control group was not used. He explains that the purpose is to determine In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary HLX22 is a novel monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). The subcutaneous formulation of atezolizumab has recently received approval. In a phase I open-label, dose-escalation study of the first-in-class covalent Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. The RPTD of radiotherapy administered in combination with ipilimumab at 10 mg/kg in patients with ARV-471: Phase 1 Dose Escalation Clinical Trial Results San Antonio Breast Cancer Symposium December 10, 2021. Dose escalation Our simulations show that including an intra-patient dose escalation stage in dose-finding phase-I trials decrease the number of subtherapeutic doses given without (i) substantially decreasing Statistical analysis of the DEC, following an initial dose-finding trial, has been the subject of recent work [7]. Dose escalation WILMINGTON, Del. This prospective single-center Phase I Dose Escalation trials in cancer immunotherapy: Modifying the Bayesian Logistic Regression Model for Cytokine Release Syndrome Matt Chapman-Rounds[1]and In summary, this first-in-human, dose-escalation, Phase 1 study reported a favourable safety profile for LY3127804 with 20 mg/kg Q2W dose determined as the RP2D for Abstract This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a The aim of this study is to investigate the safety of HF-LED-RL at doses of 480 and 640 J/cm2 in healthy Caucasian non-Hispanic individuals. This first-in-human, phase 1 dose-escalation study aimed to evaluate the safety, In phase 1a (dose escalation), seven patients were eligible and received a 60 mg Q3W fixed dosage. The results of this phase I dose escalation study show that oral attenuated S. Prespecified changes or modifications (defined in advance) that can be made to various Purpose This Phase I study evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumours. The MTD of radiotherapy combined with ipilimumab at 10 mg/kg was 9 Gy. All patients had progressive disease and eventually succumbed to their illness. Authors : In this phase 2 study, an image-guided adaptive strategy enabled radiotherapy dose escalation to over 86% of patients’ bladder tumours without significant increase in toxicity. Introduction (background) The purpose of FIH trials is to evaluate an dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. 2. Patients were enrolled in 12 US centres (appendix p 1). HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0. 10, 0. However, there is still an unmet need for efficiency and cost saving. Healthy Middle Eastern adults aged 18–50 years were included in the study. The outcome of this analysis can upfront be incorporated in the projected dose-levels, by introducing PK-based dose-escalation rules, such as, for instance, ‘If steady state of drug A increases less than Methods: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to This is an ongoing phase I to evaluate the safety of IPH5401 + durvalumab (durva) in advanced solid tumors. Additional dose escalations, if needed, A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose New strategies for dose escalation were developed to address these issues, including accelerated titration and model-based designs (). This was a Phase 1/2a, open label, dose-escalation, repeat dose study in 14 subjects with recurrent, platinum-resistant advanced stage ovarian cancer or primary peritoneal carcinoma. For dose escalation, an accelerated Thus, the dose-escalation phase is carried out first (MTD determination; Fig. 1a), of whom 37 were enrolled in the study and received the study treatment. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of This first-in-human trial (ClinicalTrials. Dose‐escalation and dose‐limiting toxicities. Once Phase 1b doses are selected for Phase 1b, participants of select advanced or Chen et al. 1. An Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. As part of the phase 1 dose escalation, Here, we present the dose-escalation phase of the first-in-human clinical evaluation of IMGN853 monotherapy in patients with advanced, FRα-positive solid tumors who were refractory to standard therapies. , Background To investigate the safety and tolerability of simultaneous integrated boost (SIB) technique concurrent with elective nodal irradiation (ENI) and dual-drug Dose escalation usually takes place across phase 1 clinical trials, where researchers establish the safest drug dosage level to administer to patients throughout the Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. 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. This increased accuracy and reduction in the trial duration are at the cost of increased sample size. One patient in 10 mg/kg In the dose escalation phase, eligible patients were adults ≥ 18 years old with histologically or cytologically confirmed, locally advanced or metastatic solid tumors who had Two types of dose-escalation designs have been proposed: algorithm-based designs, such as the standard 3 + 3 design, and model-based designs. 26 In contrast, two-stage phase 1/2 designs first identify the MTD through conventional DLT-based dose escalation and then randomize STUDY DESIGN AND METHODS: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the United States (Figure). That work, from the perspective of a comprehensive Phase 1 + DEC AIDE is adaptive in that the decision of conducting intrapatient dose escalation depends on both the patient's individual safety data, as well as other enrolled patient's safety Phase Cancer ; Drug: Ender-G : Phase 1 : Detailed Description: This study will enroll patients with various cancer types from a single academic medical center in the United States. They The study was conducted in three stages, a weight-based, dose–escalation stage (part 1), followed by a fixed-dose stage (part 2A) (Supplementary Figure S1), followed by dose expansion cohorts in selected tumor types (part 2B) treated at the recommended therapeutic dose determined in parts 1 and 2A. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Although no survival Dose escalation (Phase Ib) The dose escalation part of the trial will be conducted in adult patients with BRAF V600- dependent advance solid tumors. 6, 1. Data from dose escalation are presented. 2016 Jun;34(3):329-37. However, those results were considered inconclusive due to the small This open-label, phase I study (NCT05649761) consisted of dose escalation and expansion phases in patients with advanced solid tumors. Given the unique ICI mechanism of action and toxicities (immune The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, Additional Notes on Prior Therapy: Dose escalation phase: There was no limit on the amount of prior chemotherapy; dose expansion phase: Dose Escalation Schema: dose increase, a modified Fibonacci dose escalation will be employed for any subsequent dose escalations, with increments of 67%, 50%, and 33%. 5 to 60 mg were evaluated. • An accelerated titration was conducted in single patient at 0. Although MTD is no longer set as the dose for further Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Any participants fulfilling the eligibility criteria will be enrolled. gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and MERS002 is an open-label, non-randomised, dose-escalation, phase 1b trial. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, 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 Here, we report updated dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574). Nineteen patients received ABBV-176 at doses from 2. 1b). , 2009, LoRusso et al. 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. Blood samples are collected at various time points for Dose-Escalation Designs Phase 1 trials must prioritize safety while attempting to maintain efficiency. Eligible patients had to be aged 18 years or older and have an Eastern Cooperative Oncology Group performance status of 0–2. The starting dose of TKM-080301 was 0. typhimurium containing the human interleukin-2 gene caused no significant toxicities up to doses of 10 10 colony forming unit. In dose escalation, patients received doses ranging from Dose escalation was by an exposure-adjusted, continual reassessment method. This design may not be applied to cancer vaccines, given their unique mechanism of action. 3 mg/kg per dose (Cohort 1), and sequential cohorts were 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. , Dec. 25, 0. 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. daily or weekly dosing) once the dose escalation with another schedule has been completed. Here, a phase 1 dose escalation This work considers Phase I cancer dual-agent dose-escalation clinical trials in which one of the compounds is an immunotherapy. 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. 2, and 1. JCO 42 , e15572-e15572 (2024). The Japanese phase I recommended dose of 60 mg/m2 of docetaxel (Taxotere) had been ineffective in phase II trials in ovarian carcinoma. 25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. In the 3 + 3 dose-escalation, patients (pts) receive IPH5401 at 4 dose levels (DL) (DL1, DL2, DL3 [Q1w] and DL4 [Q2w]) single agent during the first 2 weeks (w) then in combination with durva 1500 mg Q4w. Incremental dose increases for assigned patient cohorts occur until a prespecified end point is reached, which, in general, is the A dose of 50 mg BID was considered the MTD. We propose a novel dose-finding design based on Bayesian stochastic approximation. It is the first human trial and the main goal of these studies is to establish the recommended dose and/or schedule We report results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK), and preliminary antitumor activity of ociperlimab plus tislelizumab in Moreover, any statistical design of phase I clinical trials is fundamentally adaptive because dose escalation and de-escalation decisions depend on previous dose selections and In the dose-escalation phase, the dose level (1, 3, 10, 20, and 30 mg/kg) was escalated according to a 3 + 3 design with each cohort starting with three patients [except for NCT03364400 was a phase 1, first-in-human, multicenter, open-label, dose escalation, and expansion study of VT1021 designed and sponsored by Vigeo Therapeutics, Background The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model Dose escalation and MTD . Adult pts (aged ≥18 years) with CML-CP without the T315I mutation who experienced resistance (BCR::ABL1 IS >1% with 6-12 months of first-line [1L] treatment or >10% with >12 months of 1L treatment) or intolerance Phase 1a DCSZ11 monotherapy Dose Escalation. Eligible Backfilling in phase I dose-escalation studies can substantially increase the accuracy of estimation of the maximum tolerated dose, with a larger impact in the setting with a dose-limiting toxicity event assessment period of only one cycle. Because both dacomitinib and osimertinib During dose escalation, AGS15E was administered intravenously at six levels (0. This part of the trial is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. A cohort will start the study with the standard dose and will then receive A phase I dose-escalation study will be conducted at the Ajou University Hospital in Suwon, Republic of Korea. Drug combinations have been introduced with the goal of improving treatment efficacy by increasing overall anti-tumor activity and, presumably, survival. Methods: A total of Methods: This phase 1, multicenter, single agent and combination (combo) dose escalation study (NCT05635643) of CHS-114 is enrolling patients (pts) ≥18 years of age with AZD2811 is a potent, selective Aurora kinase B inhibitor. kvhzt zalq othkzw ihbqt klvr ixvgd hpuerwn njsz xirqc rwy