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1.  A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies 
British Journal of Cancer  2013;108(4):762-765.
This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination.
Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria.
Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients.
Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.
PMCID: PMC3590658  PMID: 23322195
bortezomib; sunitinib; Phase 1; Bayesian; EWOC
2.  Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities 
Statistics in Medicine  2013;32(16):2728-2746.
The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.
PMCID: PMC3813987  PMID: 23335156
phase I; dose-finding design; continual reassessment method; quasi-continuous endpoint; multiple toxicity score; oncology; molecularly targeted agents; isotonic regression
3.  Model Calibration in the Continual Reassessment Method 
The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in dose finding clinical trials. A way to evaluate the sensitivity of a given CRM model including the functional form of the dose-toxicity curve, the prior distribution on the model parameter, and the initial guesses of toxicity probability at each dose is using indifference intervals. While the indifference interval technique provides a succinct summary of model sensitivity, there are infinitely many possible ways to specify the initial guesses of toxicity probability. In practice, these are generally specified by trial and error through extensive simulations.
By using indifference intervals, the initial guesses used in the CRM can be selected by specifying a range of acceptable toxicity probabilities in addition to the target probability of toxicity. An algorithm is proposed for obtaining the indifference interval that maximizes the average percentage of correct selection across a set of scenarios of true probabilities of toxicity and providing a systematic approach for selecting initial guesses in a much less time consuming manner than the trial and error method. The methods are compared in the context of two real CRM trials.
For both trials, the initial guesses selected by the proposed algorithm had similar operating characteristics as measured by percentage of correct selection, average absolute difference between the true probability of the dose selected and the target probability of toxicity, percentage treated at each dose and overall percentage of toxicity compared to the initial guesses used during the conduct of the trials which were obtained by trial and error through a time consuming calibration process. The average percentage of correct selection for the scenarios considered were 61.5% and 62.0% in the lymphoma trial, and 62.9% and 64.0% in the stroke trial for the trial and error method versus the proposed approach.
We only present detailed results for the empiric dose toxicity curve, although the proposed methods are applicable for other dose toxicity models such as the logistic.
The proposed method provides a fast and systematic approach for selecting initial guesses of probabilities of toxicity used in the CRM that are competitive to those obtained by trial and error through a time consuming process, thus, simplifying the model calibration process for the CRM.
PMCID: PMC2884971  PMID: 19528132
4.  Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline 
Current Oncology  2006;13(5):160-172.
In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?
What is the toxicity associated with the use of bortezomib?
Which patients are more or less likely to benefit from treatment with bortezomib?
Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback.
Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.
A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc.
The literature review found one randomized controlled trial (rct)—the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma.
The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation.
Practice Guideline
This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.
Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations:
For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.
Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.
For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent–based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent–based chemotherapy is recommended.
Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials.
Qualifying Statements
Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg.
For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes.
Bortezomib 1.3,g/m2 is given as a rapid intravenous bolus over 3–5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed.
Response to Treatment
Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone.
The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent–based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.
PMCID: PMC3394599  PMID: 22792013
Bortezomib; Velcade; multiple myeloma; lymphoma; clinical practice guideline; systematic review
5.  Toxicity burden score: a novel approach to summarize multiple toxic effects 
Annals of Oncology  2011;23(2):537-541.
Toxicity data from cancer trials are summarized into a single outcome, dose-limiting toxicity (DLT), which does not account for multiple lower grade toxic effects nor differentiates between toxicity types and gradations within DLT.
Toxicity data were summarized into a toxicity burden score (TBS) using a weighted sum. The severity weights were estimated via regression using historical data. We demonstrated the method using historical data from a bortezomib trial and illustrated the advantages of defining DLT based on TBS in a simulated dose-finding trial.
The estimated weights were 0.17, 0.40 and 0.85 for grade 1/2, grade 3 and grade 4 platelets, respectively; 0.19, 0.64, 1.03 and 2.53 for grade 1, 2, 3 and 4 neuropathy, respectively and 0.17 for each grade 3 or higher nonhematologic toxic effects unrelated to treatment. In the simulated trial, the probability of selecting doses above the maximum tolerated dose decreased when using the DLT defined based on TBS.
TBS is a feasible approach to summarize toxicity. It includes information from the grades and types of multiple toxic effects and can be applied in all phases of drug development. Further efforts should focus on validating the method in a large prospective study before applying it in practice.
PMCID: PMC3295018  PMID: 21536663
adverse event summary; dose-limiting toxicity; toxicity; toxicity types and grades
6.  Dose-finding design for multi-drug combinations 
Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose–toxicity curve.
Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori.
We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known.
We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design.
A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders.
The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials.
PMCID: PMC3485079  PMID: 21652689
7.  Incorporating lower grade toxicity information into dose finding designs 
Toxicity grades underlie the definition of a dose limiting toxicity (DLT) but in the majority of phase I designs, the information contained in the individual grades is not used. Some authors have argued that it may be more appropriate to consider a polytomous rather than dichotomous response.
We investigate whether the added information on individual grades can improve the operating characteristics of the Continual Reassessment Method (CRM).
We compare the original CRM design for a binary response with two stage CRM designs which make di erent use of lower-grade toxicity information via simulations. Specifically we study; a two-stage design that utilizes lower-grade toxicities in the first stage only, during the initial non model-based escalation, and two-stage designs where lower grades are used throughout the trial via explicit models. We postulate a model relating the rates of lower grade toxicities to the rate of DLTs, or assume the relative rates of low to high grade toxicities is unknown. The designs were compared in terms of accuracy, patient allocation and precision.
Significant gains can be achieved when using grades in the first stage of a two-stage design. Otherwise, only modest improvements are seen when the information on grades is exploited via the use of explicit models, where the parameters are known precisely. CRM with some use of grade information, increases the number of patients treated at the MTD by approximately 5%. The additional information from lower grades can lead to a small increase in the precision of our estimate of the MTD.
Our comparisons are not exhaustive and it would be worth studying other models and situations.
Although, the gains in performance were not as great as we had hoped, we observed no cases where the performance of CRM was poorer. Our recommendation is that investigators might consider using graded toxicities at the design stage.
PMCID: PMC3293181  PMID: 21835856
Dose-finding; Phase I; Toxicity Grades; Dose Limiting Toxicity
8.  The impact of non-drug-related toxicities on the estimation of the maximum tolerated dose in phase I trials 
The rate of observed dose-limiting toxicities (DLTs) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non-drug-related toxicities or other cause toxicities (OCTs) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using two trial designs—the “3+3” dose-escalation scheme and the Continual Reassessment Method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (Type A error) and when an OCT is misclassified as a DLT (Type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% Type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared to 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time in order to increase the accuracy of 3+3, otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared to the 3+3 since it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials.
PMCID: PMC3463734  PMID: 22825582
9.  Using the time-to-event continual reassessment method in the presence of partial orders 
Statistics in medicine  2012;32(1):131-141.
The time-to-event continual reassessment method (TITE-CRM) was proposed to handle the problem of long trial duration in Phase 1 trials as a result of late-onset toxicities. Here, we implement the TITE-CRM in dose–finding trials of combinations of agents. When studying multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. Therefore, the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. A CRM design for partially ordered trials (PO-CRM) was recently proposed. Simulation studies show that extending the TITE-CRM to the partial order setting produces results similar to those of the PO-CRM in terms of maximum tolerated dose recommendation yet reduces the duration of the trial.
PMCID: PMC3521068  PMID: 22806898
continual reassessment method; dose finding; Phase 1 trials; drug combination; partial order; time-to-event
10.  Concurrent whole brain radiotherapy and bortezomib for brain metastasis 
Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.
A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.
Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).
Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.
PMCID: PMC3765365  PMID: 23965287
Radiation; Brain; Melanoma; Bortezomib; Phase I; TITE-CRM; Diffusion tensor imaging; MRI
11.  Bayesian hybrid dose-finding design in phase I oncology clinical trials 
Statistics in Medicine  2011;30(17):2098-2108.
In oncology, dose escalation is often carried out to search for the maximum tolerated dose (MTD) in phase I clinical trials. We propose a Bayesian hybrid dose-finding method that inherits the robustness of model-free methods and the efficiency of model-based methods. In the Bayesian hypothesis testing framework, we compute the Bayes factor and adaptively assign a dose to each cohort of patients based on the adequacy of the dose–toxicity information that has been collected thus far. If the data observed at the current treatment dose are adequately informative about the toxicity probability of this dose (e.g. whether this dose is below or above the MTD), we make the decision of dose assignment (e.g. either to escalate or to de-escalate the dose) directly without assuming a parametric dose–toxicity curve. If the observed data at the current dose are not sufficient to deliver such a definitive decision, we resort to a parametric dose–toxicity curve, such as that of the continual reassessment method (CRM), in order to borrow strength across all the doses under study to guide dose assignment. We examine the properties of the hybrid design through extensive simulation studies, and also compare the new method with the CRM and the ‘3+3’ design. The simulation results show that our design is more robust than parametric model-based methods and more efficient than nonparametric model-free methods.
PMCID: PMC3286188  PMID: 21365672
model-free; model-based; Bayes factor; hypothesis testing; robust
12.  Continual Reassessment Method for Partial Ordering 
Biometrics  2011;67(4):1555-1563.
Much of the statistical methodology underlying the experimental design of Phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose-toxicity curve. This is a reasonable assumption for single agent trials in which the administration of greater doses of the agent can be expected to produce dose-limiting toxicities (DLTs) in increasing proportions of patients. When studying multiple agents, the assumption may not hold since the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two-dimensional dose-finding method for multiple-agent trials that simplifies to the continual reassessment method (CRM), introduced by O’Quigley, Pepe, and Fisher (1990), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose-toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders.
PMCID: PMC3141101  PMID: 21361888
Clinical trial; Continual reassessment method; Dose escalation; Dose finding studies; Maximum tolerated dose; Phase 1 trials; Partial ordering; Toxicity; Drug combination
13.  Sample size formulae for the Bayesian continual reassessment method 
Clinical trials (London, England)  2013;10(6):10.1177/1740774513497294.
In the planning of a dose finding study, a primary design objective is to maintain high accuracy in terms of the probability of selecting the maximum tolerated dose. While numerous dose finding methods have been proposed in the literature, concrete guidance on sample size determination is lacking.
With a motivation to provide quick and easy calculations during trial planning, we present closed form formulae for sample size determination associated with the use of the Bayesian continual reassessment method.
We examine the sampling distribution of a nonparametric optimal design, and exploit it as a proxy to empirically derive an accuracy index of the continual reassessment method using linear regression.
We apply the formulae to determine the sample size of a phase I trial of PTEN-long in pancreatic patients, and demonstrate that the formulae give very similar results to simulation. The formulae are implemented by an R function ‘getn’ in the package ‘dfcrm’.
The results are developed for the Bayesian continual reassessment method, and should be validated by simulation when used for other dose finding methods.
The analytical formulae we propose give quick and accurate approximation of the required sample size for the continual reassessment method. The approach used to derive the formulae can be applied to obtain sample size formulae for other dose finding methods.
PMCID: PMC3843987  PMID: 23965547
14.  Dose Escalation with Overdose Control using a Quasi-Continuous Toxicity Score in Cancer Phase I Clinical Trials 
Contemporary clinical trials  2012;33(5):949-958.
Escalation with overdose control (EWOC) is a Bayesian adaptive design for selecting dose levels in cancer Phase I clinical trials while controlling the posterior probability of exceeding the maximum tolerated dose (MTD). EWOC has been used by clinicians to design many cancer Phase I clinical trials, see e.g [1-4]. However, this design treats the toxicity response as a binary indicator of dose limiting toxicity (DLT) and does not account for the number and specific grades of toxicities experienced by patients during the trial. Chen et al. (2010) proposed a novel toxicity score system to fully utilize all toxicity information using a normalized equivalent toxicity score (NETS). In this paper, we propose to incorporate NETS into EWOC using a quasi-Bernoulli likelihood approach to design cancer Phase I clinical trials. We call the design escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS). Simulation results show that this design has good operating characteristics and improves the accuracy of MTD, trial efficiency, therapeutic effect, and overdose control relative to EWOC which is used as a representative of designs treating toxicity response as a binary indicator of DLT. We illustrate the performance of this design using real trial data in identifying the Phase II dose.
PMCID: PMC4046335  PMID: 22561391
Escalation with Overdose Control; Maximum Tolerated Dose; Multiple Toxicities; Quasi-continuous; Normalized Equivalent Toxicity Score; Toxicity Score System
15.  Calibration of prior variance in the Bayesian Continual Reassessment Method 
Statistics in medicine  2011;30(17):2081-2089.
The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in phase I clinical trials. Asymptotically, the method has been shown to select the correct dose given that certain conditions are satisfied. When sample size is small, specifying a reasonable model is important. While an algorithm has been proposed for the calibration of the initial guesses of the probabilities of toxicity, the calibration of the prior distribution of the parameter for the Bayesian CRM has not been addressed. In this paper, we introduce the concept of least informative prior variance for a normal prior distribution. We also propose two systematic approaches to jointly calibrate the prior variance and the initial guesses of the probability of toxicity at each dose. The proposed calibration approaches are compared with existing approaches in the context of two examples via simulations. The new approaches and the previously proposed methods yield very similar results since the latter used appropriate vague priors. However, the new approaches yield a smaller interval of toxicity probabilities in which a neighboring dose may be selected.
PMCID: PMC3129459  PMID: 21413054
Dose finding; indifference interval; least informative prior; phase I clinical trials
16.  Rationally designed treatment for solid tumors with MAPK pathway activation: a Phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach 
Molecular cancer therapeutics  2011;10(8):1509-1519.
In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A Phase I study was conducted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting MAPK pathway activation were treated with weekly paclitaxel and bortezomib. Starting doses were 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one Grade 3 event), fatigue (in 43.75% of patients, one Grade 3 event beyond cycle 1) and neuropathy (in 31.25% of patients, one Grade 3 event after cycle 1). Of 15 evaluable patients, one NSCLC patient with paclitaxel exposure at the adjuvant setting had a PR and five patients had SD; median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.
PMCID: PMC3155243  PMID: 21680752
MAPK; paclitaxel; bortezomib; BIM; apoptosis
17.  A phase I/II study of bortezomib plus CHOP every 2 weeks (CHOP-14) in patients with advanced-stage diffuse large B-cell lymphomas 
Bortezomib targets molecular dysregulation of nuclear factor-κB activation and cell cycle control, which are characteristic features of diffuse large B-cell lymphoma (DLBCL). We evaluated the safety and efficacy of bortezomib treatment with dose-dense cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) every 2 weeks (CHOP-14).
Untreated DLBCL patients were enrolled. A phase I dose-escalation study with 1.0, 1.3, and 1.6 mg/m2 bortezomib administration on day 1 and 4 in addition to the CHOP-14 regimen was performed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Lenograstim 5 µg/kg/d was administered on day 4-13. The bortezomib dose from the phase I study was used in the phase II study.
Nine and 37 patients were enrolled in the phase I and phase II studies, respectively. The analysis of the phase II results (40 patients) included data of the 3 patients in the last MTD dose cohort of the phase I trial. During the phase I trial, no DLT was observed at any bortezomib dose; therefore, the recommended dose was 1.6 mg/m2. In phase II, the overall response rate was 95% (complete response: 80%; partial response: 15%). Nine out of the 40 patients showed grade 3 sensory neuropathy, and 22 required at least 1 dose reduction. Three patients could not complete the intended 6 cycles of treatment because of severe neuropathy.
Bortezomib plus CHOP-14 was highly effective for the treatment of untreated DLBCL patients, but in many cases, dose or schedule modification was required to reduce neurotoxicity.
PMCID: PMC3317471  PMID: 22479278
Bortezomib; CHOP-14; Diffuse large B-cell lymphoma
18.  The Superiority of the Time-to-Event Continual Reassessment Method to the Rolling Six Design in Pediatric Oncology Phase I Trials 
The Rolling Six Design (RSD) is currently being used by the Children’s Oncology Group (COG) as their standard design for Phase I trials. Because the COG has large multi-center trials with fast accrual, the motivation for adopting the RSD is to hasten accrual and shorten the duration of their trials. However, trial suspension due to completion of follow-up still cannot be entirely avoided by the RSD. Therefore, a design that allows continuous enrollment of patients throughout the entire trial is needed.
To demonstrate the superior performance of the Time-to-Event Continual Reassessment Method (TITE-CRM) with continuous patient recruitment relative to the RSD, in terms of identifying the maximum tolerated dose (MTD) and reducing exposure of patients to toxic doses.
Using scenarios that were based on an actual pediatric Phase I trial at the University of Michigan, Monte Carlo simulations were used to investigate the operational characteristics of RSD and TITE-CRM.
The TITE-CRM treated all available patients, identified the MTD more accurately than the RSD and did not increase the probability of exposing patients to toxic doses.
Both the TITE-CRM and RSD assume that the probability of dose limiting toxicity increases with higher dose level.
The TITE-CRM, which allows for continual enrollment of patients, provides a safe design for pediatric oncology Phase I trials with better accuracy than the RSD.
PMCID: PMC4281887  PMID: 21610004
19.  Phase 1 Study of Sorafenib in Combination with Bortezomib in Patients with Advanced Malignancies 
Investigational new drugs  2013;31(5):1201-1206.
Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models.
This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles.
Fourteen patients (7 males, median age 65, range 24–74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m2, establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease.
The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m2 on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.
PMCID: PMC3779429  PMID: 23887852
Phase 1 trial; Sorafenib; Bortezomib
20.  Practical modifications to the Time-to-Event Continual Reassessment Method for phase I cancer trials with fast patient accrual and late-onset toxicities 
Statistics in medicine  2011;30(17):2130-2143.
The goal of phase I cancer trials is to determine the highest dose of a treatment regimen with an acceptable toxicity rate. Traditional designs for phase I trials, such as the Continual Reassessment Method (CRM) and the 3+3 design, require each patient or a cohort of patients to be fully evaluated for the dose-limiting toxicity (DLT) before new patients can be enrolled. As such, the trial duration may be prohibitively long. The Time-to-Event Continual Reassessment Method (TITE-CRM, Cheung and Chappell, 2000) circumvents this limitation by allowing staggered patient accrual without the need for complete DLT follow-up of previously treated patients. However, in the setting of fast patient accrual and late-onset toxicities, the TITE-CRM results in overly aggressive dose escalation and exposes a considerable number of patients to toxic doses. We examine a modification to the TITE-CRM proposed by the original TITE-CRM creator and propose an alternative approach useful in this setting by incorporating an accrual suspension rule. A simulation study designed based on a neuro-oncology trial indicates that the modified methods provide a much improved degree of safety than the TITE-CRM while maintaining desirable design accuracy. The practical aspects of the proposed designs are discussed. The modifications presented are useful when planning phase I trials involving chemoradiation therapy.
PMCID: PMC3904348  PMID: 21590790
phase I clinical trials; time-to-event continual reassessment method; dose finding; late-onset toxicity; adaptive design; Bayesian inference
21.  Monitoring late-onset toxicities in phase I trials using predicted risks 
Biostatistics (Oxford, England)  2007;9(3):442-457.
Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average.
PMCID: PMC3294317  PMID: 18084008
Adaptive design; Bayesian inference; Dose finding; Isotonic regression; Latent variables; Markov chain Monte Carlo; Ordinal modeling; Predictive probability
22.  A Simulation Based Comparison of the Traditional Method, Rolling-6 Design and a Frequentist Version of the Continual Reassessment Method with Special Attention to Trial Duration in Pediatric Phase I Oncology Trials 
Contemporary clinical trials  2010;31(3):259-270.
The Traditional Method (TM), also known as the 3+3 up-and-down design, and the Continual Reassessment Method (CRM) are commonly used in Phase I Oncology Trials to identify the maximum tolerated dose (MTD). The Rolling-6 is a relative newcomer which was developed to shorten trial duration by minimizing the period of time during which the trial is closed to accrual for toxicity assessment. In this manuscript we have compared the performance of these three approaches via simulations not only with respect to the usual parameters such as overall toxicity, sample size and percentage of patients treated at doses above the MTD but also in terms of trial duration and the dose chosen as the MTD. Our results indicate that the toxicity rates are comparable across the three designs, but the TM and the Rolling-6 tend to treat a higher percentage of patients at doses below the MTD. With respect to trial duration, Rolling-6 leads to shorter trials compared to the TM but not compared to the CRM. Additionally, the doses identified as the MTD by the TM and the Rolling-6 differ in a large percentage of trials. Our results also indicate that the body surface area-based dosing used in pediatric trials can make a difference in dose escalation/de-escalation patterns in the CRM compared to the cases where such variations are not taken into account in the calculations, even leading to different MTDs in some cases.
PMCID: PMC2863035  PMID: 20298812
Body Surface Area Based Dosing; Pediatric Trials; Dose Finding; Maximum Tolerated Dose
23.  A Phase I and Pharmacologic Study of the Combination of Bortezomib and Pegylated Liposomal Doxorubicin in Patients with Refractory Solid Tumors 
Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We therefore conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.
Patients received bortezomib, 0.9-1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.
A total of 37 patients with 4 median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1/6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1/6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.
A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
PMCID: PMC4312589  PMID: 18327587
phase I; proteasome inhibition; bortezomib; pegylated liposomal doxorubicin; breast cancer
24.  A Phase I Study of Weekly Everolimus (RAD001) in Combination with Docetaxel in Patients with Metastatic Breast Cancer 
Cancer  2011;118(9):2378-2384.
Inhibition of mTOR with everolimus may result improve efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.
Patients and Methods
15 patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m2 IV on day 1 of a 21 day cycle) in combination with everolimus (doses ranging from 20-50 mg po on days 1 and 8 of a 21 day cycle) in a phase I trial using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). The first two patients developed DLT (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.
15 patients were treated. Dose limiting toxicity included grade 3 mucositis (n=1), prolonged grade 4 neutropenia (n=1), and grade 3 infection/febrile neutropenia (n=3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40mg/m2. Eleven patients underwent complete PK evaluation for everolimus and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs and the study was terminated due to lack of efficacy and concerns regarding toxicity seen with the combination.
Weekly everolimus in combination with Q 3-week docetaxel was associated with excessive neutropenia and variable clearance of both drugs making combination therapy unpredictable, even at low doses of both drugs.
PMCID: PMC3893000  PMID: 22006179
Phase I; everolimus; docetaxel
25.  Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018 
Journal of Clinical Oncology  2010;29(3):324-329.
A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics.
Patients and Methods
Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m2/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21).
Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m2/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m2/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied.
Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m2/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.
PMCID: PMC3056466  PMID: 21149652

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