A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

BACKGROUND: Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. PATIENTS AND METHODS: Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. RESULTS: Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. CONCLUSION: The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00720174.

Novel approaches and future directions in castration-resistant prostate cancer.

Recent advances in the treatment of castration-resistant prostate cancer (CRPC) have started to change the therapeutic landscape allowing clinicians to choose from a broad range of treatment options. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state has enabled investigators to explore critical pathways involved in such process allowing for rational therapeutic design. These novel therapies complement the modest success that chemotherapy has demonstrated in recent years. In this review, we discuss the different mechanisms that render PCA castration resistant and elaborate on the nonchemotherapy approaches evolving in CRPC. These include agents targeting the epidermal growth factor receptor, endothelin receptor antagonists, angiogenesis inhibitors, immunomodulatory agents, immunotherapy, novel antiandrogens, and delivery of cytotoxic agents via therapeutic antibodies. This timely review coincides with the identification of newer therapies in this setting affirming our steady movement towards better disease control.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).

BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure.

PURPOSE: TG4010 is a recombinant MVA vector expressing the tumor-associated antigen MUC1 and IL2. We explored the effect two schedules of TG4010 on PSA in men with PSA progression. PATIENTS AND METHODS: A randomized phase II trial was conducted in 40 patients with PSA progression. Patients had PSA doubling times less than 10 months, with no overt evidence of disease. Patients received either weekly subcutaneous injection (sc) of TG4010 10(8) pfu for 6 weeks, then one injection every 3 weeks or sc injection of TG4010 10(8) pfu every 3 weeks. RESULTS: The primary endpoint of a 50% decrease in PSA values from baseline was not observed. Nevertheless, 13 of 40 patients had a more than two fold improvement in PSA doubling time. Ten patients had their PSA stabilized for over 8 months. Therapy was well tolerated. CONCLUSIONS: Although the primary endpoint was not achieved, there is evidence of biologic activity of TG4010 in patients with PSA progression, further investigation in prostate cancer is warranted.

Patient Perceptions of Care as Influenced by a Large Institutional Pharmacogenomic Implementation Program.

Despite growing clinical use of genomic information, patient perceptions of genomic-based care are poorly understood. We prospectively studied patient-physician pairs who participated in an institutional pharmacogenomic implementation program. Trust/privacy/empathy/medical decision-making (MDM)/personalized care dimensions were assessed through patient surveys after clinic visits at which physicians had access to preemptive pharmacogenomic results (Likert scale, 1 = minimum/5 = maximum; mean [SD]). From 2012-2015, 1,261 surveys were issued to 507 patients, with 792 (62.8%) returned. Privacy, empathy, MDM, and personalized care scores were significantly higher after visits when physicians considered pharmacogenomic results. Importantly, personalized care scores were significantly higher after physicians used pharmacogenomic information to guide medication changes (4.0 [1.4] vs. 3.0 [1.6]; P < 0.001) compared with prescribing visits without genomic guidance. Multivariable modeling controlling for clinical factors confirmed personalized care scores were more favorable after visits with genomic-influenced prescribing (odds ratio [OR] = 3.26; 95% confidence interval [CI] = (1.31-8.14); P < 0.05). Physicians seem to individualize care when utilizing pharmacogenomic results and this decision-making augmentation is perceived positively by patients.

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.

Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells.

CDKN2/p16 inhibits the cyclin D/cyclin-dependent kinase complexes that phosphorylate pRb, thus blocking cell cycle progression. We previously reported that p16 levels are low to undetectable in normal human uroepithelial cells (HUCs) and in immortalized uroepithelial cells with functional pRb, whereas p16 levels are markedly elevated in immortal HUCs with altered pRb (T. Yeager et al., Cancer Res., 55: 493-497, 1995). We now report that elevation of p16 levels occurs at senescence in HUCs, including HUCs transformed by human papillomavirus 16 E7 or E6, whose oncoprotein products lead to functional loss of pRb and p53, respectively. We also report that six of six independently immortalized E7 HUCs show high levels of p16 similar to those observed at HUC senescence, whereas p16 is undetectable in five of five immortal E6 HUCs. Four of the five independent E6 HUCs that lost p16 at immortalization showed hemizygous deletion of the 9p21 region. However, no homozygous CDKN2 deletions were detected, and only one CDKN2 mutation was identified. For the first time, these data associate elevated p16 with senescence in human epithelial cells. These data also suggest that a component of immortalization may be abrogation, either by pRb inactivation (as in the E7-transformed HUCs) or by p16 inactivation (as in the E6-transformed HUCs), of a p16-mediated senescence cell cycle block.

Homozygous deletions within chromosomal bands 9p21-22 in bladder cancer.

The loss of DNA sequences on chromosomal bands 9p21-22 has been documented in a variety of malignancies including leukemias, gliomas, lung cancers, and melanomas. Because of the high incidence of monosomy 9 detected by both cytogenetics and loss of heterozygosity studies in bladder cancer, we examined seven bladder cancer cell lines for deletions in this region. Using seven DNA probes that span the region of 9p21-22 as well as a functional assay for methylthioadenosine phosphorylase (MTAP), which maps to 9p21, we found four cell lines that had small homozygous deletions. These deletions map centromeric to the interferon (IFN) gene cluster and telomeric to D9S171. Only one of the cell lines with deletions had a cytogenetically evident lesion in this chromosomal region. Preliminary loss of heterozygosity studies with 10 primary bladder cancer specimens using 10 markers spanning chromosome 9 revealed loss of heterozygosity at the IFN locus with retention of heterozygosity with more centromeric 9p markers and all informative 9q markers in the tumor of one patient. These data suggest that loss of a tumor suppressor gene on 9p21-22, which may represent a general pathway of oncogenesis, is important in bladder cancer development.

Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17.

The introduction of a discontinuous approximately 70-cM portion of human chromosome 17 significantly suppresses the metastatic ability of AT6.1 rat prostate cancer cells without affecting tumorigenicity (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). We have recently demonstrated that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the metastasis suppressor region is lost (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). A series of in vivo studies indicated that the observed growth inhibition was due to the effect of a gene(s) at the metastatic site (M. A. Chekmareva et al., Cancer Res., 58: 4963-4969, 1998). We have now identified the mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1) gene as a candidate metastasis suppressor gene encoded by the approximately 70-cM region. AT6.1 cells were transfected with a MKK4/SEK1 expression construct, and the cells were tested in standard spontaneous metastasis assays. Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was approximately 2 cm. Furthermore, histological examination of the lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the original approximately 70-cM chromosomal region. These studies implicate MKK4/SEK1 as a metastasis suppressor gene encoded by human chromosome 17.

Chromosome 17-mediated dormancy of AT6.1 prostate cancer micrometastases.

To improve the diagnosis and treatment of cancer, an increased understanding of the molecular and cellular changes that regulate metastatic ability is required. We have recently demonstrated a prostate cancer metastasis-suppressor activity encoded by a discontinuous approximately 70-cM region of human chromosome. The presence of this region suppresses the spontaneous metastatic ability of AT6.1 rat prostatic cancer cells by greater than 30-fold (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). Interestingly, a number of potentially important genes which have been mapped to human chromosome 17, including TP53, NM23, and BRCA1, are not retained (M. A. Chekmareva et al., cited above) or are not expressed in these microcell hybrids (B. A. Yoshida et al., In Vivo, in press), which suggests the presence of a novel metastasis-suppressor gene(s) or novel function of a known gene(s) encoded by this region(s). We hypothesize that identification of the "step" in the metastatic cascade that is inhibited by the presence of the approximately 70-cM metastasis-suppressor region will facilitate the identification of candidate metastasis-suppressor genes. For a cancer cell to metastasize, it must escape from the primary tumor, enter the circulation, arrest in the microcirculation, extravasate into a tissue compartment, and grow. This suppression of spontaneous macroscopic lung metastases could be due to the inhibition of a number of steps within this cascade. Results of the current study demonstrate that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the metastasis-suppressor region is lost. This growth inhibition seems to result from an effect of one or more genes at the metastatic site and not from a circulating angiogenesis inhibitor. Our findings suggest that the approximately 70-cM region of human chromosome 17 may encode a gene(s) that regulates the "dormancy" of AT6.1-17-4 micrometastases.

Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers.

We have shown recently (B. A. Yoshida et al., Cancer Res., 59: 5483-5487) that mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo. Evaluation of the expression of components of the MKK4 signaling cascade showed a loss or down-regulation of expression of MKK4 or c-Jun, a downstream mediator of MKK4, in six of eight human prostate cancer cell lines. Given these findings, we next assessed whether MKK4 dysregulation occurs during the development of clinical prostate cancer. Immunohistochemical studies showed high levels of MKK4 expression in the epithelial but not the stromal compartment of normal prostatic tissues. In neoplastic tissues, a statistically significant, direct, inverse relationship between Gleason pattern and MKK4 was established. These results demonstrate that MKK4 protein is consistently down-regulated during prostate cancer progression and support a role for dysregulation of its signaling cascade in clinical disease. To test the possibility that down-regulation of MKK4 protein is the result of allelic loss, metastatic prostate cancer lesions were examined for loss of heterozygosity (LOH) within the MKK4 locus (D17S969). These studies showed a 31% (5 of 16) LOH of MKK4 that is not associated with coding region mutations, which suggests that the nucleotide sequence of the gene in the remaining allele is infrequently mutated.

Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer.

PURPOSE: To determine the activity of single-agent gemcitabine in previously untreated patients with metastatic transitional cell cancer. METHODS: Forty patients with measurable disease and a Karnofsky performance status > or = 60% were enrolled at five institutions between March 1994 and October 1995. Treatment consisted of gemcitabine (1,200 mg/m2) administered weekly times three on a 4-week cycle. One patient was ineligible for response evaluation because pathology review showed a metastatic melanoma. Responses were confirmed by all investigators and an independent radiologist and were maintained for at least 4 weeks. RESULTS: There were four complete and seven partial responses, for an overall response rate of 28%. Responses were seen at all sites, including liver. Median progression-free and overall survival times were 20 and 54 weeks, respectively. Toxicity was mild, with only two grade 4 toxicities. Twenty-five percent of patients experienced grade 3 neutropenia or thrombocytopenia that was rapidly reversible. CONCLUSION: Gemcitabine exhibits significant activity in metastatic transitional cell cancer with minimal toxicity, but survival remains short. Trials of gemcitabine in combination with other active agents are thus suggested.

Multicenter phase II trial of interleukin-2, interferon-alpha, and 13-cis-retinoic acid in patients with metastatic renal-cell carcinoma.

PURPOSE: To determine the response rate and toxicity of oral 13-cis-retinoic acid (CRA) added to an outpatient regimen of subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in previously untreated patients with metastatic renal-cell carcinoma (RCC). PATIENTS AND METHODS: Eligibility included a performance status of 2 or better, no significant end-organ dysfunction, and written informed consent. Characteristics of 47 of 48 assessable patients included a median performance status of 0, prior nephrectomy in 68% of patients, one metastatic site in 30% of patients, and lung-only metastatic disease in 21% of patients. Therapy consisted of IL2 11 x 10(6) IU 4 days per week for 4 weeks, IFNA 9 x 10(6) IU 2 days per week for 4 weeks, and CRA 1 mg/kg daily on a 6-week cycle. RESULTS: Eight of 47 patients (17%) responded (one complete response, seven partial responses). Three partial responders were rendered disease free by subsequent surgical resection. Four additional patients experienced a minor response in lung or soft tissue metastases. The median duration of response, which included minor responses, was 42 weeks, and median survival was 74 weeks (17 months). Grades 3 or greater toxicities during the first cycle included flu-like symptoms (21% of patients), fatigue (6% of patients), and nausea and vomiting (15% of patients). Significant cumulative toxicities were hyperlipidemia (four of 18 patients), and cardiomyopathy (one of 18 patients). There was one therapy-related death. CONCLUSION: Outpatient CRA plus IL2 and IFNA is feasible and modestly effective in metastatic RCC. The prolonged median survival is encouraging, but randomized trials are required to show that the combination represents an improvement over single-agent immunotherapy.

Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study.

PURPOSE: Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population. PATIENTS AND METHODS: Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed. RESULTS: There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs. CONCLUSION: Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.

Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal carcinoma.

PURPOSE: Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m(2) of TNP-470 infused over 1 hour three times per week. RESULTS: Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression. CONCLUSION: Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.

Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer.

PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m(2) over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m(2)/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle. Patients had a Cancer and Leukemia Group B performance status of 0 or 1, with a median time since diagnosis of metastatic disease of 10 months (range, 0 to 129 months). Thirty-three patients (80%) had multiple metastatic sites, and 34 patients (83%) had prior chemotherapy or immunotherapy. RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. The duration of response for the seven partial responders was 2, 3, 7, 8, 10, 11, and 14 months. Median progression-free survival for the gemcitabine/5-FU group was 28.7 weeks versus 8 weeks for a similar cohort of patients treated on previous phase II studies at the University of Chicago (P =.008). The regimen was well tolerated, with fatigue, mucositis, nausea/vomiting, and grade 2 hematologic toxicities being most common. CONCLUSION: Weekly gemcitabine with continuous infusion 5-FU is an active combination in patients with metastatic RCC. Therapy was well tolerated and produced an improvement in progression-free survival over historical controls.

Study of cohort-specific consent and patient control in phase I cancer trials.

PURPOSE: To address the challenging ethical dilemmas created from the participation of advanced cancer patients in phase I trials, we assessed the feasibility of a clinical trial design that uses an interactive informed consent process in which patient-subjects can choose to become directly involved in decisions of dose escalation. PATIENTS AND METHODS: Subjects were advanced cancer patients in the Hematology/Oncology Clinics at the University of Chicago who were eligible to participate in a phase I trial in which they underwent a three-step informed consent process that used cohort-specific consent and allowed them the option to choose their own doses of the chemotherapeutic agents under study, vinorelbine (NVB) and paclitaxel (TAX), within predetermined limits. NVB and TAX were administered in conventional 21- to 28-day cycles for two cycles while on study. Dose escalation occurred when a patient-subject chose a higher untested dose after they received information on all previously assessable patient-subjects. In addition to the phase I trial itself, a survey that consisted of structured interviews, which sought to evaluate patients' experiences with the interactive subject-choice phase I trial design and consent process, was conducted with participating subjects. The phase I trial itself sought to determine the associated toxicities of the agents under study. The survey results were compared with a similar survey of a matched control population of subjects who participated in other concurrently active conventional phase I trials at our institution. RESULTS: Twenty-nine patient-subjects participated in the phase I trial, with 24 who agreed to and completed the survey interviews. Seventy-six percent of patient-subjects opted to choose their dose of the agents under study, and 28% chose the highest available doses. More than half of the patient-subjects (56%) felt some degree of comfort in being asked to choose their dose of chemotherapy, with 53% stating that being asked to choose their dose made them feel in control, fully informed, or content. However, there were no statistically significant improvements in objective measures of the informed consent process, which included surveyed subjects' stated understanding of either provided information about phase I trials and alternatives to trial participation or of the research purpose of phase I trials. By making choices, the group of patients in the interactive subject choice trial changed the size of the dose cohorts and modified the process of dose escalation in this phase I study. CONCLUSION: Although complex, our innovative phase I trial design is feasible. In addition to the use of cohort-specific consent, the trial design may reduce the magnitude of many of the commonly recognized ethical dilemmas associated with this form of clinical research, which include difficulties with information provision and the understanding of possible risks and benefits of phase I trial participation, through direct subject involvement in research decision making by otherwise potentially vulnerable cancer patients.

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience.

Nonmyeloablative allogeneic stem cell transplantation (NST) has considerable activity in patients with metastatic renal cell carcinoma (RCC), although there are limited long-term follow-up data. Between February 1999 and May 2003, 18 patients with metastatic RCC underwent 19 matched-sibling NSTs after conditioning with fludarabine and cyclophosphamide with tacrolimus and mycophenolate mofetil as post-transplant immunosuppression. Among the four objective responses, all were partial and have relapsed with a median response duration of 609 days (range, 107-926). All responders are alive at a median of 41 months. Median overall survival for the entire cohort was 14 months. There were four early treatment-related deaths and one late treatment-related death. Eight patients died from progressive disease and five (28%) from treatment-related mortality. Stratifying transplant outcome as early death, intermediate (no response, no early death), or response, the combination of pre-treatment anemia and decreased performance status, was associated with adverse outcome (P = 0.015) and reduced survival (HR 5.4, 95% confidence interval of 1.4 to 21, P = 0.007). Responders demonstrated prolonged survival compared to nonresponders (P = 0.002). NST leads to durable responses in a minority of metastatic RCC patients. Appropriate patient selection is paramount. Anemia and decreased performance status may enable risk stratification.