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Biomedical subjects

Walter M Stadler

Publications and source records attributed to Walter M Stadler.

At least 37 records · Page 2Linked to original sources
PubMed2005

Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma--CALGB 69901.

PURPOSE: To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design. PATIENTS AND METHODS: Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups. RESULTS: A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted. CONCLUSION: CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents.

Adult↗
PubMed2005

Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma.

PURPOSE: Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations. EXPERIMENTAL DESIGN: In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes. RESULTS: Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively. CONCLUSIONS: The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.

Adolescent↗
PubMed2005

Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668.

PURPOSE: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. RESULTS: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. CONCLUSIONS: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Adult↗
PubMed2005

Novel kinase inhibitors in renal cell carcinoma: progressive development of static agents.

The rapidly expanding knowledge regarding neoplastic diseases is providing a plethora of new targets for drug discovery and development as exemplified by recent data in renal cell carcinoma. The initial experience with molecularly "targeted" agents has demonstrated that development of the newer non-cytotoxic agents will provide unique challenges requiring modification of many traditional drug development concepts and methods. We discuss recently reported data from a few renal cell carcinoma trials with putative cytostatic agents and highlight issues that need to be addressed for efficient development of cytostatic agents during various phases of clinical development.

Angiogenesis Inhibitors↗
PubMed2005

A phase II trial of sequential chemotherapy with docetaxel and methotrexate followed by gemcitabine and cisplatin for metastatic urothelial cancer.

Administration of noncross-resistant agents in a sequential fashion may improve outcome by targeting tumor cells with different sensitivity profiles. We evaluated the toxicity and response rate of docetaxel and methotrexate (DM) followed by gemcitabine and cisplatin (GC) in patients with metastatic or unresectable transitional cell carcinoma of the urothelium. Patients received 3 cycles of DM (40 mg/m2 methotrexate on days 1 and 8 and 100 mg/m2 docetaxel on day 8 repeated every 21 days) followed by GC (1000 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 cisplatin on day 1 repeated every 21 days). The most common toxicities were hematologic, with grade 3/4 neutropenia and thrombocytopenia observed in 4 and 2 patients, respectively. Four partial responses were observed after DM (4 of 12, 33% response rate) and 6 responses (3 partial response, 3 complete response, 6 of 9, 67% response rate) after GC for an overall response rate of 7 of 13 (54%). Three patients who progressed on DM responded to GC and 3 responders to DM achieved further response to GC. The median overall survival was 13.6 months. Although we do not recommend this particular sequence of chemotherapy for further study, the uncompromised median survival and the ability to salvage responses with GC suggest that testing of novel agents in sequence with GC is a feasible strategy.

Adult↗
PubMed2005

A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer.

OBJECTIVE: To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulphone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clinical studies suggested activity against prostate cancer and synergy with cytotoxic agents. PATIENTS AND METHODS: Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and intravenous docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m2. Toxicity was then evaluated using standard criteria. RESULTS: The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m2, with escalation to 75 mg/m2 after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycaemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months. CONCLUSION: The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.

Administration, Oral↗
PubMed2005

A phase II study of nilutamide in men with prostate cancer after the failure of flutamide or bicalutamide therapy.

OBJECTIVE: To determine the prostate-specific antigen (PSA) response and time to PSA or radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. PATIENTS AND METHODS: Men with histologically confirmed prostate cancer not amenable to curative surgery or radiation therapy were eligible for the study if they had radiographic or PSA progression on at least one antiandrogen (not nilutamide) despite continued androgen suppression and standard antiandrogen withdrawal periods. All men received nilutamide 150 mg/day orally for > or = 8 weeks unless there was unacceptable toxicity or disease progression. All men were evaluated for response, safety and toxicity. Baseline PSA levels, chest X-ray, bone scan and abdominopelvic computed tomography studies were obtained; the re-evaluation included PSA levels every 4 weeks and repeated imaging every 8 weeks in those with baseline abnormalities. The chest X-ray was repeated if there were pulmonary symptoms. Nineteen men were consented and 16 were evaluable for response. RESULTS: The median (range) Gleason score was 7 (6-9) and the median number of previous second-line therapies was 2 (1-4). Bicalutamide therapy had failed in all patients. At baseline, 13 (of 16 men) had radiographically evident disease, nine with diffuse osseous and four with radiographically measurable metastases. There was no grade 3/4 toxicity; the commonest grade 1/2 toxicities were constipation (three), sensory neuropathy (four), fatigue (six), and visual changes (two) involving transiently altered colour vision and sensitivity to light, respectively. Responses included three partial and 13 with progressive disease. CONCLUSIONS: The study was discontinued after a planned interim analysis because nilutamide had no apparent activity. Although well tolerated, nilutamide offers benefit to few men with prostate cancer in whom bicalutamide has failed.

Adult↗
PubMed2004

Therapeutic options for variant renal cancer: a true orphan disease.

Variant or nonclear cell renal cell cancer is a rare disease constituting only approximately 5% to 8% of the metastatic renal cell cancer population. Pathological criteria for the three main variant subtypes, papillary, chromophobe, and collecting duct, have been specified. Nonetheless, there may be subtypes within these variants, many poorly differentiated tumors cannot be reliably classified, and expertise in recognizing specific subtypes is not widespread. Expression analysis and other molecular techniques are beginning to clarify and standardize the pathological classification scheme. Because these classifications are relatively new and the number of patients with any one subtype is limited, little is known about appropriate therapies for patients with metastatic disease. Retrospective series strongly suggest that immunotherapy is not effective in any nonclear cell subtype. Case reports suggest that cytotoxic chemotherapy used for transitional cell cancers may be helpful in patients with collecting duct cancers. A central registry of patients with variant renal cell cancer should be created in which response to various therapies is recorded. Such a registry could provide support for a more formal multi-institutional study investigating a specific drug or regimen.

Carcinoma, Renal Cell↗
PubMed2004

Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.

PURPOSE: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion. EXPERIMENTAL DESIGN: Patients with documented progressive disease and </=1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m(2)) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H(2) blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF. RESULTS: Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008). CONCLUSIONS: SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.

Adult↗
PubMed2004

A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer.

PURPOSE: To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer. PATIENTS AND METHODS: Thirty-six chemotherapy naïve patients were randomized to treatment with SU5416 (145 mg/m(2)) and dexamethasone premedication or dexamethasone alone. Patients in the control arm could cross over to experimental therapy after progression. Prostate-specific antigen (PSA) was measured every 2 weeks, and radiological evaluation was performed every 8 weeks. In vitro assessment of SU5416 on PSA secretion was assessed in the LNCaP cell line. Baseline serum basic fibroblast growth factor and plasma vascular endothelial growth factor (VEGF) were explored as prognostic factors. RESULTS: VEGF receptor-2 expression is detectable in prostate cancer cell lines, and SU5416 inhibited in vitro PSA secretion. No effect of SU5416 on PSA secretion or time to progression is detectable in patients. VEGF and basic fibroblast growth factor were not prognostic. Headache and fatigue were the most common SU5416 toxicities, but hyperglycemia, hyponatremia, lymphopenia, infection, and adrenal suppression, all attributable to steroids and the required central line, were common. CONCLUSION: No disease modifying effects of SU5416 were detectable in this small study. Modest toxicity, an inconvenient administration schedule, and availability of other VEGFR-targeted agents support the decision to halt further evaluation of SU5416 in prostate cancer.

Aged↗
PubMed2004

Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).

PURPOSE: Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of > or =50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. PATIENTS AND METHODS: AiPCa patients were randomized to undergo AAWD alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone (30 mg p.o. each morning, 10 mg p.o. each evening; n=128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. RESULTS: Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P=.0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P=.02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. CONCLUSION: K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

Adenocarcinoma↗
PubMed2004

Gene expression profiling of renal medullary carcinoma: potential clinical relevance.

BACKGROUND: Renal medullary carcinoma is a rare kidney tumor with highly aggressive behavior. This tumor occurs exclusively in young patients with sickle cell trait or disease. To the authors' knowledge, very little is known to date regarding the underlying molecular genetics of this tumor, and no effective therapy has been established. METHODS: The authors analyzed the gene expression profiles of 2 renal medullary carcinomas from patients with sickle cell trait using microarrays containing 21,632 cyclic DNA (cDNA) clones and compared them with the gene expression profiles of 64 renal tumors. RESULTS: Based on global gene clustering with 3583 selected cDNAs, the authors found a distinct molecular signature of renal medullary carcinoma, which clustered closely with urothelial (transitional cell) carcinoma of the renal pelvis, rather than renal cell carcinoma (RCC). This finding of a significant difference in the gene expression patterns of renal medullary carcinoma compared with RCC suggests that this tumor should not be treated as a conventional RCC but, rather, as a special malignancy. This study also identified genes/proteins that may serve as biomarkers for renal medullary carcinoma or as potential targets of novel therapies. In addition, comparative genomic microarray analysis allowed the authors to predict the lack of chromosomal imbalances in this tumor. CONCLUSIONS: To the authors' knowledge, the current study is the first molecular profiling of renal medullary carcinoma, a rare but highly aggressive kidney carcinoma. The genes that are expressed specifically in this tumor may lead to not only a better understanding of its molecular pathways and discoveries of novel diagnostic markers but also, more important, to effective therapeutic interventions.

Adult↗
PubMed2004

Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.

PURPOSE: To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics. RESULTS: CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar. CONCLUSION: In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

Aged↗
PubMed2004

A Phase II trial of suramin monthly x 3 for hormone-refractory prostate carcinoma.

BACKGROUND: The goal of the current study was to determine the prostate-specific antigen (PSA) and objective response rates and the pharmacokinetics associated with a monthly x 3 one-hour infusion of suramin in 58 patients with hormone-refractory prostate carcinoma. METHODS: A PSA response was defined as a > 50% reduction in the PSA level from baseline for at least 3 consecutive evaluations over a minimum of 6 weeks. The suramin dose was 2400 mg/m(2) taken intravenously on Day 1, 1620 mg/m(2) on Day 29, and 1292 mg/m(2) on Day 57. All patients received 0.5 mg dexamethasone twice daily. RESULTS: Among 56 evaluable patients (median entry PSA level, 229.5 ng/mL), there were 21 PSA responders (37.5%). Among 27 patients with measurable disease, there were 5 responders (4 partial and 1 complete). The median overall survival time was 15.3 months. Grade III fatigue (14.1%) was the predominant toxicity observed. Suramin plasma levels remained high even 3 months after treatment was discontinued. Among the 12 evaluable patients who previously had received chemotherapy, the PSA response rate was 42%; one response was observed among 4 patients with measurable disease, and the median survival was 12 months. CONCLUSIONS: Monthly bolus suramin was well tolerated, reduced PSA levels, and induced objective responses, even in patients who previously had received chemotherapy.

Adult↗
PubMed2004

Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study.

PURPOSE: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS: PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

Adult↗
PubMed2004

Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: Variability and changes in tumor tissue over time.

PURPOSE: To evaluate variability of a simplified method for measuring semiquantitative DCE-MRI parameters in patients with cancer and to explore effects of treatment with a putative anti-angiogenic compound. MATERIALS AND METHODS: A total of 19 patients enrolled on treatment trials with the putative anti-angiogenic agent SU5416 underwent contrast enhanced examinations, and 11 had a second examination eight weeks post therapy. Contrast media concentration as a function of time was calculated using changes in signal and literature baseline T(1) values in normal muscle or liver reference tissue. Semiquantitative DCE-MRI parameters, including the area under the contrast concentration vs. time curve (AUC), were calculated for regions-of-interest in normal liver and muscle, and in tumors. RESULTS: The coefficients of variation for pretherapy parameters in normal tissue were 11% to 37%. No significant changes were detected in normal liver over two months of therapy. In tumors and muscle, a significant decrease in the AUC and maximum contrast concentration was observed. CONCLUSION: Variability of semiquantitative DCE-MRI parameters utilizing a method based on known T(1) values in a reference tissue is low enough to detect changes in tumors during therapy. Use of this method as a pharmacodynamic marker should be further investigated.

Angiogenesis Inhibitors↗