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

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.

A Bayesian dose-finding design for outcomes evaluated with uncertainty

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.

A phase I trial of chemoimmunotherapy combining bacillus Calmette-Guerin (BCG) and intravesical gemcitabine for patients with BCG-relapsing high-grade nonmuscle-invasive bladder cancer.

TPS509 Background: Intravesical BCG is the most effective treatment for high-grade non-muscle invasive bladder cancer (NMIBC), yet recurrences are common. Patients with BCG-relapsing NMIBC are often re-treated with BCG or BCG with interferon (IFN) with an expected response rate of only 40–60%. Several studies show that a major mechanism of resistance to BCG is high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the pretreatment tumor microenvironment. Gemcitabine is a commonly used intravesical treatment for NMIBC that, in addition to direct anti-tumor cytotoxic effects, may also reduce MDSCs and Tregs. Prior trials combining BCG with intravesical mitomycin C have shown improved efficacy over BCG alone but with higher toxicity. While gemcitabine has been shown to be better tolerated than mitomycin as an intravesical treatment, no study has looked at combined BCG and intravesical gemcitabine. We hypothesize that combining BCG and intravesical gemcitabine will be well tolerated and result in higher response rates by reducing levels of MDSCs and Tregs. A novel aspect of our trial design is the use of a modified continual reassessment method to more accurately identify the maximum tolerated dose instead of the traditional 3 + 3 design used in most NMIBC phase I trials. Methods: This is an investigator-initiated phase I trial (NCT04179162) that will study the safety of alternating intravesical gemcitabine and BCG. Inclusion and exclusion criteria are designed so most patients who would ordinarily be re-treated with BCG or BCG/IFN would be eligible. Patients must have recurrent high-grade NMIBC within 24 months of their last BCG treatment without meeting the criteria for BCG-unresponsive NMIBC. Intravesical gemcitabine is given twice a week on weeks 1, 4, 7, and 10, for a total of 8 doses. BCG (50 mg) is given once a week on weeks 2, 3, 5, 6, 8, and 9, for a total of 6 doses. The trial is monitored using a modified continual reassessment method with increasing dose levels of gemcitabine (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) being evaluated. Adverse events are assessed using the Common Terminology Criteria for Adverse Events version 5.0. The primary objective is to determine the maximum tolerated dose of this combination to inform our planned phase II trial. Correlative studies will look at the immunomodulating effects of gemcitabine by evaluating changes in immune cell populations in serial blood and urine specimens. Tissue and urine will also be evaluated for molecular determinants of response and resistance to the combination. The trial is open to enrollment with 10 of 25 planned patients accrued to date. Clinical trial information: NCT04179162.

Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies

Background The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various “true” dose-toxicity relationships. Methods One thousand studies were simulated for each “true” dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%. Results For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method. The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship. Conclusion Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.

Determination of the ED95 of intrathecal hyperbaric prilocaine with sufentanil for scheduled cesarean delivery: a dose-finding study based on the continual reassessment method

Background Scheduled cesarean section is routinely performed under spinal anesthesia using hyperbaric bupivacaine. The current study was undertaken to determine the clinically relevant 95% effective dose of intrathecal 2% hyperbaric prilocaine co-administered with sufentanil for scheduled cesarean section, using continual reassessment method. Methods We conducted a dose-response, prospective, double-blinded study to determine the ED95 values of intrathecal hyperbaric prilocaine used with 2,5 mcg of sufentanil and 100 mcg of morphine for cesarean delivery. Each parturient enrolled in the study received an intrathecal dose of hyperbaric prilocaine determined by the CRM and the success or failure of the block was assessed as being the primary endpoint. Results The doses given for each cohort varied from 35 to 50 mg of HP, according to the CRM, with a final ED95 lying between 45 and 50 mg of Prilocaine after completion of the 10 cohorts. Few side effects were reported and patients were globally satisfied. Conclusions The ED95 of intrathecal hyperbaric prilocaine with sufentanil 2.5 μg and morphine 100 μg for elective cesarean delivery was found to be between 45 and 50 mg. It may be an interesting alternative to other long-lasting local anesthetics in this context. Trial registration The study was registered on January 30, 2017 – retrospectively registered – and results posted at the public database clinicaltrials.gov (NCT03036384).

Determination of the ED95 of intrathecal hyperbaric prilocaine with sufentanil for scheduled cesarean delivery: A dose-finding study based on the continual reassessment method

Background – Scheduled cesarean section is routinely performed under spinal anesthesia using hyperbaric bupivacaine. The current study was undertaken to determine the clinically relevant 95% effective dose of intrathecal 2% hyperbaric prilocaine co-administered with sufentanil for scheduled cesarean section, using continual reassessment method.Methods – We conducted a dose-response, prospective, double-blinded study to determine the ED95 values of intrathecal hyperbaric prilocaine used with 2,5 mcg of sufentanil and 100 mcg of morphine for cesarean delivery. Each parturient enrolled in the study received an intrathecal dose of hyperbaric prilocaine determined by the CRM and the success or failure of the block was assessed as being the primary endpoint.Results – The doses given for each cohort varied from 35 to 50 mg of HP, according to the CRM, with a final ED95 lying between 45 and 50 mg of Prilocaine after completion of the 10 cohorts. Few side effects were reported and patients were globally satisfied.Conclusions – The ED95 of intrathecal hyperbaric prilocaine with sufentanil 2.5 μg and morphine 100 μg for elective cesarean delivery was found to be between 45 and 50 mg. It may be an interesting alternative to other long-lasting local anesthetics in this context.Trial registration – The study was registered on January 30, 2017 – retrospectively registered – and results posted at the public database clinicaltrials.gov (NCT03036384 – https://clinicaltrials.gov/ct2/show/NCT03036384).