A phase 2, single-arm study of ramucirumab in patients with metastatic renal cell carcinoma with disease progression on or intolerance to tyrosine kinase inhibitor therapy.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) have antitumor activity in metastatic renal cell carcinoma (mRCC). Resistance to these agents develops frequently, and their use is often limited by intolerance. Ramucirumab is a recombinant human monoclonal antibody directed against human vascular endothelial growth factor receptor-2. For this study, the authors investigated the clinical efficacy and safety of ramucirumab in patients with TKI-resistant/intolerant mRCC. METHODS: In this single-arm phase 2 trial, patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity. The primary endpoint was the best objective response rate (ORR); additional endpoints included the disease control rate (DCR), progression-free survival (PFS), the median duration of overall response, and safety. RESULTS: Thirty-nine patients with RCC received ramucirumab monotherapy. Prior TKI therapy included sunitinib (59% of patients), sunitinib and sorafenib (30.8% of patients), and sorafenib (10.3% of patients). The ORR was 5.1% (95% confidence interval [CI], 0.6%-17.3%). The 12-week DCR was 64.1% (95% CI, 47.2%-78.8%). The median PFS was 7.1 months (95% CI, 4.1-9.7 months), and the median overall survival was 24.8 months (95% CI, 18.9-32.6 months). Grade 3 or higher adverse events that occurred in ≥5% of patients included grade 3 hypertension (7.7%) and proteinuria (5.1%). There was 1 on-study death from multiorgan failure. CONCLUSIONS: Although the study did not meet its primary endpoint of ≥15% ORR, ramucirumab was associated with evidence of antitumor activity in patients with TKI-resistant/intolerant mRCC. Ramucirumab was safe and well tolerated.

A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma.

BACKGROUND: Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 µg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles. RESULTS: Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 µg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥ 80 months, respectively. Partial responses were seen in both clear cell and papillary histology. CONCLUSION: This combination of 37.5 mg of temsirolimus with 20 µg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.

A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer.

PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥ 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer.

BACKGROUND: AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). PATIENTS AND METHODS: AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1. RESULTS: None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. CONCLUSIONS: AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Serum amino acid levels as a biomarker for renal cell carcinoma.

PURPOSE: Prognosis in renal cell carcinoma is dependent on tumor stage at presentation, with significant differences in survival between early and late stage disease. Currently to our knowledge no screening tests or biomarkers have been identified for the early detection of kidney cancer. Therefore, we investigated whether serum amino acid profiles are a potentially useful biomarker in patients with renal cell carcinoma. MATERIALS AND METHODS: The concentrations of 26 amino acids were determined in serum taken preoperatively from 189 patients with renal cell carcinoma, and from 104 age and sex matched controls. RESULTS: Statistically significant changes were observed in patient levels of 15 amino acids, with 13 being decreased and 2 being increased. A logistic regression model using 8 amino acids including cysteine, ornithine, histidine, leucine, tyrosine, proline, valine and lysine was created to distinguish cases from controls. A receiver operator curve based on this model had an area under the curve of 0.81. This same model also had predictive value in terms of overall survival and tumor recurrence in patients with renal cell carcinoma. CONCLUSIONS: Our findings suggest that serum amino acid levels may be useful as a screening tool for the identification of individuals with renal cell carcinoma and the prediction of outcomes.

Selecting targeted therapies for patients with renal cell carcinoma.

Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non-clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC.

NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy.

The outcome of patients with metastatic renal cell carcinoma has been substantially improved with administration of the currently available molecularly targeted therapies. However, proper selection of therapy and management of toxicities remain challenging. NCCN convened a multidisciplinary task force panel to address the clinical issues associated with these therapies in attempt to help practicing oncologists optimize patient outcomes. This report summarizes the background data presented at the task force meeting and the ensuing discussion.

Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma.

Karyotypic analysis and genomic copy number analysis with single nucleotide polymorphism (SNP)-based microarrays were compared with regard to the detection of recurrent genomic imbalances in 20 clear cell renal cell carcinomas (ccRCCs). Genomic imbalances were identified in 19 of 20 tumors by DNA copy number analysis and in 15 tumors by classical cytogenetics. A statistically significant correlation was observed between the number of genomic imbalances and tumor stage. The most common genomic imbalances were loss of 3p and gain of 5q. Other recurrent genomic imbalances seen in at least 15% of tumors included losses of 1p32.3-p33, 6q23.1-qter and 14q and gain of chromosome 7. The SNP-based arrays revealed losses of 3p in 16 of 20 tumors, with the highest frequency being at 3p21.31-p22.1 and 3p24.3-p25.3, the latter encompassing the VHL locus. One other tumor showed uniparental disomy of chromosome 3. Thus, altogether loss of 3p was identified in 17 of 20 (85%) cases. Fourteen tumors showed both overlapping losses of 3p and overlapping gains of 5q, and the karyotypic assessment performed in parallel revealed that these imbalances arose via unbalanced 3;5 translocations. Among the latter, there were common regions of loss at 3p21.3-pter and gain at 5q34-qter. These data suggest that DNA copy number analysis will supplant karyotypic analysis of tumor types such as ccRCC that are characterized by recurrent genomic imbalances, rather than balanced rearrangements. These findings also suggest that the 5q duplication/3p deficiency resulting from unbalanced 3;5 translocations conveys a proliferative advantage of particular importance in ccRCC tumorigenesis.

Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

BACKGROUND: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. METHODS: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. RESULTS: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02). CONCLUSIONS: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).

Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated superior efficacy over interferon (IFN)-alpha in a phase III trial in first-line, metastatic renal cell carcinoma (RCC). Herein, we report the results of a phase I dose-finding study of sunitinib in combination with IFN-alpha as first-line treatment in patients with metastatic RCC. PATIENTS AND METHODS: Treatment-naive patients with clear-cell metastatic RCC received sunitinib at a starting dose of 50 mg or 37.5 mg orally once daily in 6-week cycles (schedule 4/2) plus IFN-alpha at a starting dose of 3 MU subcutaneously 3 times a week, with weekly intrapatient dose escalation to a maximum of 9 MU as tolerated. Patients who did not tolerate either drug received lower doses of either or had dose interruptions. RESULTS: Twenty-five patients were enrolled; their median age was 64 years (range, 45-77 years). All patients experienced grade 3/4 treatment-emergent adverse events; the most common were neutropenia, fatigue, and thrombocytopenia. After a median of 4 cycles (range, 1-9 cycles), 3 patients (12%) had a partial response, and 20 (80%) had stable disease. CONCLUSION: Although reduced starting doses were tolerated (37.5 mg for sunitinib and 3 MU for IFN-alpha), even these lower doses might not be well tolerated for long-term treatment of patients with metastatic RCC. Based on historical data, sunitinib on schedule 4/2 appears to be more effective as single-agent therapy. Further study of sunitinib plus IFN-alpha on this schedule is not being pursued in RCC.

Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies.

Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus (Torisel) or interferon-alpha (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.

Phase II Trial of Eribulin in Patients With Metastatic Hormone Refractory Prostate Cancer: A Trial of the ECOG-ACRIN Cancer Research Group (E5805).

BACKGROUND: Eribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels. METHODS: In a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata. RESULTS: In total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia. CONCLUSIONS: In summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.

Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data.

BACKGROUND: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer. METHODS: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used. FINDINGS: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275). INTERPRETATION: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.

BACKGROUND: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment. METHODS: Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011. FINDINGS: In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44.2% (95% CI 30.5-58.7). Median response duration was 23.0 months (20.9-not estimable; range 4.2-29.8). However, 12 of 23 initial responders progressed with response duration ranging from 4.2 months to 26.5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15.7 months (8.4-23.4, range 0.03-31.5) and median overall survival was 29.9 months (20.3-not estimable; range 2.4-35.8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline. INTERPRETATION: Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.

INTRODUCTION: This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest. RESULTS: Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant. CONCLUSION: The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.

New paradigm in dose-finding trials: patient-specific dosing and beyond phase I.

We propose a new paradigm for the clinical evaluation of new cancer therapies. It entails adjusting the search for the optimal dose on the basis of measurable patient characteristics that may be predictive of adverse responses to treatment, and extending this search beyond phase I and into phases II and III. We provide examples of (a) how the fine-tuning of dose may involve utilization of patient-specific attributes to obtain a personalized treatment regimen, and (b) how novel methods for phase I design can be used to update the working dose for the conduct of phase II and III cancer clinical trials. These examples should be interpreted as an enticement for the development of new methods to implement the proposed new paradigm.

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.

Impact of zoledronic acid on renal function in patients with cancer: Clinical significance and development of a predictive model.

Zoledronic acid is a potent bisphosphonate licensed for the treatment of myeloma and bone metastases from solid tumors. Renal deterioration is the most significant toxicity associated with zoledronic acid. We attempted to define the incidence and clinical significance of renal deterioration in patients receiving zoledronic acid and to develop a risk-factor profile for this treatment sequela. This study is a retrospective analysis of all patients who received zoledronic acid at Fox Chase Cancer Center, Philadelphia, Pa, between 1/10/02 and 1/30/04. Data recorded included patient demographics, tumor characteristics, comorbid illnesses, concomitant medications, cancer therapy, number of zoledronic acid doses administered, and serial creatinine measurements. In total, 3,115 evaluable doses of zoledronic acid were administered to 446 patients (median, 4 doses; mean, 6.98 doses; range, 1-28 doses) at a dose of 4 mg over 15 minutes every 3-4 weeks. Of these 446 patients, 42 experienced renal deterioration (median rise in creatinine level, 1.0 mg/dL; range, 0.5-4.4 mg/dL), requiring discontinuation of zoledronic acid therapy in 8 cases. No patient required dialysis and no patient died as a result of zoledronic acid-induced renal dysfunction. On multivariable analysis, predictive factors for the development of renal deterioration were patient age, a diagnosis of myeloma or renal cell cancer, cumulative number of doses, concomitant therapy with a nonsteroidal anti-inflammatory drug, and current or prior therapy with cisplatin. Using these factors, we constructed a predictive model with an area under the receiver operating characteristic curve of 0.75. The incidence of clinically significant renal deterioration in patients treated with zoledronic acid is low.We present a predictive model for decision support when estimating this risk.