Phase I Trial Using a Time-to-Event Continual Reassessment Strategy for Dose Escalation of Cisplatin Combined With Gemcitabine and Radiation Therapy in Pancreatic Cancer

2004 ◽  
Vol 22 (2) ◽  
pp. 238-243 ◽  
Author(s):  
Jeffrey H. Muler ◽  
Cornelius J. McGinn ◽  
Daniel Normolle ◽  
Theodore Lawrence ◽  
Diane Brown ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Full Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Purpose The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. Patients and Methods Nineteen patients were treated. Gemcitabine 1,000 mg/m2 was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m2, escalated to a targeted dose of 50 mg/m2 using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. Results Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m2 cisplatin dose level. Patients treated at 30 and 40 mg/m2 cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. Conclusion Cisplatin at doses up to 40 mg/m2 may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

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 Phase I cancer clinical trials†

2016 ◽  
Vol 4 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Juan R. Cabrera ◽  
Jennie W. Taylor ◽  
Annette M. Molinaro
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Maximum Tolerated Dose ◽  
Cancer Clinical Trials ◽  
Dose Estimation ◽  
Time To Event ◽  
Timely Manner ◽  
Continual Reassessment Method ◽  
Continual Reassessment

Abstract An efficient phase I trial is a crucial step in developing a new drug in a safe and timely manner. The main objective of a phase I trial is to determine the maximum tolerated dose in order to recommend the dose for a phase II trial. There are many designs that are implemented in phase I trials. Rule-based designs such as the traditional 3 + 3 method and rolling six design are easy to implement and assess for safety using a conservative approach. Model-based designs such as the continual reassessment method and the time-to-event continual reassessment method use mathematical models to increase the precision of dose estimation. The advantages and shortcomings of these designs, along with other designs, are reviewed.

Designing Dose-Escalation Trials With Late-Onset Toxicities Using the Time-to-Event Continual Reassessment Method

2006 ◽  
Vol 24 (27) ◽  
pp. 4426-4433 ◽  
Author(s):  
Daniel Normolle ◽  
Theodore Lawrence
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Late Onset ◽  
Maximum Tolerated Dose ◽  
Phase I Trials ◽  
Operating Characteristics ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Standard Design ◽  
Continual Reassessment

Purpose The standard design for phase I trials of combined chemotherapy and radiation, which enters either three or six patients per dose level, has little statistical basis and is subject to opening and closing because of delayed toxicities that disrupt patient accrual. We compared the operating characteristics of this standard design and the time-to-event continual reassessment method (TITE-CRM) for dose-escalation trials of combination chemotherapy and radiation. Methods The operating characteristics were determined by Monte Carlo simulation of 60,000 phase I trials. Results Compared with the standard trial design, in studies with delayed toxicity (ie, where four or more patients are expected to enter onto the study during a single previously enrolled patient's observation for toxicity), TITE-CRM trials are significantly shorter when toxicity observation times are long, treat more patients at or above the maximum-tolerated dose, identify the maximum-tolerated dose (MTD) more accurately, and provide phase II information, but do not expose patients to significant additional risk. Estimation precision and overdose control of TITE-CRM increase as the design assumptions more closely resemble the true state of nature, but are reduced if, for instance, the toxicity of treatment has been grossly underestimated. Conclusion Compared with the standard design, if there is any prior knowledge concerning the toxicity profile of a treatment, TITE-CRM can leverage it to produce more accurate estimates of the MTD and does not expose patients to significant excess risk, but requires timely communication between clinical investigators, data managers, and study statisticians.

A phase I study of oxaliplatin, full-dose gemcitabine and concurrent radiation therapy in patients with pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4107-4107 ◽  
Author(s):  
S. P. Desai ◽  
E. Ben-Josef ◽  
T. J. Lawrence ◽  
I. R. Francis ◽  
J. K. Greenson ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Full Dose ◽  
Synergistic Cytotoxicity ◽  
Level 3 ◽  
Grade 3 ◽  
Gi Bleed

4107 Background: We previously demonstrated safety and efficacy of full dose gemcitabine (GEM) and radiation therapy (RT) in patients (pts) with pancreatic cancer (PC). Our preclinical studies have shown that GEM with oxaliplatin (OX) preserves radiosensitization with synergistic cytotoxicity. To enhance local and systemic treatment effects, we initiated a study of OX and GEM with concurrent RT. Methods: Pts with untreated PC received up to 4 cycles of GEM day 1, 8, 15 and OX days 1, 15 repeated at 28 day intervals. RT (27 Gy in 1.8 Gy fractions to gross tumor volume with 1 cm margin) was given during cycle 1 and repeated in cycle 4. Surgery occurred after cycle 2 in resectable pts. Dose escalation was guided using time-to-event continuous reassessment method (TITE-CRM). Dose levels 1–4 GEM 1 g/m2 IV over 30 min and OX 40, 55, 70, 85 mg/m2 IV over 90 min; dose level 5, 6 OX dose remained 85 mg/m2 but infusion time for GEM 1 g/m2 was increased to 65, 100 min, respectively. Trial objective is to determine dose level associated with DLT thru cycle 2 in ≤ 20% of pts; planned accrual is 40 pts evaluable for DLT. Results: 40 pts have been enrolled (median age 63, men/women 26/14) with resectable (10), unresectable (27), and metastatic (3) PC. 29 pts have completed 2 cycles and 11 pts 4 cycles. After 2 cycles CA19–9 decreased > 50% in 14 of 24 evaluable pts (58%). Six of 8 explored pts underwent margin negative resection with 1 path CR and 2 with small residual microscopic foci only. Per RECIST, CT response of the primary lesion after 2 cycles included 3 PR, 23 SD and 1 PD. Two additional PR were seen after cycle 4. Thirty pts are presently evaluable for DLT; 7 pts have suffered DLT including grade 4 platelets (4), decline in PS (2), GI bleed (1) and grade 3 weight loss (1). Current estimated probability of DLT is 21% (95% CI 11%,34%) for dose level 3 and 24% (95% CI 13%,37%) for dose level 4. Conclusions: The addition of OX 70–85 mg/m2 days 1, 15 to full dose GEM based RT is tolerable and efficacious. A neoadjuvant phase II study in resectable PC using the MTD defined in this phase I study is planned. Supported by Sanofi-Aventis. [Table: see text]

scholarly journals Evaluation of irrational dose assignment definitions using the continual reassessment method

2019 ◽  
Vol 16 (6) ◽  
pp. 665-672
Author(s):  
Nolan A. Wages ◽  
Evan Bagley
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Simulation Study ◽  
Phase I Clinical Trials ◽  
Target Dose ◽  
Continual Reassessment Method ◽  
Trial Conduct ◽  
Family Of Curves ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Background: This article studies the notion of irrational dose assignment in Phase I clinical trials. This property was recently defined by Zhou and colleagues as a dose assignment that fails to de-escalate the dose when two out of three, three out of six, or four out of six patients have experienced a dose-limiting toxicity event at the current dose level. The authors claimed that a drawback of the well-known continual reassessment method is that it can result in irrational dose assignments. The aim of this article is to examine this definition of irrationality more closely within the conduct of the continual reassessment method. Methods: Over a broad range of assumed dose-limiting toxicity probability scenarios for six study dose levels and a variety of target dose-limiting toxicity rates, we simulated 2000 trials of n = 36 patients. For each scenario, we counted the number of irrational dose assignments that were made by the continual reassessment method, according to the definitions of Zhou and colleagues. For each of the irrational decisions made, we classified the dose assignment as an underdose assignment, a target dose assignment, or an overdose assignment based on the true dose-limiting toxicity probability at that dose. Results: Across eight dose-toxicity scenarios, there were a total of 181,581 dose assignments made in the simulation study. Of these assignments, 8165 (4.5%) decisions were made when two out of three, three out of six, or four out of six patients had experienced a dose-limiting toxicity at the current dose. Of these 8165 decisions, 1505 (18.4%) recommended staying at the current dose level and would therefore be classified as irrational by Zhou and colleagues. Among the irrational decisions, 41.2% were misclassified, meaning they were made either at the true target dose (17.9%) or at a true underdose (23.3%). The remaining 58.8% were made at a true overdose and therefore truly irrational. Overall, irrational dose assignments comprised <1% of the total dose assignments made during the simulation study. Similar findings are reported in simulations across 100 randomly generated dose-toxicity scenarios from a recently proposed family of curves. Conclusion: Zhou and colleagues argue that the behavior of the continual reassessment method is disturbing due to its ability to make irrational dose assignments. These definitions are based on rules that mimic the popular 3 + 3 design, which should not be the benchmark used to construct guidelines for trial conduct of modern Phase I methods. Our study illustrates that these dose assignments occur very seldom in the continual reassessment method and that even when they do occur, they can often be considered sensible when accounting for all accumulated data in the study.

scholarly journals Modeling adverse event counts in phase I clinical trials of a cytotoxic agent

2018 ◽  
Vol 15 (4) ◽  
pp. 386-397 ◽  
Author(s):  
Daniel G Muenz ◽  
Thomas M Braun ◽  
Jeremy MG Taylor
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Phase I Clinical Trials ◽  
Continual Reassessment Method ◽  
Low Level ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient’s richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

1995 ◽  
Vol 13 (11) ◽  
pp. 2842-2850 ◽  
Author(s):  
D A Rinaldi ◽  
H A Burris ◽  
F A Dorr ◽  
J R Woodworth ◽  
J G Kuhn ◽  
...  
Keyword(s):  
Dose Level ◽  
Thymidylate Synthase ◽  
Dose Escalation ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Treatment Schedule ◽  
Continual Reassessment Method ◽  
Toxic Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

PURPOSE To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Phase I Study of Oxaliplatin, Full-Dose Gemcitabine, and Concurrent Radiation Therapy in Pancreatic Cancer

2007 ◽  
Vol 25 (29) ◽  
pp. 4587-4592 ◽  
Author(s):  
Sameer P. Desai ◽  
Edgar Ben-Josef ◽  
Daniel P. Normolle ◽  
Isaac R. Francis ◽  
Joel K. Greenson ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Dose Level ◽  
Performance Status ◽  
Resectable Pancreatic Cancer ◽  
Probability Interval ◽  
Full Dose ◽  
Level 3 ◽  
Gi Toxicity ◽  
Dose Levels

PurposeTo determine a biweekly dose of oxaliplatin for combination with full-dose gemcitabine and concurrent radiation therapy (RT) in pancreatic cancer.Patients and MethodsPatients with previously untreated pancreatic cancer received gemcitabine days 1, 8, and 15, and oxaliplatin days 1 and 15, repeated at 28-day intervals. RT (27 Gy in 1.8-Gy fractions) was administered during cycle 1. Dose escalation was guided using the time-to-event continuous reassessment method. Dose levels 1 to 4 included gemcitabine 1 g/m2intravenously (IV) during 30 minutes and oxaliplatin 40, 55, 70, or 85 mg/m2IV during 90 minutes, respectively; for dose levels 5 and 6, oxaliplatin dose remained 85 mg/m2but infusion time for gemcitabine 1 g/m2was increased to 65 or 100 minutes, respectively. The trial objective was to determine the dose level associated with dose-limiting toxicity (DLT) through cycle 2 in ≤ 20% of patients.ResultsForty-four patients were enrolled (median age, 64 years; 27 men, 17 women) with resectable (n = 12), unresectable (n = 29), and metastatic (n = 3) pancreatic cancer. Ten DLTs occurred in nine patients, including grade 4 platelets (n = 4), decline in performance status (n = 2), GI bleeding (n = 2), and GI toxicity (n = 2). The estimated probability of DLT for dose level 3 was .21 (90% posterior probability interval [PI], .12 to .33); for dose level 4, the estimated probability was .24 (90% PI, .14 to .36).ConclusionThe addition of oxaliplatin 85 mg/m2days 1 and 15 to full-dose gemcitabine and radiation therapy was well tolerated. On the basis of these results, a multi-institutional neoadjuvant phase II study in resectable pancreatic cancer is planned.

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]

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