A system for determining maximum tolerated dose in clinical trial

Toxicity study,especially in determining the maximum tolerated dose(MTD)in phase I clinical trial,is an important step in developing new life-saving drugs.In practice,toxicity levels may be categorised as binary grades,multiple grades,or in a more generalised case,continuous grades.In this study,we propose an overall MTD framework that includes all the aforementioned cases for a single toxicity outcome(response).The mechanism of determining MTD involves a function that is predetermined by user.Analytic properties of such a system are investigated and simu-lation studies are performed for various scenarios.The concept of the continual reassessment method(CRM)is also implied in the framework and Bayesian analysis,including Markov chain Monte Carlo(MCMC)methods are used in estimating the model parameters.

Review on Hydroxyurea Usage in Young Children with Sickle Cell Disease: Examining Hemoglobin Induction, Potential Benefits, Responses, Safety, and Effectiveness

Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.

Safety,tolerability,and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer:An open-label,dose-escalation,phase I study

Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.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.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors(NepoMUC):a phase I dose escalation trial

Background:More than 25%of patients with solid cancers develop intracerebral metastases.Aside of surgery,radia-tion therapy(RT)is a mainstay in the treatment of intracerebral metastases.Postoperative fractionated stereotactic RT(FSRT)to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recur-rence.However,FSRT has to be delayed until a sufficient wound healing is attained;hence systemic therapy might be postponed.Neoadjuvant stereotactic radiosurgery(SRS)might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy.Here,we conducted a study to find the maximum tolerated dose(MTD)of neoadjuvant SRS for intracerebral metastases.Methods:This is a single-center,phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital,Technical University of Munich.The rule-based traditional 3+3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied.The primary endpoint is the MTD for which no dose-limiting toxicities(DLT)occur.The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0 continuously during the study until the first follow-up visit(4-6 weeks after surgery).Secondary endpoints include local control rate,survival,immunological tumor characteristics,quality of life(QoL),CTCAE grade of late clinical,neurological,and neurocognitive toxicities.In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS.Depending on the occurrence of DLT up to 72 patients will be enrolled.The recruitment phase will last for 24 months.Discussion:Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity,such as better target volume definition with subsequent higher efficiency of eliminating tumor cells,and lower damage to surrounding healthy tissue,and much-needed systemic chemotherapy could be initiated more rapidly.