Biomedical subjects

P F Thall

Publications and source records attributed to P F Thall.

At least 19 recordsLinked to original sources

PubMed2004

Comparison of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects.

We evaluated the 100-day mortality rates associated with busulfan-based myeloablative conditioning regimens based on data from 1812 chronic myelogenous leukemia patients who underwent allogeneic blood or marrow transplantation (allotx). In all, 47 patients received intravenous (i.v.) busulfan and cyclophosphamide (i.v.BuCy2) with allotx at MD Anderson Cancer Center (MDACC) during 1995-1999. The remaining 1765 patients, whose data were supplied by the International Bone Marrow Transplant Registry (IBMTR), received alternative preparative regimens, primarily Cy-total body irradiation ( approximately 45%) or oral BuCy ( approximately 35%) during 1997-1998. As patients were not randomized between conditioning regimens, the i.v.BuCy2-versus-alternative treatment effect is confounded with a possible center effect due to nontreatment differences associated with factors differing between MDACC and the IBMTR centers. Additional complications are that the i.v.BuCy2-MDACC patients all survived 100 days, and three prognostic subgroups were included. Bayesian sensitivity analyses were performed to assess treatment effect on the probability of 100-day mortality, over a range of possible MDACC-versus-IBMTR center effects. For these patients, the posterior probability that i.v.BuCy2 was superior to alternative conditioning regimens ranges from 0.54 to 0.99, depending on prognosis and the magnitude of the assumed center effect.

Adult↗

PubMed2001

Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts.

It has been unclear whether regimens containing topotecan + ara-C (TA) or fludarabine + ara-C (FA) +/- idarubicin are superior to regimens containing idarubicin + ara-C (IA) without either fludarabine or topotecan for treatment of newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or RAEB. Of 1279 patients treated here for these diagnoses between 1991 and 1999, 322 received IA regimens, 600 FA regimens, and 357 TA regimens. All regimens used ara-C doses of 1 to 2 gm/m(2)/d, given by continuous infusion in IA, and over 2 to 4 hours in FA and TA. Complete remission (CR) rates were lower with FA (55%) and TA (59%) than with IA (77%). Both event-free survival (EFS) in CR and survival were shorter: median EFS in CR (95% confidence interval) was 63 weeks (range, 55-76 weeks) for IA, 40 (range, 31-46 weeks) for FA, and 36 (range, 27-44 weeks) for TA; median survival was 77 weeks (range, 57-88 weeks) for IA, 30 (range, 27-35 weeks) for FA, and 41 (range, 35-50 weeks) for TA. These trials were not randomized, and patients with worse prognoses were disproportionately given the FA and TA regimens. Nonetheless, after accounting for prognosis the FA and TA regimens remained highly significantly associated with lower CR rates, shorter EFS in CR, and shorter survival. Accounting for possible effects of individual trials within each of the IA, FA, and TA groups did not alter these findings. It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments.

Anemia, Refractory, with Excess of Blasts↗

PubMed2001

Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Thalidomide has been shown to have antiangiogenic effects in preclinical models as well as a significant antitumor effect in hematologic tumors such as multiple myeloma. The authors performed this Phase II study to determine the activity, toxicity profile, and antiangiogenic effect of thalidomide in patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Twenty-one patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with single-agent thalidomide. All patients had received radiation therapy, and most had undergone surgery (95%) and/or chemotherapy (90%). Thalidomide was initiated at 200 mg;3>daily and increased to a target dose of 1000 mg daily. Patients continued treatment until disease progression, unacceptable toxicity, or death occurred. RESULTS: All 21 patients eventually developed progressive disease. Median time to progression was 50 days (95% confidence interval, 28-70), with median overall survival time of 194 days (95% lower confidence boundary, 151), similar to the progression and survival times reported for this patient group with other agents. Thalidomide was generally well tolerated, with few patients experiencing Grades 3 to 4 toxicities. Serum vascular endothelial growth factor and basic fibroblast growth factor levels increased in six of seven patients, for whom paired serum samples were available and all of whom had progressive disease. CONCLUSIONS: In this heavily pretreated population of patients with advanced squamous cell carcinoma of the head and neck, thalidomide does not appear to have single-agent antitumor activity. Further evaluation of the mechanism of action of thalidomide is indicated. Potentially, future evaluations of thalidomide may be performed in combination with other antiangiogenic or cytotoxic agents in patients with earlier stage disease or in patients with minimal residual disease.

Administration, Oral↗

PubMed2001

Optimal two-stage designs for clinical trials based on safety and efficacy.

In clinical trials designed to evaluate treatment efficacy, it is common practice to terminate a treatment arm in which the observed rate of an adverse event is unacceptably high. This practice may be formalized by a group-sequential test based on a multivariate outcome including both adverse and efficacy events. Recently, Thall and Cheng proposed a family of tests for randomized trials of an experimental treatment versus a standard where patient outcome is bivariate with entries characterizing efficacy and safety. The test is motivated by the idea that clinically meaningful improvements over the standard may be characterized by a two-dimensional parameter quantifying trade-offs between efficacy and safety. We provide optimal two-stage designs based on this test that minimize either the mean sample size under the null hypothesis of no treatment difference, or the maximum sample size if the trial continues to a second stage. A more general group-sequential version of the design also is described, an illustration is provided, and application to the special case of single-arm phase II trials is discussed.

Clinical Trials as Topic↗

PubMed2001

Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.

A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional myeloablative therapies because of age or comorbidity. Seventy-eight patients received fludarabine 25 mg/m(2) daily for 5 days in combination with melphalan 180 mg/m(2) (n = 66) or 140 mg/m(2) (n = 12). Eight patients received cladribine 12 mg/m(2) continuous infusion for 5 days with melphalan 180 mg/m(2). The median age was 52 years (range, 22-70 years). Disease status at transplantation was either first remission or first chronic phase in 7 patients, untreated first relapse or subsequent remission in 16 patients, and refractory leukemia or transformed chronic myelogenous leukemia in 63 patients. Nonrelapse mortality rates on day 100 were 37.4% for the fludarabine/melphalan combination and 87.5% for the cladribine/melphalan combination. The median percentage of donor cells at 1 month in 75 patients was 100% (range, 0%-100%). The probability of grade 2-4 and 3-4 acute graft-versus-host disease was 0.49 (95% CI, 0.38-0.60) and 0.29 (95% CI, 0.18-0.41), respectively. Disease-free survival at 1 year was 57% for patients in first remission or chronic phase and 49% for patients with untreated first relapse or in a second or later remission. On multivariate analysis the strongest predictor for disease-free survival was a good or intermediate risk category. In summary, fludarabine/melphalan combinations are feasible in older patients with associated comorbidities, and long-term disease control can be achieved with reduced-intensity conditioning in this population.

Acute Disease↗

PubMed2001

Dose-finding based on feasibility and toxicity in T-cell infusion trials.

A new modality for treatment of cancer involves the ex vivo growth of cancer-specific T-cells for subsequent infusion into the patient. The therapeutic aim is selective destruction of cancer cells by the activated infused cells. An important problem in the early phase of developing such a treatment is to determine a maximal tolerated dose (MTD) for use in a subsequent phase II clinical trial. Dose may be quantified by the number of cells infused per unit body weight, and determination of an MTD may be based on the probability of infusional toxicity as a function of dose. As in a phase I trial of a new chemotherapeutic agent, this may be done by treating successive cohorts of patients at different dose levels, with each new level chosen adaptively based on the toxicity data of the patients previously treated. Such a dose-finding strategy is inadequate in T-cell infusion trials because the number of cells grown ex vivo for a given patient may be insufficient for infusing the patient at the current targeted dose. To address this problem, we propose an algorithm for trial conduct that determines a feasible MTD based on the probabilities of both infusibility and toxicity as functions of dose. The method is illustrated by application to a dendritic cell activated lymphocyte infusion trial in the treatment of acute leukemia. A simulation study indicates that the proposed methodology is both safe and reliable.

Algorithms↗

PubMed2001

Decision-theoretic designs for pre-phase II screening trials in oncology.

A Bayesian decision-theoretic method is proposed for conducting small, randomized pre-phase II selection trials. The aim is to improve on the design of Thall and Estey (1993, Statistics in Medicine 12, 1197-1211). Designs are derived that optimize a gain function accounting for current and future patient gains, per-patient cost, and future treatment development cost. To reduce the computational burden associated with backward induction, myopic versions of the design that consider only one, two, or three future decisions at a time are also considered. The designs are compared in the context of a screening trial in acute myelogenous leukemia.

Bayes Theorem↗

PubMed2000

Evaluating multiple treatment courses in clinical trials.

In oncology, a patient's treatment often involves multiple courses of chemotherapy. The most common medical practice in choosing treatments for successive courses is to repeat a treatment that is successful in a given course and otherwise switch to a different treatment. Patient outcome thus consists of a sequence of dependent response variables and corresponding treatments. Despite the widespread use of such adaptive 'play-the-winner-and-drop-the-loser' algorithms in medical settings involving multiple treatment courses, most statistical methods for treatment evaluation characterize early patient outcome as a single response to a single treatment, resulting in a substantial loss of information. In this paper, we provide a statistical framework for multi-course clinical trials involving some variant of the play-the-winner-and-drop-the-loser strategy. The aim is to design and conduct the trial to more closely reflect actual clinical practice, and thus increase the amount of information per patient. The proposed design is similar to a multi-stage cross-over trial, with the essential difference that here all treatments after the first course are assigned adaptively. We illustrate the method by application to a randomized phase II trial for androgen independent prostate cancer. We consider the goals of selecting one best treatment, or selecting a best ordered pair of treatments with the second given if the first fails to achieve a patient success. A simulation study is reported, and extensions to trials involving toxicity or regimen-related death are discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB.

The authors examined the relationship between the time required to enter complete remission (CR) after a first course of chemotherapy for newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or refractory anemia with excess blasts (RAEB). They also examined subsequent survival time and disease-free survival time after accounting for cytogenetic status, age, and treatment. The data set consisted of 1101 patients with these diagnoses treated at the M. D. Anderson Cancer Center between 1980 and 1996 for whom outcomes were established after first-course therapy. Of the 1101 patients, 740 (67%) were in CR after this time; 508 of these 740 (69%) have died (80% had disease recurrence before death). The authors used the parametric model of Shen and Thall to estimate, in particular, T(C) (time to CR), T(C,D) (time from CR to death = residual survival after CR), and T(C,R) (residual disease-free survival [DFS] after CR) as functions of the covariates noted above and to estimate the dependence of T(C,D) and T(C,R) on T(C). There was a strong inverse association between T(C) and both T(C,D) and T(C,R) (P <.001 for both) that was independent of cytogenetic status, age, or treatment. The residual survival time of patients who required >50 days to enter CR was closer to the residual survival time of resistant patients than to that of patients known to be in CR within approximately 30 days of the start of treatment. Time to CR is an independent predictor of residual survival and disease-free survival in patients with newly diagnosed AML who achieve CR after 1 course of chemotherapy. (Blood. 2000;95:72-77)

Age Factors↗

PubMed2000

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

BACKGROUND: This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. METHODS: In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. RESULTS: The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. CONCLUSIONS: The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

Adult↗

PubMed2000

Approximate Bayesian evaluation of multiple treatment effects.

We propose an approximate Bayesian method for comparing an experimental treatment to a control based on a randomized clinical trial with multivariate patient outcomes. Overall treatment effect is characterized by a vector of parameters corresponding to effects on the individual patient outcomes. We partition the parameter space into four sets where, respectively, the experimental treatment is superior to the control, the control is superior to the experimental, the two treatments are equivalent, and the treatment effects are discordant. We compute posterior probabilities of the parameter sets by treating an estimator of the parameter vector like a random variable in the Bayesian paradigm. The approximation may be used in any setting where a consistent, asymptotically normal estimator of the parameter vector is available. The method is illustrated by application to a breast cancer data set consisting of multiple time-to-event outcomes with covariates and to count data arising from a cross-classification of response, infection, and treatment in an acute leukemia trial.

Antineoplastic Agents↗

PubMed1999

A phase I trial of intravenous melphalan, paclitaxel, and cisplatin plus granulocyte-colony stimulating factor in patients with suboptimal advanced epithelial ovarian carcinoma or peritoneal carcinoma.

BACKGROUND: The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma. METHODS: Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase I study. In the first stage of the study, the doses of paclitaxel and cisplatin were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of intravenous melphalan was escalated in consecutive cohorts of 3-6 patients depending on toxicity. The planned dose escalation levels of melphalan were 6 mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225 mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS: Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS: The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted.

Adult↗

PubMed1999

Accrual strategies for phase I trials with delayed patient outcome.

Phase I dose-finding trials typically are conducted using adaptive rules that select dose levels for successive patient cohorts based on the outcomes of patients treated previously in the trial. When patient outcome cannot be observed immediately after treatment, the problem arises of how to deal with new patients while waiting to observe the current patient cohort's outcomes. We consider two alternative approaches to this problem in the context of a phase I trial conducted using the continual reassessment method. With the first approach, a patient requiring treatment before the next cohort opens is treated off protocol with standard therapy, and otherwise waits until the next cohort opens. The second approach treats each patient immediately upon arrival at the dose recommended based on currently available data. We compare these two approaches by simulation under varying dose--toxicity curves, accrual rates, cohort sizes and early stopping rules. We evaluate patient waiting time, trial duration, number of patients treated off protocol and the probabilities of toxicity and of selecting the correct dose. We also study three strategies for assigning patients to trials when two or more phase I trials may be ongoing simultaneously. Based on our results, we provide practical guidelines for deciding among these approaches and strategies in a given clinical setting.

Antineoplastic Agents↗

PubMed1999

Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.

Preclinical data suggest that retinoids, eg, all-trans retinoic acid (ATRA), lower concentrations of antiapoptotic proteins such as bcl-2, possibly thereby improving the outcome of anti-acute myeloid leukemia (AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has been considered to be potentially synergistic with ATRA in this regard. Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RAEB-t, 62 patients) to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required one of the following: age over 71 years, a history of abnormal blood counts before M.D. Anderson (MDA) presentation, secondary AML/MDS, failure to respond to one prior course of chemotherapy given outside MDA, or abnormal renal or hepatic function. For the two treatment arms containing ATRA, ATRA was given 2 days (day-2) before beginning and continued for 3 days after completion of FAI. For the two treatment arms including G-CSF, G-CSF began on day-1 and continued until neutrophil recovery. Patients with white blood cell (WBC) counts >50,000/microL began ATRA on day 1 and G-CSF on day 2. Events (death, failure to achieve complete remission [CR], or relapse from CR) have occurred in 77% of the 215 patients. Reflecting the poor prognosis of the patients entered, the CR rate was only 51%, median event-free survival (EFS) time once in CR was 36 weeks, and median survival time was 28 weeks. A Cox regression analysis indicated that, after accounting for patient prognostic variables, none of the three adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with FAI. Similarly, there were no significant effects of either ATRA ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a diagnosis of RAEB or RAEB-t rather than AML was insignificant. There were no indications that the effect of ATRA differed according to cytogenetic group, diagnosis (AML or MDS), or treatment schedule. Logistic regression analysis indicated that, after accounting for prognosis, addition of G-CSF +/- ATRA to FAI improved CR rate versus either FAI or FAI + ATRA, but G-CSF had no effect on the other outcomes. We conclude that addition of ATRA +/- G-CSF to FAI had no effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly diagnosed AML or high-risk MDS.

Acute Disease↗

PubMed1999

A new statistical method for dose-finding based on efficacy and toxicity in early phase clinical trials.

Most statistical methods for dose-finding in phase I clinical trials determine a maximum tolerable dose based on toxicity while ignoring efficacy. Most phase II designs assume that an acceptable dose has been determined and aim to estimate treatment efficacy, possibly with early stopping rules for safety monitoring. The purpose of this paper is to describe a new statistical strategy for dose-finding in single-arm clinical trials where patient outcome is characterized in terms of both response and toxicity. The strategy, which may be considered a phase I/II hybrid, was first proposed by Thall and Russell [1] and subsequently modified by Thall [2]. The underlying mathematical model expresses the probabilities of response and toxicity as interdependent functions of dose. The method is based on fixed standards for the minimum probability of response and the maximum probability of toxicity appropriate for the particular trial. The best acceptable dose is chosen for each successive patient cohort adaptively, based on the fixed standards and the dose-outcome data from patients treated previously in the trial. The scientific goals are to select one best acceptable dose for future patients and to estimate the response and toxicity probabilities at that dose, or to stop the trial early if it becomes sufficiently unlikely that any dose is both safe and efficacious. An application of the method to a trial of donor lymphocyte infusion as salvage therapy for chemo-refractory AML/MDS patients is described. To illustrate the method's flexibility and potential breadth of application, two additional examples are provided, including a hypothetical trial in which a 5% response rate is of interest.

Clinical Trials as Topic↗

PubMed1999

Treatment of newly diagnosed AML, RAEB-t or RAEB with lisofylline or placebo in addition to chemotherapy.

To determine whether the addition of lisofylline (LSF) to idarubicin (12 mg/m2 daily x 3) + ara-C (1.5 g/m2 daily x 4) affects the rates of infection, serious infection, CR or mortality during remission induction of newly diagnosed AML, RAEB-t or RAEB, we randomized 70 patients to 3 mg/kg lisofylline or placebo every 6 h i.v., to begin 6 h before the first dose of idarubicin and to continue until recovery of neutrophil and platelet counts or for 28 days, whichever came first. Eligibility required that patients be below age 71 years, have no history of abnormal counts, or chemotherapy for a prior malignancy, and have a creatinine <1.6 mg/dl and bilirubin <3.0 mg/dl. The study was double-blinded and infections were tabulated separately and independently at MD Anderson and by a three-member outside panel of experts. Logistic regression was used to assess the relative effects of treatment arm (LSF or placebo), age, performance status, treatment site (laminar air flow room or not), and cytogenetics on rates of infection and serious infection following the first course of chemotherapy, and on CR rate. There were 84% and 87% concordance between the expert panel and MD Anderson enumerations of infection and serious infections, respectively. Both analyses found no significant (P < 0.05) differences between the rates of infection, or serious infection, in the placebo and LSF groups. CR, 60-day, and overall mortality rates were similar in the two groups, as were time to neutrophil and blood count recovery and outcome once in CR. Logistic regression analyses supported the above conclusions. Severe nausea/vomiting and mucositis were more frequent in the LSF group. Our results suggest that larger studies of LSF in newly diagnosed AML, RAEB-t, or RAEB are not warranted.

Acute Disease↗

PubMed1999

Treatment comparisons based on two-dimensional safety and efficacy alternatives in oncology trials.

In addition to their desired anticancer effects, most cancer treatments may also cause transient toxicity, permanent organ damage, or death. A critical question in comparing an experimental treatment to a standard is how much increase in an adverse event rate is an acceptable trade-off for achieving a targeted improvement in efficacy, or vice versa. We consider settings where one may characterize patient outcome as a bivariate (efficacy, safety) variable and quantify treatment effect as a corresponding two-dimensional parameter. A set of target parameters, each representing a clinically meaningful improvement over the standard, are elicited from the physician. Each target is a two-dimensional generalization of the usual one-dimensional shift parameter. We define the alternative hypothesis in the two-dimensional effect space as the convex hull of the sets of parameters that are at least as desirable as each target point. The rejection region is obtained by shifting the alternative toward (0,0) to achieve a given type I error, with sample size computed to achieve a given power at the targets. The method is illustrated by application to two cancer chemotherapy trials.

Antineoplastic Agents, Alkylating↗

PubMed1999

Decision theoretic designs for phase II clinical trials with multiple outcomes.

In many phase II clinical trials, it is essential to assess both efficacy and safety. Although several phase II designs that accommodate multiple outcomes have been proposed recently, none are derived using decision theory. This paper describes a Bayesian decision theoretic strategy for constructing phase II designs based on both efficacy and adverse events. The gain function includes utilities assigned to patient outcomes, a reward for declaring the new treatment promising, and costs associated with the conduct of the phase II trial and future phase III testing. A method for eliciting gain function parameters from medical collaborators and for evaluating the design's frequentist operating characteristics is described. The strategy is illustrated by application to a clinical trial of peripheral blood stem cell transplantation for multiple myeloma.

Bayes Theorem↗