Dose escalation phase. Newer methods of dose .

Dose escalation phase. In current oncology trial practice, dose escalation decisions are usually guided by statistical approaches to model or analyze the dose limiting toxicity (DLT) data, which represents severe or Apr 14, 2021 · Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e. The main objectives of a dose escalation trial are to establish the safety, tolerability, and optimal dosing of a new drug. A low starting dose combined with small dose increments could lead to a lengthy dose escalation and could expose patients unnecessarily to … To address this challenge, we propose a new Phase I dose-finding design, denoted as IP-CRM, that integrates intra-patient dose escalation with the continual reassessment method (CRM). Apr 26, 2020 · Innovations in statistics, programming and data management are changing the very nature of clinical development. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for Jul 23, 2012 · In practice, however, the modified Fibonacci sequence, the most popular dose-escalation guidance scheme in dose-seeking phase I trials is a term which is too vague and should be avoided. Jun 26, 2019 · Background A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Feb 1, 2021 · For phase I trials of novel anticancer treatments, many of the assumptions of traditional dose-finding designs are no longer valid. Keywords: Phase I trials, Recommended phase 2 dose, Toxicity Highlights Comprehensive review of optimal safety and dosing in early phase cancer trials. Feb 20, 2025 · This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). 6 2. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample si … Jun 10, 2024 · 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. The pivotal aspect of a phase 1 oncology trial, assessing a new cancer treatment’s safety and dosage, revolves around determining the appropriate dose escalation given the observations of toxicity. In current oncology trial practice, dose escalation decisions are usually guided by statistical approaches to model or analyze the dose limiting toxicity (DLT) data, which represents severe or Nov 26, 2018 · The MHRA GCP inspectors inspect against the legislation and the relevant early phase guidance 1 so expect to see a formalised procedure for DE and for a specific clinical trial to be able to reconstruct the dose escalation as described in the formalised procedure and approved protocol. By leveraging pharmacokinetics, dose escalation considers exposure and interindividual variability on a continuous rather than discrete domain, offering additional information for dose-escalation decisions. From that point or after completion of ATD phase, Bayesian optimal interval (BOIN) design was adopted in the rest doses for dose escalation and determination of maximum tolerated dose (MTD). The corresponding key question is: how to efficiently and reliably identify the maximum tolerated dose (MTD) using a sample size as small as possible? We propose model-assisted and model-based designs wi … May 1, 2015 · The purpose of early stage clinical trials is to determine the recommended dose and toxicity profile of an investigational agent or multi-drug combina… During the dose-escalation phase, a dose-finding algorithm identifies the maximum-tolerated dose (MTD), and during the expansion phase, an additional number of patients (six, 10, or more) are treated at the MTD. If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Cytel thought-leaders reveal cutting-edge techniques that streamline and truly Nov 5, 2024 · The duration from initiation of priming phase to the end of the first cycle was defined as the dose-limiting toxicity (DLT) observation period. 3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. May 11, 2024 · A dose escalation trial, also known as a dose-ranging study, is a type of clinical trial design used primarily in Phase I of drug development. 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. 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. This process is especially important for drugs with low therapeutic indices (TI), such as cytotoxic drugs used in oncology, where the balance between effectiveness Jul 30, 2024 · The pivotal aspect of a phase 1 oncology trial, assessing a new cancer treatment’s safety and dosage, revolves around determining the appropriate dose escalation given the observations of toxicity. 1. Apr 14, 2022 · The FDA issued the final guidance document for first-in-human trial designs that consist of both dose escalation as well as multiple expansion cohorts to evaluate safety, anti-tumor activity, and other properties of oncology drug products, all within a single protocol. 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. A. This effect was unexpected based on preclinical studies. 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. The dosing regimen combines both accelerated titration and standard cohort dose escalation schemata, which will be used jointly to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BVD-523 in human patients. 3. 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. In the acceleration phase of the accelerated titration design, the advantage is that there is only one patient per dose group, and intrapatient dose escalation reduces the number of patients exposed to the ineffective dose, ensuring that patients can receive higher and more effective doses. 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. A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO CONTROLLED, SINGLE- AND MULTIPLE-DOSE ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF Feb 16, 2024 · In recent years, there has been increased interest in incorporation of backfilling into dose-escalation clinical trials, which involves concurrently assigning patients to doses that have been previously cleared for safety by the dose-escalation design. Assessing Safety of Recommended Phase 2 Dose Expansion cohorts can be intended to further evaluate safety beyond the initial dose-escalation portion of a trial. Oct 13, 2015 · These studies typically involve a small number of patients. Backfilling generates additional information on … Nov 5, 2024 · A Phase 1/1b Open-Label, Dose Escalation, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Leukemic Activity of the Orally Available CDC-like Kinase Inhibitor, BH-30236, in Adults with R/R AML or HR-MDS This is an open-label, multi-center Phase 1/2 study with a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2) in patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS). Dose escalation was limited to five treated patients due to severe thrombocytopenia. 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. Revised: April 26, 2017 – Incorporates changes proposed in Amendment 2, march 6, 201. 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. Yet, the traditional 3+3 design is still the most commonly used. Methods Patients with advanced solid tumors were treated with ivonescimab 0. Despite these design challenges resulting Sep 28, 2022 · Endpoints should include consideration of all longitudinal toxicity. Jul 19, 2022 · We pursue dose escalation until the maximum tolerated exposure (corresponding to the MTD) is reached. 3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining Responsible scientists and physicians are typically blinded to the study treatment allocation during these early‐phase evaluations. 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). This paper explains the 3+3 method along with its advantages and Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. Various innovative phase 1 trial designs have been proposed to address the issues and new challenges posed by molecularly targeted agents. . Sep 14, 2014 · Abstract. To reach this endpoint, study designs will have many components of this process outlined in the protocol, including starting dose/regimen, dose levels, dosing regimen, titrations, dose Feb 18, 2025 · Phase I dose-escalation study of the next-generation nectin-4 targeting antibody–drug conjugate CRB-701 (SYS6002) in US and UK patients with urothelial cancer and other solid tumors. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining PHASE I CLINICAL TRIALS – NON LIFE-THREATENING DISEASES Healthy normal volunteers Primarily for PK properties Help recommend dosing frequency Estimate maximally tolerated dose (MTD) Dose escalation design or crossover designs are popular in Phase I Dec 25, 2024 · To address this challenge, we propose a new Phase I dose-finding design, denoted as IP-CRM, that integrates intra-patient dose escalation with the continual reassessment method (CRM). Feb 12, 2024 · Dose escalation and deescalation rules are based on the nearest neighborhood continual reassessment method for a combination drug, and we specify all possible dose-toxicity orderings in the trial. The aim is to utilize the information from both the completed and the ongoing schedules to inform decisions on the dose level for the next dose cohort. 2 Dose-Escalation and Maximum Dose and Duration in Phase 1 For new investigational drugs given to humans for the first time, the time course of any potential AE is unknown. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of clinica … Nov 15, 2022 · ASC2ESCALATE: A Phase 2, Single-Arm, Dose-Escalation Study of Asciminib Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with 1 Prior Tyrosine Kinase Inhibitor (TKI) Jul 24, 2023 · 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-cancer treatment. , rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are under-treated, speed the completion of phase I trials, and provide a substantial increase in the information obtained. Apr 8, 2024 · In seamless phase 1/2 adaptive designs, dose escalation studies to assess safety and tolerability transition into efficacy studies without having to pause and restart the trial. 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. Dose escalation will continue until MTD/recommended phase II dose and preferred phase Ib schedule for each schedule is determined. The ideal starting dose for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. May 12, 2023 · A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide, ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced 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. Background: Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Jan 13, 2021 · Only two articles relied on an adaptive dose escalation design. Its straightforward algorithm and logistical simplicity for the clinical investigators to carry out make it the most widely practiced design for Phase-I trials. AMENDMENTS FROM PREVIOUS VERSION(S). The primary objectives of this study were to assess the safety and tolerability, dose-limiting toxicities (DLTs), and to determine the maximum tolerated dose (MTD) or maximum administered dose. This article shares details of the guidance as well as advantages and risks of using this trial design. Newer methods of dose Nov 4, 2024 · Between April 23, 2021, and November 30, 2023, a total of 122 patients were enrolled in the phase 1 study, with 17 patients in the dose-escalation phase and 105 patients in the dose-expansion phase. How Does Dose Escalation to Find MTD Work in Phase 1 Clinical Trials? Dose escalation is a critical part of Phase 1 clinical trials, where the main goal is to determine the Maximum Tolerated Dose (MTD) of an investigational drug. Immunotherapy drugs are associated with Cytokine Release Syn-drome, a systemic immune system reaction that can be mitigated when initial lower doses of the drug are administered to generate immune tolerance. De-escalation occurs when two or more DLT occur at a dose level, whereas escalation can be performed when 3/3, 4/4, 5/5, 5/6 or 6/6 patients are evaluated without DLT. 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 effects. This design may not be applied to cancer vaccines, given their unique mechanism of action. Phase I protocols with dose expansions consist of two phases: the dose escalation phase followed by a dose expansion phase (Figure 1). May 20, 2009 · Abstract Phase I clinical trials are an essential step in the development of anticancer drugs. 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. Conclusion: Accelerated titration (i. Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. 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. This Feb 15, 2024 · Many product developers are propelled by the goal of delivering life-saving treatments as quickly and as safely as possible to patients who are left with The standard 3+3 dose escalation in oncology study design in first-in-human (FIH) clinical trials is still the standard, however, we should consider alternative Phase 1 study designs to achieve the optimal recommended Phase 2 dose. Apr 15, 2024 · Dose escalation studies are pivotal in the early phases of clinical drug development for evaluating the safety profile of a new therapeutic agent and identifying a recommended dose for further investigation. Feb 18, 2025 · The dose escalation phase will follow an i3+3 design, with each cohort able to backfill up to 20 participants for further characterization of the safety, tolerability and preliminary efficacy of dose and schedules. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. Despite widely adopted, rule-based dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and t … A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require Jun 16, 2023 · 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). Apr 24, 2024 · This was an FIH, phase 1a, multicenter trial which was conducted in six sites in Australia and included dose-escalation and dose-expansion portions. VT1021 is found to be safe and May 12, 2009 · Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation meth-ods that have been developed to evaluate new anticancer agents. In Phase 1 clinical trials, dose escalation is a critical step in determining the maximum tolerated dose (MTD) or identifying a biologically effective dose. A phase I/II dose escalation trial with expansion cohorts to evaluate safety and preliminary efficacy of BNT142 in patients with prospectively confirmed claudin 6-positive solid tumors. g. Apr 19, 2024 · Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. These blinded evaluations of data are formalized in the study protocol as dose escalation meetings and are used to project the safety and tolerability profile of the compound in a higher dose. daily or weekly dosing) once the dose escalation with another schedule has been completed. 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. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity. The FDA recently published “Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines Starting dose level is 15 mg BID; QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee. In addition, strategies are proposed to overcome these challenges to develop phase I trials that can more accurately define the recommended dose and identify adverse events. 2012]. Traditional dose-escalation methods, such as the 3 + 3 design, primarily focus on safety, often resulting in prolonged exposure to subtherapeutic or excessively toxic doses. See full list on quanticate. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. 6 INTRODUCTION 6 2. The design you choose directly influences patient safety, study duration, statistical rigor, and regulatory acceptance. 3+3 is a popular rule based design that allows dose escalation and de-escalation based on the number of dose-limiting toxicities observed in a cohort of 3 patients. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid Apr 30, 2024 · Introduction A main goal of Phase 1 trials is to establish the recommended dose and/or dosing regimen of new drugs for efficacy testing in Phase 2 trials, using a detailed and monitored dose escalation process. e. report findings from a first-in-human dose escalation study of the tumor microenvironment modulator VT1021 in patients with advanced solid tumors. Despite their great importance, many dose-escalation studies use study designs based on 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. This study will be conducted at up to 6 study centers. Drug combinations have been introduced with the goal of improving treatment efficacy by increasing overall anti-tumor activity and, presumably, survival. However, in spite of these proposals, the conventional design is still the most widely utilized. 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. In the rapid acceleration phase, patients are treated with different doses of the drug and increments are achieved through single-or double-dose escalations. Furthermore, the CRM has been shown to assign more trial Nov 5, 2024 · A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 (Lacutoclax) As Monotherapy and in Combination with Azacitidine in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML) Therefore, the phase I trial is designed as a dose-escalation study to determine the maximum tolerable dosage (MTD), that is, the maximum dose associated with an acceptable level of dose-limiting toxicity (DLT--usually defined to be grade 3 or above toxicity, excepting grade 3 neutropenia unaccompanied by either fever or infection 35). Study Overvie. The primary objectives for the dose-escalation portion were to define the MTD, if observed; select a recommended phase II dose (RP2D); and to investigate the safety and tolerability profile of BT5528. Escalation with over-dose control (the EWOC) is a Bayesian Jan 13, 2024 · Mahalingam et al. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The main distinguishing features of these designs are (1) a rapid initial escalation phase; (2) intra-patient dose escalation; and (3) the ability to analyze trial results using a dose-toxicity model that incorporates parameters for intra-patient and inter-patient variation in toxicity and cumulative toxicity. 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. Jan 31, 2024 · This month, we continue our series by discussing dose escalation and dose expansion, terms you may see if you are learning about a phase I trial. Additionally, these methods may fail to account for modern therapies’ complex pharmacokinetics and pharmacodynamics ATDs consist of 3 steps: (1) rapid acceleration phase, (2) intra-patient dose escalation phase and (3) assessment of dose-toxicity relationship. Dec 16, 2024 · In this phase I first-in-human study, we administered BAY 2666605, a selective and potent molecular glue that binds SLFN12 and PDE3A together, to patients with solid tumors. Phase I clinical trials are an essential step in the development of anticancer drugs. Nov 5, 2022 · Designing Phase I clinical trials is challenging when accrual is slow or sample size is limited. This can be both inefficient and introduces Jun 3, 2014 · 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]. Managing a dose escalation study is difficult enough, and when you pair it with a Phase 2 study that often requires expansion into additional countries, the complexity of execution goes to another level. 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 monit… Dose escalation and dose expansion are terms that have unique significance in early-phase clinical trials, especially for studies of new drugs being developed as treatment options to help cure cancer. Sep 4, 2024 · The phase I part reported here is the dose-escalation portion; a dose-expansion portion is ongoing and will be reported at a later date. 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, and consider scenarios where different populations may require different dosages. Jan 22, 2025 · Dose optimization in Phase I oncology trials balances therapeutic efficacy and patient safety. Dec 6, 2023 · 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. 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 monit… Oct 23, 2023 · In the dose-escalation phase, patients were treated with QL1604 at 0. Oct 25, 2022 · 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 safety, (ii) decreasing accuracy, (iii) increasing sample size when the correct RP2D is the highest dose. com Aug 1, 2025 · Together, these dose-escalation strategies offer flexibility and precision in identifying safe and effective doses in phase I trials, supporting the seamless transition to dose-expansion cohorts. May 27, 2021 · Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. . QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. Aug 18, 2020 · Schematic diagram of Phase I 3 + 3 design: 3 + 3 design strategy has been clearly laid out in FDA guidance for industry “ Clinical Considerations for Therapeutic Vaccines ” as the following: The traditional standard dose escalation schedule in the development of cancer therapeutics uses the so-called “3 + 3 design” to avoid selection of a phase 2 clinical trial dose that causes a Dose Escalation Study Design Example (With Results) Disclaimer: The following information is fictional and is only intended for the purpose of illustrating key concepts for results data entry in the Protocol Registration and Results System (PRS). Jan 4, 2015 · The traditional standard dose escalation schedule in the development of cancer therapeutics uses the so-called “3 + 3 design” to avoid selection of a phase 2 clinical trial dose that causes a treatment-limiting toxicity in more than 17% of subjects, a standard considered acceptable as an outpatient therapeutic for patients with limited Jun 1, 2018 · 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. To save valuable time and resources in new drug development, Phase I/II clinical trials with toxicity control and drug efficacy as dual primary endpoints have become increasingly popular. This MTD Mar 10, 2013 · Learn about four key dose-finding study types used in Phase II trials to improve efficacy and safety. jkol ju5 3yz gobdm kkke4 acok nlat 3vifou ew swxst