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Peter F Thall

Publications and source records attributed to Peter F Thall.

34 records · Page 2Linked to original sources
PubMed2003

Randomized, multicenter, phase II trial of two multicomponent regimens in androgen-independent prostate cancer.

PURPOSE: Several multicomponent regimens have been reported to be useful in advanced androgen-independent prostate cancer. We used a randomized phase II design to evaluate and compare two such regimens. Patients were accrued primarily in the community setting. PATIENTS AND METHODS: Patients with progressive, androgen-independent prostate cancer were randomly assigned to one of two treatments: either ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time. RESULTS: A total of 75 patients were registered; 71 are included in the analysis. By the criterion of an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months) for patients treated with KA/VE. Many patients (24%) failed to complete at least 6 weeks of therapy, including five (8%) treatment-related early deaths. CONCLUSION: Each of these regimens produced clinically significant responses, and the observed median survival (18.9 months for all 71 patients) compares favorably with previously published results, especially in the community setting. Nonetheless, it is apparent that these first-generation regimens must be applied judiciously, and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting.

Adenocarcinoma↗
PubMed2003

Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma.

BACKGROUND: In this Phase II study, the authors assessed the toxicity and anti-tumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa). METHODS: Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1-14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1-14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response. RESULTS: Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was two (range, one-seven cycles). Twenty-nine percent of the patients were found to have a > 50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal. CONCLUSIONS: CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity.

Adenocarcinoma↗
PubMed2003

New designs for phase 2 clinical trials.

Conventional phase 2 clinical trials are typically single-arm experiments, with outcome characterized by one binary "response" variable. Clinical investigators are poorly served by such conventional methodology. We contend that phase 2 trials are inherently comparative, with the results of the comparison determining whether to conduct a subsequent phase 3 trial. When different treatments are studied in separate single-arm trials, actual differences between response rates associated with the treatments, "treatment effects," are confounded with differences between the trials, "trial effects." Thus, it is impossible to estimate either effect separately. Consequently, when the results of separate single-arm trials of different treatments are compared, an apparent treatment difference may be due to a trial effect. Conversely, the apparent absence of a treatment effect may be due to an actual treatment effect being cancelled out by a trial effect. Because selection involves comparison, single-arm phase 2 trials thus fail to provide a reliable means for selecting which therapies to investigate in phase 3. Moreover, reducing complex clinical phenomena, including both adverse and desirable events, to a single outcome wastes important information. Consequently, conventional phase 2 designs are inefficient and unreliable. Given the limited number of patients available for phase 2 trials and the increasing number of new therapies that must be evaluated, it is critically important to conduct these trials efficiently. These concerns motivated the development of a general paradigm for randomized selection trials evaluating several therapies based on multiple outcomes. Three illustrative applications of trials using this approach are presented.

Acute Disease↗
PubMed2003

Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers.

OBJECTIVE: The objective of this study was to determine if the Src tyrosine kinase is overexpressed and activated in late-stage human ovarian cancers. METHODS: Western analysis and immune complex kinase assays were performed on a panel of human ovarian cancer cell lines and normal ovarian epithelial cell cultures, and immunohistochemical analysis for Src and activated Src were performed on a panel of late-stage human ovarian tumors. RESULTS AND CONCLUSIONS: Src is overexpressed and activated in a majority of late-stage ovarian tumors as well as in a panel of cultured malignant human ovarian epithelium grown in vitro, but not in normal ovarian epithelium (NOE) or immortalized NOE. Src overexpression was found to be frequently, but not always, associated with HER-2/neu overexpression, but no statistical association between Src and Her-2/neu overexpression could be demonstrated.

Enzyme Activation↗
PubMed2003

Ex vivo expansion of megakaryocyte precursors from umbilical cord blood CD34 cells in a closed liquid culture system.

Umbilical cord blood (UCB) provides a rich source of stem cells for transplantation after myeloablative therapy. One major disadvantage of UCB transplantation is delayed platelet engraftment. We propose to hasten platelet engraftment by expanding the number of megakaryocyte (MK) precursors (CD34/CD41 cells) through cytokine stimulation within a closed, pre-clinical liquid culture system. Clinical engraftment data suggest a 5- to 10-fold increase in MK precursors in a UCB unit can accelerate platelet engraftment, so this was our goal. Thirteen UCB samples from full-term births were Ficoll-separated and frozen for subsequent use. On thawing, the mononuclear cell population was positively selected for CD34(+) expression. The cells were cultured in gas-permeable Teflon-coated bags in serum-free medium containing the following cytokines: recombinant human interleukin-3, recombinant human Flt3 ligand, recombinant human stem cell factor, and recombinant human thrombopoietin. MK lineage cell expansion was assessed using mononuclear cell count and flow cytometry (CD34/41, CD41, CD34/61, and CD61 expression) on days 7, 11, and 14. Optimal expansion of CD34/41 and CD41 cells was observed at day 11, with a median 6-fold and 33-fold increase in the starting cell doses, respectively. CD34/61 and CD61 cell expansion at day 11 was 7-fold and 14-fold, respectively. MK precursors can be successfully expanded from CD34(+) UCB cells in a closed liquid culture system using interleukin-3, recombinant human Flt3 ligand, recombinant human stem cell factor, and recombinant human thrombopoietin to a level that should have a clinical impact in the transplantation setting. Our ex vivo expansion technique needs to be further optimized before it can be used in a pilot UCB transplantation trial.

Antigens, CD↗
PubMed2003

Dose-finding with two agents in Phase I oncology trials.

We propose an adaptive two-stage Bayesian design for finding one or more acceptable dose combinations of two cytotoxic agents used together in a Phase I clinical trial. The method requires that each of the two agents has been studied previously as a single agent, which is almost invariably the case in practice. A parametric model is assumed for the probability of toxicity as a function of the two doses. Informative priors for parameters characterizing the single-agent toxicity probability curves are either elicited from the physician(s) planning the trial or obtained from historical data, and vague priors are assumed for parameters characterizing two-agent interactions. A method for eliciting the single-agent parameter priors is described. The design is applied to a trial of gemcitabine and cyclophosphamide, and a simulation study is presented.

Algorithms↗
PubMed2002

A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma.

BACKGROUND: The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis. METHODS: In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity. RESULTS: Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments. CONCLUSIONS: Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials.

Administration, Oral↗
PubMed2002

Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate.

PURPOSE: To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa. PATIENTS AND METHODS: Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m(2) as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m(2)/d and cisplatin 25 mg/m(2)/d IV on days 2 to 4. RESULTS: Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival. CONCLUSION: SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.

Aged↗
PubMed2002

Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside.

We investigated treatment with gemtuzumab ozogamicin (GO) in 51 patients aged 65 years or older with newly diagnosed acute myeloid leukemia (AML), refectory anemia (RA) with excess of blasts in transformation, or RA with excess blasts. GO was given in doses of 9 mg/m(2) of body-surface area on days 1 and 8 or, therapeutically equivalently, on days 1 and 15, with or without interleukin 11 (IL-11; 15 microg/kg per day on days 3 to 28), with assignment to IL-11 treatment made randomly. Complete remission (CR) rates were 2 of 26 (8%) for GO without IL-11 and 9 of 25 (36%) for GO with IL-11. Regression analyses indicated that IL-11 was independently predictive of CR but not survival. We compared GO with or without IL-11 with idarubicin plus cytosine arabinoside (IA), as previously administered, in similar patients. The CR rate with IA was 15 of 31 (48%), and survival was superior with IA compared with GO with or without IL-11 (P =.03). Besides accounting for possible covariate effects on outcome, we also accounted for possible trial effects (TEs) arising because IA and GO with or without IL-11 were not arms of a randomized trial. Bayesian posterior probabilities that GO with or without IL-11 produced longer survival than IA, after accounting for covariates and TEs, were less than 0.01 in patients with abnormal cytogenetic findings (AC) and less than 0.15 in patients with normal cytogenetic findings (NC). Regarding CR, the analogous probabilities were less than 0.02 for GO without IL-11 (all cytogenetic groups), and for GO with IL-11, less than 0.25 for AC groups and about 0.50 for NC groups. TEs 2 to 5 times the magnitude of those previously observed would be needed to conclude that survival with GO with or without IL-11 is likely longer than with IA. Thus, there is little evidence to suggest that GO with or without IL-11 should be used instead of IA in older patients with newly diagnosed AML or myelodysplastic syndrome.

Acute Disease↗
PubMed2002

Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission.

Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.

Adult↗
PubMed2002

Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia.

Complete bioavailability of i.v. busulfan (Bu) provides dose assurance by reducing the interdose and interpatient variability in Bu systemic exposure (Bu-SE) associated with the oral formulation. We hypothesized that Bu-SE, represented by the area under the plasma concentration versus time curve (AUC), would correlate with treatment outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). Therefore, we analyzed the risk of death, incidence of regimen-related toxicity, and incidence of acute GVHD (aGVHD) as functions of the per dose i.v. Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the i.v. BuCy2 regimen. Per-dose Bu AUCs were calculated for each subject using data obtained for doses 1, 5, 9, and 13. Toxicity was evaluated using the modified National Cancer Institute criteria. Because no patient developed veno-occlusive disease, increased serum bilirubin was used to characterize hepatotoxicity. We found that the probabilities of developing gastrointestinal toxicity (P = .01), hepatotoxicity (P < .01), mucositis (P = .09), and aGVHD (P < .01) all increased with increasing AUC. Further, the risk of death was significantly lower for patients having a per-dose AUC between approximately 950 and 1520 microMol-min, whereas the risk increased sharply with either lower or higher AUC values. These data suggest that an optimal Bu therapeutic window, based on per-dose AUC, exists. Given the ability of i.v. Bu to provide a more consistent per-dose AUC, these results should be useful in designing future i.v.V Bu-based treatment protocols for stem cell transplantation.

Acute Disease↗
PubMed2002

Monitoring the rates of composite events with censored data in phase II clinical trials.

In many phase II clinical trials, interim monitoring is based on the probability of a binary event, response, defined in terms of one or more time-to-event variables within a time period of fixed length. Such outcome-adaptive methods may require repeated interim suspension of accrual in order to follow each patient for the time period required to evaluate response. This may increase trial duration, and eligible patients arriving during such delays either must wait for accrual to reopen or be treated outside the trial. Alternatively, monitoring may be done continuously by ignoring censored data each time the stopping rule is applied, which wastes information. We propose an adaptive Bayesian method that eliminates these problems. At each patient's accrual time, an approximate posterior for the response probability based on all of the event-time data is used to compute an early stopping criterion. Application to a leukemia trial with a composite event shows that the method can reduce trial duration substantially while maintaining the reliability of interim decisions.

Bayes Theorem↗
PubMed2002

Adaptive decision making in a lymphocyte infusion trial.

We describe an adaptive Bayesian design for a clinical trial of an experimental treatment for patients with hematologic malignancies who initially received an allogeneic bone marrow transplant but subsequently suffered a disease recurrence. Treatment consists of up to two courses of targeted immunotherapy followed by allogeneic donor lymphocyte infusion. The immunotherapy is a necessary precursor to the lymphocyte infusion, but it may cause severe liver toxicity and is certain to cause a low white blood cell count and low platelets. The primary scientific goal is to determine the infusion time that has the highest probability of treatment success, defined as the event that the patient does not suffer severe toxicity and is alive with recovered white blood cell count 50 days from the start of therapy. The method is based on a parametric model accounting for toxicity, time to white blood cell recovery, and survival time. The design includes an algorithm for between-patient immunotherapy dose de-escalation based on the toxicity data and an adaptive randomization among five possible infusion times according to their most recent posterior success probabilities. A simulation study shows that the design reliably selects the best infusion time while randomizing greater proportions of patients to superior infusion times.

Algorithms↗
PubMed2002

Seamlessly expanding a randomized phase II trial to phase III.

A sequential Bayesian phase II/III design is proposed for comparative clinical trials. The design is based on both survival time and discrete early events that may be related to survival and assumes a parametric mixture model. Phase II involves a small number of centers. Patients are randomized between treatments throughout, and sequential decisions are based on predictive probabilities of concluding superiority of the experimental treatment. Whether to stop early, continue, or shift into phase III is assessed repeatedly in phase II. Phase III begins when additional institutions are incorporated into the ongoing phase II trial. Simulation studies in the context of a non-small-cell lung cancer trial indicate that the proposed method maintains overall size and power while usually requiring substantially smaller sample size and shorter trial duration when compared with conventional group-sequential phase III designs.

Adenoviridae↗
PubMed2002

Ethical issues in oncology biostatistics.

A medical statistician's routine professional activities are likely to have important ethical consequences. This is due in part to the fact that good medical practice and scientifically valid medical research both require as precursors high quality statistical design and data analysis. In this paper I discuss various ethical issues that I have encountered while working as a biostatistician at M.D. Anderson Cancer Center. I describe particular experiences and the ethical issues involved. Topics include medical decision making, benefit-harm trade-offs, safety monitoring, adaptive randomization, informed consent, and publication bias.

Biometry↗