Showing papers by "Walter M. Stadler published in 2002"

Randomized Discontinuation Design: Application to Cytostatic Antineoplastic Agents

Abstract: PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients. METHODS: In the setting of renal cell carcinoma, some patients’ tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors. RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential ...

Allogeneic Stem-Cell Transplantation of Renal Cell Cancer After Nonmyeloablative Chemotherapy: Feasibility, Engraftment, and Clinical Results

Abstract: PURPOSE: To evaluate the feasibility and safety of nonmyeloablative allogeneic stem-cell transplantation in patients with metastatic renal cell cancer (RCC) and to evaluate efficacy with respect to engraftment and tumor regression. PATIENTS AND METHODS: Between February 1999 and June 2001, patients with refractory, metastatic RCC were screened for enrollment. A fludarabine and cyclophosphamide–based conditioning regimen was used. Patients received granulocyte-macrophage colony-stimulating factor–mobilized, unmanipulated stem cells from a 6/6 HLA-matched sibling donor. Prophylaxis against graft rejection and graft-versus-host disease (GVHD) included tacrolimus and mycophenolate mofetil. RESULTS: A total of 284 patients with metastatic RCC were seen during this time period. Eighty-four patients who had siblings available for HLA typing were actively screened for enrollment, and 15 patients have undergone treatment. Durable donor engraftment was achieved in one of the first four patients treated. Patients no...

Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer.

Abstract: Purpose: To assess long-term survival and prognostic indicators of survival in patients with advanced urothelial cancer treated with gemcitabine and cisplatin. Materials and methods: Survival data from three previously published phase II trials of gemcitabine/cisplatin were updated. Baseline hemoglobin, performance status, and presence of visceral metastases, which are known prognostic factors with other regimens, were examined. Survival curves were constructed by the Kaplan-Meier method and significance assessed using the log-rank statistic. Cox's Proportional Hazards Model was used to construct univariate and multivariate survival models. Results and conclusions: Overall median survival of 121 included patients was 13.2 (11.0 to 14.9) months and estimated 4 year survival was 13 ± 6%. In a univariate analysis, the presence of visceral metastases and a hemoglobin <12.5 mg/dl had significant adverse prognostic implications (P<0.001 and P=0.02, respectively). Performance status was not a significant predictor of survival, perhaps due to the fact that only 14% of patients had a performance status of 2. In a multivariate analysis, only the absence of visceral metastases retained its prognostic importance with an estimated 24% 4-year survival in such patients. These results lend further evidence for the clinical benefit of this regimen in advanced transitional cell cancer.

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480

Abstract: PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m2, respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P = .49). The objective response rate was 9%, 7%, and 15%, respectively (P = .10). PSA response rates were 24%, 28%, and 34%, respectively (P = .082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival....

Flt-3 ligand and sequential FL/interleukin-2 in patients with metastatic renal carcinoma: clinical and biologic activity.

Abstract: Flt3 (fms-like tyrosine kinase 3) ligand, a cytokine that stimulates increases in the number of dendritic cells (DC) in vivo, has been shown to have antitumor activity in murine models via an immune-mediated mechanism. Therefore, we examined the clinical activity of this cytokine in patients with an immunologic-responsive cancer, metastatic renal cell carcinoma. Flt3 ligand (25 μg/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle. Although the treatment was well tolerated and was confirmed to induce expansion of lineage (Lin) - /HLA-DR + /CD11c + myeloid DC and Lin - /HLA-DR + /CD123 + plasmacytoid DC, no clinical activity was observed. Reasoning that DC expanded by Flt3 ligand might potentiate the clinical activity of low-dose interleukin-2, a second study was conducted of sequential administration of 25 μg/kg of Flt3 ligand daily for 7 days was followed by 11 x 10 6 IU of subcutaneous interleukin-2 for 4 consecutive days x 4 weeks. In this study, increased numbers of circulating DC were again observed, which was followed by increased numbers of activated T cells, confirming a biologic effect of each cytokine. However, toxicity and clinical efficacy were similar to what has been seen with low-dose interleukin-2 alone, with two minor responses observed. These results demonstrate that Flt3 ligand, although capable of inducing expansion of circulating myeloid and plasmacytoid DC in patients with metastatic renal cell carcinoma, lacks significant clinical activity at the doses and schedules examined.

A phase II trial of oral temozolomide in patients with metastatic renal cell cancer.

Abstract: Purpose. To determine the activity of temozolomide, an oral imidazotetrazine alkylating agent that has exhibited broad antitumor activity in preclinical studies, in renal cell cancer (RCC) patients. Methods. Metastatic RCC patients were treated with temozolomide, 200 mg/m2 per day orally, and traditional radiologic response endpoints were assessed. O6-Alkylguanine-DNA alkyltransferase (AGT) activity was measured in four pretreatment biopsies. Results. Among 12 patients, there were no responses. High AGT activity was observed in all four biopsies analyzed. Conclusions. Temozolomide is not active against RCC and this clinical observation may be due to high levels of AGT in this tumor.

New trial designs to assess antitumor and antiproliferative agents in prostate cancer.

Abstract: The discovery of multiple putative therapeutic targets and multiple putative agents for these targets in prostate cancer in the coming years poses significant challenges for clinical trial design. This is especially true for cytostatic agents that are not expected to lead to frank tumor shrinkage or declines in the PSA. The most promising agents will need to be identified early in their development. Since surrogate biologic markers are likely to play a critical role, the identification and validation of these markers is discussed. A number of non-traditional phase I and phase II clinical trial designs, including pre-operative dosing for assessing drug effect on a marker and the randomized discontinuation phase II design, are also discussed in detail. Use of such designs as well as surrogate marker validation will likely be required to efficiently choose appropriate agents for definitive study in the phase III setting.