scholarly journals A comparison of phase I dose-finding designs in clinical trials with monotonicity assumption violation

2020 ◽  
Vol 17 (5) ◽  
pp. 522-534
Author(s):  
Rachid Abbas ◽  
Caroline Rossoni ◽  
Thomas Jaki ◽  
Xavier Paoletti ◽  
Pavel Mozgunov
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Partial Ordering ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Optimal Interval ◽  
Correct Dose ◽  
Monotonicity Assumption ◽  
Continual Reassessment ◽  
Dose Levels

Background/Aims In oncology, new combined treatments make it difficult to order dose levels according to monotonically increasing toxicity. New flexible dose-finding designs that take into account uncertainty in dose levels ordering were compared with classical designs through simulations in the setting of the monotonicity assumption violation. We give recommendations for the choice of dose-finding design. Methods Motivated by a clinical trial for patients with high-risk neuroblastoma, we considered designs that require a monotonicity assumption, the Bayesian Continual Reassessment Method, the modified Toxicity Probability Interval, the Bayesian Optimal Interval design, and designs that relax monotonicity assumption, the Bayesian Partial Ordering Continual Reassessment Method and the No Monotonicity Assumption design. We considered 15 scenarios including monotonic and non-monotonic dose–toxicity relationships among six dose levels. Results The No Monotonicity Assumption and Partial Ordering Continual Reassessment Method designs were robust to the violation of the monotonicity assumption. Under non-monotonic scenarios, the No Monotonicity Assumption design selected the correct dose level more often than alternative methods on average. Under the majority of monotonic scenarios, the Partial Ordering Continual Reassessment Method selected the correct dose level more often than the No Monotonicity Assumption design. Other designs were impacted by the violation of the monotonicity assumption with a proportion of correct selections below 20% in most scenarios. Under monotonic scenarios, the highest proportions of correct selections were achieved using the Continual Reassessment Method and the Bayesian Optimal Interval design (between 52.8% and 73.1%). The costs of relaxing the monotonicity assumption by the No Monotonicity Assumption design and Partial Ordering Continual Reassessment Method were decreases in the proportions of correct selections under monotonic scenarios ranging from 5.3% to 20.7% and from 1.4% to 16.1%, respectively, compared with the best performing design and were higher proportions of patients allocated to toxic dose levels during the trial. Conclusions Innovative oncology treatments may no longer follow monotonic dose levels ordering which makes standard phase I methods fail. In such a setting, appropriate designs, as the No Monotonicity Assumption or Partial Ordering Continual Reassessment Method designs, should be used to safely determine recommended for phase II dose.

scholarly journals Would the Recommended Dose Have Been Different Using Novel Dose-Finding Designs? Comparing Dose-Finding Designs in Published Trials

2021 ◽  
pp. 1024-1034
Author(s):  
Rebecca B. Silva ◽  
Christina Yap ◽  
Richard Carvajal ◽  
Shing M. Lee
Keyword(s):  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Simulation Studies ◽  
Toxicity Data ◽  
Continual Reassessment Method ◽  
Optimal Interval ◽  
Patient Allocation ◽  
Continual Reassessment ◽  
Continuous Use ◽  
Dose Levels

PURPOSE Simulation studies have shown that novel designs such as the continual reassessment method and the Bayesian optimal interval (BOIN) design outperform the 3 + 3 design by recommending the maximum tolerated dose (MTD) more often, using less patients, and allotting more patients to the MTD. However, it is not clear whether these novel designs would have yielded different results in the context of real-world dose-finding trials. This is a commonly mentioned reason for the continuous use of 3 + 3 designs for oncology trials, with investigators considering simulation studies not sufficiently convincing to warrant the additional design complexity of novel designs. METHODS We randomly sampled 60 published dose-finding trials to obtain 22 that used the 3 + 3 design, identified an MTD, published toxicity data, and had more than two dose levels. We compared the published MTD with the estimated MTD using the continual reassessment method and BOIN using target toxicity rates of 25% and 30% and toxicity data from the trial. Moreover, we compared patient allocation and sample size assuming that these novel designs had been implemented. RESULTS Model-based designs chose dose levels higher than the published MTD in about 40% of the trials, with estimated and observed toxicity rates closer to the target toxicity rates of 25% and 30%. They also assigned less patients to suboptimal doses and permitted faster dose escalation. CONCLUSION This study using published dose-finding trials shows that novel designs would recommend different MTDs and confirms the advantages of these designs compared with the 3 + 3 design, which were demonstrated by simulation studies.

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.

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.

A phase I dose-finding study of everolimus in combination with capecitabine and oxaliplatin (XELOX) as the first-line chemotherapy for patients with advanced gastric cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 86-86
Author(s):  
Inkeun Park ◽  
Min-Hee Ryu ◽  
Baek-Yeol Ryoo ◽  
Myoung Joo Kang ◽  
Changsuk Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Dose Level ◽  
Dose Intensity ◽  
Dose Finding ◽  
Good Tolerability ◽  
Level 1 ◽  
Dose Levels ◽  
Line Chemotherapy

86 Background: The purpose of this phase I study is to determine the recommended dose (RD) of everolimus (E), an mTOR inhibitor, in combination with capecitabine (XEL) and oxaliplatin (OX) and to explore feasibility of EXELOX at the RD in advanced gastric cancer (AGC). Methods: The standard 3+3 method was used to determine the RD of 3-weekly EXELOX during the first cycle. The doses of each drug [E (mg/day, D1-D21)/XEL (mg/m2/day, D1-D14)/OX (mg/m2, D1)] were as follows: level 1, 7.5/1600/100; level 2A, 7.5/1,600/130; level 2B, 7.5/2,000/100; level 3A, 10/1,600/130; level 3B, 10/2,000/100; level 4, 7.5/2,000/130. Results: During the first cycle of chemotherapy, no dose limiting toxicity (DLT) was noted in each cohort of 3 patients (pts) at dose levels 1-3A. At dose level 3B, 1 DLT (delay of the next cycle over 3 weeks because of Gr2 thrombocytopenia and Gr2 AST) was observed out of 6 pts. At dose level 4, DLTs (Gr3 fatigue and Gr4 thrombocytopenia) were found in 2 out of 3 pts. However, with frequent dose delay or reduction in subsequent cycles, the actual dose intensity of XELOX during the first 3 cycles was not higher at dose levels 2 or 3 than at dose level 1. Accordingly, dose level 1 was finally considered more suitable to maintain the actual dose intensity over chemotherapy cycles. At dose level 1, with no DLT during the first 3 cycles in 3 more pts accrued to confirm the safety, 12 additional pts were enrolled in the extension cohort to explore feasibility of EXELOX in the aspect of efficacy. Among 16 patients with measurable disease at dose level 1, 8 (50%) pts achieved a confirmed PR, 7 (44%) had SD, and 1 (6%) showed PD as a best response. With a median follow-up period of 12 months (range 4.9–12.8 months), the median progression-free survival and overall survival were 5.5 and 8.1 months, respectively at dose level 1. Conclusions: In this study, the doses of XEL (1,600 mg/m2/day), OX (100 mg/m2), and E (7.5 mg/day) were recommended with good tolerability for the 3 weekly EXELOX combination as the 1st line chemotherapy for AGC. The efficacy of this combination needs to be evaluated in future trials. Clinical trial information: NCT01049620.

Phase I/II trial of bortezimib and pemetrexed in patients with advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18145-18145 ◽  
Author(s):  
R. B. Natale ◽  
M. McKinley ◽  
J. Hilger ◽  
T. Myers
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Mantle Cell ◽  
Finding Study ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Previously Treated Patients ◽  
Grade 3 ◽  
Dose Levels

18145 Background: Bortezomib (Vc) is a novel proteosome inhibitor with activity in several malignancies including multiple myeloma, mantle cell lymphoma, and NSCLC. In NSCLC, Vc has additive activity combined with carboplatin and gemcitabine in first line and with docetaxel in second line treatment. Pemetrexed (P) is active in NSCLC and preclinical data suggests a pro-apoptotic synergy between Vc and P. Therefore, we initiated a phase I/II dose finding study of Vc + P in previously-treated patients (pts) with advanced or metastatic NSCLC. Methods: Fifteen pts have been accrued to 3 of 4 planned dose levels of Vc + P. Starting doses (and # pts treated) were Vc 1.4 mg/m2 day 1 & 8 + P 400 mg/m2 day 1 every 3 weeks (3 pts). The 2nd and 3rd dose levels were Vc 1.6 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (8 pts, 5 new + 3 from dose level 1) and Vc 1.8 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (7 pts). Results: 15 pts are evaluable for response and toxicity and include 8 males, 7 females, median age 67 (range, 55–82), PS 0/1 (3/12 pts), median of 2 prior therapies (range 1–3). Confirmed PRs occurred in 2 pts (13%) and stable disease in 5 (33%). Dose limiting toxicities consisted of grade 4 fatigue (1 pt) and neutropenia/fever (1 pt) at dose level 2, and grade 3 abdominal pain and fatigue (1 pt) and grade 3 diarrhea and vomiting (1 pt) at dose level 3. Conclusions: The above combination is safe at the doses tested thus far and active in pts with heavily pretreated, advanced NSCLC. We are currently exploring Vc 2.0 mg.m2 Day 1 & 8 + P 500 mg/m2 day 1 every 3 weeks to determine the MTD and plan a multi-site Phase II study to determine response rate and survival in a larger pt population. No significant financial relationships to disclose.

Optimization of Fludarabine + Melphalan Conditioning for Marrow Transplantation From Unrelated Donors for Patients with Hematopoietic Malignancies: A Prospective Dose-Finding Trial Using Modified Continual Reassessment Method.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2273-2273
Author(s):  
Seitaro Terakura ◽  
Masashi Sawa ◽  
Haruhiko Ohashi ◽  
Tomonori Kato ◽  
Satoshi Nishiwaki ◽  
...  
Keyword(s):  
Phase I ◽  
Graft Failure ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Donor Chimerism ◽  
Continual Reassessment ◽  
Level 3 ◽  
Unrelated Donors ◽  
Level 1 ◽  
Level 2

Abstract Abstract 2273 Poster Board II-250 Background Development of reduced intensity conditioning (RIC) regimen has enabled older patients, who are not expected to tolerate the toxicity of myeloablative conditioning, to be treated with allogeneic HSCT. Because the risk of rejection after BMT is substantially higher than that of PBSCT in RIC transplantation, PBSC is commonly used for RIC transplantation. However, PBSCT from unrelated donors is not currently available in Japan. Therefore, a better dosage of conditioning to ensure engraftment in RIC with BM is needed. Here, we selected the fludarabine plus melphalan regimen which has sufficient potential to induce marrow engraftment if melphalan at 180mg/m2 is used, and planned further optimization of melphalan dosage. The rationale for modulating the dose of melphalan resulted from accumulated observations that melphalan is associated with toxicities, while fludarabine is not. Because the optimal dose of melphalan to minimize regimen-related toxicities and to enable sustained engraftment remains unknown to date, we investigated the recommended dose of melphalan in a phase I study. Patients and Methods To adjust the melphalan dose, we adopted a modified continual reassessment method (CRM) which has been hypothesized to allow a faster and more accurate dose reduction/escalation in patients needed to reach the recommended dose compared with classical algorithmic dose modification design. The conditioning regimen consisted of 125 mg/m2 intravenous fludarabine (day-6∼-2) in combination with the examination dose of intravenous melphalan (day-3, -2). Because the use of fludarabine at 125mg/m2 and melphalan at 180mg/m2 was known to induce reliable engraftment, we set the first dose level to receive 160mg/m2 of melphalan. The primary endpoint was an achievement of donor-type T-cell chimerism at day 28 with successful engraftment defined as 90% or more donor cells. Five patients were planned to be accrued for each dose level and chimerism data was used to determine the next dose. A maximum dose reduction of melphalan for the next level was limited to 30mg/m2 to avoid the potential risk of graft-failure. GVHD prophylaxis consisted of short term methotrexate and tacrolimus. The eligibility criteria were 1) patients with hematological malignancies, who have had more than 3 course of chemotherapy, 2) age, 55 to 65 years, or 40 to 54 years with substantial comorbidity (HCT-CI of 1 or more), 3) no prior stem cell transplantation. The protocol was approved by the Institutional Review Board of each institution. All patients and donors provided written informed consent. Results Seventeen patients were enrolled at doses between 130mg/m2 and 160mg/m2, including one protocol violation and one early death (brain hemorrhage). Both were unavailable for assessment according to the study definition in advance. Of the 15 evaluable patients (9 male, 6 female), the median age was 58 years old (range: 45-63), and their diagnosis were 10 AML, 2 NHL, 1 CML 1 ALL and 1 plasmacytoma. The dose was reduced from 160mg/m2 (level-1) to 130mg/m2 (level-2) after 5 consecutive full donor chimerism (all were 100% at day 28) were observed in level-1. In the level-2, we observed four patients with 100% chimera, and one with 0% chimera at day 28, which eventually resulted in graft-failure. Following the calculation by CRM from level-2, the examination dose was increased to 135mg/m2 (level-3). In the level-3, 5 consecutive full donor chimerism (four 100% and one 90.4%) were observed again. Because the next examination dose was calculated as within 5mg/m2 from the level-3 (135mg/m2), the study was complete as projected. We could not detect any significant difference among the dose levels in terms of toxicity, relapse rate or survival. Discussion Successful dose finding using modified CRM was accomplished. The strategy using engraftment as a primary endpoint instead of toxicity promotes a better chance to determine the optimal dosage compared with the classical phase I trial design with modified Fibonacci method. Our findings demonstrated the melphalan dose of 135mg/m2 in combination with fludarabine is able to induce initial full donor chimerism after unrelated donor BMT and is recommended for further phase II evaluation. Disclosures: No relevant conflicts of interest to declare.

Application of the Continual Reassessment Method to Dose-finding Studies in Regional Anesthesia

2013 ◽  
Vol 119 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Abhinav Kant ◽  
Pawan Kumar Gupta ◽  
Sarah Zohar ◽  
Sylvie Chevret ◽  
Philip M. Hopkins
Keyword(s):  
Prospective Trial ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Double Blind ◽  
Upper Limb Surgery ◽  
Continual Reassessment ◽  
Starting Dose ◽  
Statistical Program ◽  
Supraclavicular Block ◽  
Dose Levels

Abstract Background Previously reported estimates of the ED95 doses for local anesthetics used in brachial plexus blocks vary. The authors used the continual reassessment method, already established in oncology trials, to determine the ED95 dose for 0.5% bupivacaine for the ultrasound-guided supraclavicular block. Methods A double-blind, prospective trial was scheduled for 40 patients of American Society of Anesthesiologists class I–III presenting for upper limb surgery and supraclavicular block. The study dose to be administered was arbitrarily divided into six dose levels (12, 15, 18, 21, 24, and 27 ml) with a priori probabilities of success of 0.5, 0.75, 0.90, 0.95, 0.98, and 0.99 respectively. A continual reassessment method statistical program created a dose–response curve, which would shift direction depending on the success or failure of the block. Our starting dose was 21 ml and the next allocated dose was reestimated by the program to be the dose level with the updated posterior response probability closest to 0.95. Results After recruitment of eight patients, our initial dose levels and associated probabilities were deemed too low to determine the ED95. Updated a prioris were calculated from the statistical program, and the study recommenced with a new starting dose of 30 ml. On completion, the ED95 dose was estimated to be 27 ml (95% CI, 24–28 ml). Conclusions The continual reassessment method trial design provided a credible estimate for the ED95 dose for 0.5% bupivacaine for our technique of supraclavicular block and may be of value as a statistically robust method for dose-finding studies in anesthesiology.

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
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