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.

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.

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.

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.

The role of systemic chemotherapy in the treatment of kidney cancer.

Traditional cytotoxic chemotherapy has been considered to be ineffective in renal cell carcinoma, likely due to multiple mechanisms of high-level drug resistance proteins such as p-glycoprotein expressed by these cancers. Nonetheless, low level activity of several nucleoside analogues and the elucidation of critical molecular pathways and targets in this disease, such as the angiogenic pathway, provide hope that important advances can and will be made.

Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma.

Expression profiling has demonstrated that transcriptomes of primary malignancies differ from those in normal tissue. It is unknown, however, whether there exist "surrogate" transcriptional markers in peripheral blood mononuclear cells (PBMCs) of patients with solid tumors. We identified transcripts expressed differentially between PBMCs from renal cell carcinoma patients and normal subjects, some of which appear to reflect specific immune responses of circulating cells.

Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer.

Purpose: Combination gemcitabine and 5-fluorouracil (5-FU) may have activity in metastatic renal cell cancer. To identify patient subgroups most likely to benefit and compare survival to that in previously described patient series long-term survival as a function of known and suspected prognostic variables was determined.

Materials And Methods: The survival status of 153 patients with metastatic renal cell cancer treated on 1 phase I and 4 phase II trials of gemcitabine/5-FU based regimens was updated.

Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663.

Purpose: The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation.

Angiogenesis inhibitors in genitourinary cancers.

Despite much enthusiasm, no clear clinical benefit to any antiangiogenic agent has yet been demonstrated. Phase I trials demonstrate that endostatin, an endothelial cell toxin, can be administered safely, but no obvious anti-tumor effects were observed. Certain matrix metalloproteinase inhibitors appear ineffective, but later generation inhibitors with less systemic toxicity continue to be investigated.

Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck.

Purpose: The epidermal growth factor receptor (EGFR) is a mediator of squamous cell carcinoma of the head and neck (SCCHN) development. ZD1839 is an orally active, selective EGFR tyrosine kinase inhibitor. This phase II study sought to explore the activity, toxicity, and pharmacodynamics of ZD1839 in SCCHN.

Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site.

Purpose: The prevention and treatment of prostate cancer metastasis continue to provide a significant clinical challenge. Identification of the rate limiting steps of metastasis and their underlying molecular mechanisms may lead to new therapeutic targets and also allow more accurate risk stratification for clinical metastases. We review the literature supporting growth of disseminated tumor cells at the secondary site as a key rate limiting step in metastasis.

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

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.

Randomized discontinuation design: application to cytostatic antineoplastic agents.

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.

A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.

Background: The objective of this study was to determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) and daily oral thalidomide in patients with metastatic renal cell carcinoma (RCC).

Methods: Between June, 2000 and January, 2001, 21 patients with metastatic RCC were enrolled onto this multi-institutional Phase II study of gemcitabine at 600 mg/m(2) per day on Days 1, 8, and 15; 5-FU at 150 mg/m(2) per day by continuous IV infusion through a permanent catheter on Days 1-21; and oral thalidomide on Days 1-28 starting at a dose of 200 mg daily. After the first 2 weeks of therapy, the thalidomide dose was escalated by 100 mg per day every week to a maximum dose of 400 mg per day unless it was precluded by toxicity.

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.

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.

A phase II trial of intravenous gemcitabine and 5-fluorouracil with subcutaneous interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma.

Background: The objective of this study was to determine the response rate and toxicity of gemcitabine and continuous-infusion 5-fluorouracil (5-FU) in combination with subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in patients with metastatic renal cell carcinoma.

Methods: Forty-one patients were treated with gemcitabine 600 mg/m2 on Days 1, 8, and 15 and continuous-infusion 5-FU on Days 1-21. The dose of 5-FU was 200 mg/m2 per day for the initial 8 patients but was reduced to 150 mg/m2 per day for all remaining patients due to toxicity.

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

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.

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

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 microg/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle.

Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results.

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.

Gemcitabine doublets in advanced urothelial cancer.

Gemcitabine was identified as an active agent in the treatment of urothelial cancer early in its clinical development. A gemcitabine/cisplatin regimen has been shown to lead to comparable survival in a phase III comparison to methotrexate/vinblastine/doxorubicin/cisplatin in the metastatic setting with less toxicity. Nonetheless, cisplatin-related toxicity is not inconsequential.