scholarly journals Phase I dose-escalation oncology trials with sequential multiple schedules

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Burak Kürsad Günhan ◽  
Sebastian Weber ◽  
Abdelkader Seroutou ◽  
Tim Friede
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Relevant Information ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Multiple Schedules ◽  
Number Of Patients ◽  
Dose Recommendations ◽  
Bayesian Logistic Regression ◽  
Sequential Phase

Abstract Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. 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. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results In a simulation study, the developed approach is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-predictive prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The and code for the implementation of an illustrative sequential phase I trial example in oncology is publicly available (https://github.com/gunhanb/TITEPK_sequential). Conclusion In phase I oncology trials with sequential multiple schedules, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

scholarly journals A Bayesian Time-to-event Pharmacokinetic Model for Sequential Phase I Dose-escalation Trials with Multiple Schedules

2020 ◽  
Author(s):  
Burak Kürsad Günhan ◽  
Sebastian Weber ◽  
Abdelkader Seroutou ◽  
Tim Friede
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Relevant Information ◽  
Treatment Schedule ◽  
Phase I Trials ◽  
Time To Event ◽  
Multiple Schedules ◽  
Number Of Patients ◽  
Bayesian Logistic Regression ◽  
Sequential Phase

Abstract Background: Phase I dose-escalation trials constitute the first step in investigating the safety of potentially promising drugs in humans. Conventional methods for phase I dose-escalation trials are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial.Methods: Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing dose-escalation trial to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results: In a simulation study, the developed appraoch is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The R and Stan code for the implementation of an illustrative sequential phase I trial example is publicly available (https://github.com/gunhanb/TITEPK sequential).Conclusion: In sequential phase I dose-escalation trials, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.

An evaluation of phase I clinical trial designs of chemotherapeutic agents tested on solid tumors and approved in last 10 years.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13127-e13127
Author(s):  
Chetan Dilip Deshmukh ◽  
Ganesh Divekar ◽  
Shailesh Arjun Bondarde ◽  
Minish Mahendra Jain ◽  
Kumar Prabhash
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Therapeutic Benefit ◽  
Chemotherapeutic Agents ◽  
Biologically Active ◽  
Phase I Trials ◽  
Number Of Patients ◽  
Dose Limiting Toxicity

e13127 Background: Phase I trials are performed with the aim of finding the maximum tolerated dose and often start with a very low dose that is subsequently escalated based on the toxicity seen. As a result patients treated on these trials often receive doses of chemotherapeutic agents that are frequently either below or above the biologically active level, thus reducing their chances for therapeutic benefit or increasing chances for toxicity. This evaluation was undertaken to determine how phase I trials are currently conducted and to correlate phase I doses tested with MTD and marketed doses. Methods: Published phase I trials of 16 chemotherapeutic agents tested on solid tumors and approved in last 10-years were identified by searching the Medline database and reviewed to determine methodology employed, cohorts taken to complete the trial, definition of dose limiting toxicity (DLT), number of cohorts treated below MTD, relation between MTD and marketed dose and DLT (dose limiting toxicity). Results: Twenty-three published trials involving 891 patients were identified. These trialsused the standard method of enrolling cohorts of patients at increasing dose levels and observing toxic effects to determine next dose.. Of these 15 used traditional dose escalation, 6 used accelerated titration, 2 used continual reassessment method. Six trials that used accelerated titration method of dose escalation, 2 were used to test cytotoxic agent (5 trials) while 1 tested targeted therapy. Sixty five cohorts were treated below MTD. Average number of cohorts required to complete trial were 6.2. Nineteen trials defined MTD as a dose below DLT dose while 4 trials defined MTD being DLT. Five of 23 trials were completed with-out reaching MTD. Marketed dose for these 16 chemotherapeutic agents was 0 to 50% lower than MTD. DLT reported was myelosupression, fatigue, rash, hypertension or diarrhea. Conclusions: These results show the need for methods to reduce cohorts to reduce number of patients recruited at doses significantly lower than MTD and complete the trials rapidly so that effective agents can be marketed sooner.

scholarly journals Addition of erlotinib to fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab: Two sequential phase I trials

2011 ◽  
Vol 2 (3) ◽  
pp. 449-455 ◽  
Author(s):  
CHIARA CARLOMAGNO ◽  
GENNARO DANIELE ◽  
ROBERTO BIANCO ◽  
ROBERTA MARCIANO ◽  
VINCENZO DAMIANO ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trials ◽  
Sequential Phase

scholarly journals Efficiency of New Dose Escalation Designs in Dose-Finding Phase I Trials of Molecularly Targeted Agents

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51039 ◽  
Author(s):  
Christophe Le Tourneau ◽  
Hui K. Gan ◽  
Albiruni R. A. Razak ◽  
Xavier Paoletti
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Targeted Agents ◽  
Molecularly Targeted Agents

scholarly journals A product of independent beta probabilities dose escalation design for dual‐agent phase I trials

2015 ◽  
Vol 34 (8) ◽  
pp. 1261-1276 ◽  
Author(s):  
Adrian P. Mander ◽  
Michael J. Sweeting
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Trials

scholarly journals Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology

2018 ◽  
Vol 17 (4) ◽  
pp. 1012-1015 ◽  
Author(s):  
Denis L. Jardim ◽  
Débora de Melo Gagliato ◽  
Razelle Kurzrock
Keyword(s):  
Phase I ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Dose Finding ◽  
Priority Review ◽  
Marketing Approval ◽  
Phase I Trials ◽  
Clinical Cancer Research ◽  
Number Of Patients

Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

scholarly journals Immune checkpoint inhibitor-based combinations: is dose escalation mandatory for phase I trials?

2019 ◽  
Vol 30 (11) ◽  
pp. 1751-1759 ◽  
Author(s):  
V. Simmet ◽  
L. Eberst ◽  
A. Marabelle ◽  
P.A. Cassier
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Phase I Trials

Multi-Institutional Phase I Trials of Anticancer Agents

2008 ◽  
Vol 26 (12) ◽  
pp. 1926-1931 ◽  
Author(s):  
Afshin Dowlati ◽  
Sudhir Manda ◽  
Joseph Gibbons ◽  
Scot C. Remick ◽  
Lauren Patrick ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Agents ◽  
Maximum Tolerated Dose ◽  
National Institutes Of Health ◽  
Cytotoxic Agents ◽  
Phase I Trials ◽  
Tumor Type ◽  
Targeted Agents ◽  
Phase I Studies ◽  
Number Of Patients

Purpose Physicians involved in the conduct of phase I studies of novel anticancer agents have raised concerns about the emergence of multi-institutional phase I trials and about using the optimal biologic dose (OBD) as an alternative to the maximum-tolerated dose (MTD) as the primary end point in early drug development. We sought to determine the factors associated with multi-institutional phase I studies and OBD determination. Patients and Methods We reviewed all published phase I trials between January 1998 and June 2006 from two major clinical cancer journals. The following components from each trial were determined: number of participating sites, sponsor, nation where study was conducted, MTD or OBD established, number of patients accrued, mechanism of action of the studied agent, accrual time, and tumor type. Results We identified 463 trials. Fifty-six percent were performed in single institutions. Only 30% reported accrual time. The number of patients enrolled on single institution studies was significantly lower than on multi-institutional studies (P < .05), but there was no difference in accrual time. There was no association between the number of institutions and the sponsor or the mechanism of drug action. National Institutes of Health–sponsored trials enrolled fewer patients per trial than pharmaceutical-sponsored trials (P < .05). Although 99% of trials with cytotoxic agents determined an MTD, only 64% of trials with targeted agents did. Conclusion Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

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