Using the continual reassessment method: Lessons Learned from an EORTC phase I dose finding study

2006 ◽  
Vol 42 (10) ◽  
pp. 1362-1368 ◽  
Author(s):  
Xavier Paoletti ◽  
Benoît Baron ◽  
Patrick Schöffski ◽  
Pierre Fumoleau ◽  
Denis Lacombe ◽  
...  
Keyword(s):  
Phase I ◽  
Lessons Learned ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Finding Study ◽  
Dose Finding Study

A prospective PGx and PK/PD dose-finding study of irinotecan based on UGT1A1*6 and *28 genotyping (UGT0601)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14560-e14560
Author(s):  
T. Esaki ◽  
T. Satoh ◽  
T. Ura ◽  
T. Tsujinaka ◽  
Y. Sasaki ◽  
...  
Keyword(s):  
Initial Dosage ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Hematological Toxicity ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3 ◽  
Dose Limiting Toxicity

e14560 Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m2 in Wild, 100 mg/m2 in Hetero, and 75 mg/m2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m2 in Homo. At 150 mg/m2, DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m2, and 37.4% at 150 mg/m2. The MTD was determined 150 mg/m2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m2 during the 1st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m2). In one pt of Homo for *28/*28 died of septic shock during the 2nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo. [Table: see text]

scholarly journals How to design a dose-finding study using the continual reassessment method

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Graham M. Wheeler ◽  
Adrian P. Mander ◽  
Alun Bedding ◽  
Kristian Brock ◽  
Victoria Cornelius ◽  
...  
Keyword(s):  
Dose Finding ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Finding Study ◽  
Dose Finding Study

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

scholarly journals A Phase I Dose-Finding Study of the Novel Toll-like Receptor 8 Agonist VTX-2337 in Adult Subjects with Advanced Solid Tumors or Lymphoma

2014 ◽  
Vol 20 (14) ◽  
pp. 3683-3691 ◽  
Author(s):  
Donald W. Northfelt ◽  
Ramesh K. Ramanathan ◽  
Peter A. Cohen ◽  
Daniel D. Von Hoff ◽  
Glen J. Weiss ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
The Novel ◽  
Toll Like Receptor ◽  
Finding Study ◽  
Dose Finding Study

576 Phase I dose-finding study of the combination of alimta (pemetrexed) and paclitaxel in patients with solid tumors

2003 ◽  
Vol 1 (5) ◽  
pp. S174-S175
Author(s):  
D. Zingel ◽  
C. Bolling ◽  
T. Graefe ◽  
D. Radtke ◽  
J. Latz ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Finding ◽  
Finding Study ◽  
Dose Finding Study
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