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Phase II study of carboxyamidotriazole in patients with advanced renal cell carcinoma refractory to immunotherapy†‡§
E4896, an Eastern Cooperative Oncology Group study
Version of Record online: 12 OCT 2005
Copyright © 2005 American Cancer Society
Volume 104, Issue 11, pages 2392–2399, 1 December 2005
How to Cite
Dutcher, J. P., Leon, L., Manola, J., Friedland, D. M., Roth, B. and Wilding, G. (2005), Phase II study of carboxyamidotriazole in patients with advanced renal cell carcinoma refractory to immunotherapy. Cancer, 104: 2392–2399. doi: 10.1002/cncr.21473
The following institutions participated in the current study: ECOG Statistical Center, Boston, MA (Robert Gray, Ph.D., supported by Grant CA-23318); Our Lady of Mercy Cancer Center, Bronx, NY (Peter H. Wiernik, M.D.); Cancer Institute of New Jersey, New Brunswick, NJ (Joseph Aisner, M.D.); Vanderbilt University, Nashville, TN (David Johnson, M.D.); University of Wisconsin, Madison, WI (James A. Stewart, M.D.); Northwestern University, Chicago, IL (Al Bowen Benson, M.D.); University of Pennsylvania, Philadelphia, PA (Daniel Haller, M.D.); University of Rochester, Rochester, NY (John M. Bennett, M.D.); Mayo Clinic, Rochester, MN (Thomas M. Haberman, M.D.); Johns Hopkins University, Baltimore, MD (Arlene A. Forastiere, M.D.); Moffitt Cancer Center, Tampa, FL (Julie A. Kish, M.D.); Decatur Memorial Hospital, Decatur, IL (James L. Wade, M.D.); Case Western-MetroHealth Medical Center, Cleveland, OH (Edward G. Mansour, M.D.); Drexel University College of Medicine, Philadelphia, PA (Pamela A. Crilley, M.D.); Metro-Minnesota Community Clinical Oncology Program: Abbott-NW, Minneapolis, MN (Patrick Flynn, M.D.); Tufts/New England Medical Center, Boston, MA (John K. Erban, M.D.); Lankenau Hospital, Wynnewood, PA (Paul B. Gilman, M.D.); and Columbus Community Clinical Oncology Program, Columbus, OH (J. Philip Kuebler, M.D.).
The contents of the current article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Presented in part at the 2003 Annual Meeting of the American Society of Clinical Oncology. May 31–June 3, 2003 Chicago, Illinois.
- Issue online: 18 NOV 2005
- Version of Record online: 12 OCT 2005
- Manuscript Accepted: 30 JUN 2005
- Manuscript Revised: 12 JUN 2005
- Manuscript Received: 25 APR 2005
- Public Health Service. Grant Numbers: CA-23318, CA66636, CA21115, CA39229, CA49957, CA21076
- National Cancer Institute
- National Institutes of Health
- Department of Health and Human Services
- Eastern Cooperative Oncology Group (ECOG)
- renal cell carcinoma (RCC);
- antiangiogenesis therapy;
- Phase II study;
The current study evaluated the response rate and 6-month time to disease progression of the antiangiogenesis agent carboxyamidotriazole (CAI) in patients with metastatic renal cell carcinoma (RCC).
Fifty-seven patients with histologically confirmed metastatic RCC that progressed after biologic therapy (interferon or interleukin-2) were enrolled. Four patients were ineligible. CAI was administered orally as a 28-day cycle. Response and time to disease progression were evaluated.
Fifteen of 53 eligible patients received > 5 cycles, but 13 patients eventually discontinued treatment because of progressive disease. The majority of toxicities were Grade 1. However, Grade 3/4 toxicities did occur, the majority of which were gastrointestinal in nature. One of 47 patients evaluable achieved a partial response (1.9%) lasting 172 days. Six of 53 patients were alive and disease progression free at 6 months from the start of treatment (11.3%). The median overall survival was 12.5 months. The survival periods in the low-risk, intermediate-risk, and poor-risk groups were 16.2 months, 20.9 months, and 5.8 months, respectively.
Patients in trials of second-line therapy appear to have a better prognosis than previously considered, in part because they are eligible for another clinical trial. CAI was found to have little to no effect on the natural history of progressive RCC. Cancer 2005. © 2005 American Cancer Society.
Renal cell carcinoma (RCC) is a malignancy with an aggressive but variable course. There can be virulent disease progression in some patients and indolent behavior in others. The management of advanced RCC has limited options, with the mainstay being immunotherapy. Agents such as interleukin-2 (IL-2) and interferon-α (IFN-α) or combinations have been employed as standard therapy.1–6 Response rates have been reported to be 15–25% in trials with high-dose IL-2 by various investigators,2, 7, 8 and in the 10–20% range with IFN-α.6, 9 To our knowledge, only limited data exist regarding the use of these agents as second-line therapies. Efficacy estimates have been derived primarily from studies evaluating the results of crossover from an initial treatment with IL-2 or IFN-α to the other cytokine. In 1 randomized trial, Negrier et al.4 compared IFN-α with IL-2 or with the combination, and the crossover response rates after initial therapy were 0% for IFN-α and 5% for IL-2. This randomized trial suggests that there is no standard second-line therapy after initial single-agent immunotherapy. Several series have investigated the use of thalidomide in patients with RCC who were previously treated with immunotherapy.10–12 Responses have been documented in ≤ 10% of patients. The mechanism of action of thalidomide is demonstrated to be angiogenesis inhibition, suggesting that a prolongation of stable disease (SD) might occur.13 However, a recent Eastern Cooperative Oncology Group (ECOG) trial of IFN-α versus IFN-α plus thalidomide in patients with metastatic RCC showed no difference in survival or in time to disease progression between the two arms.14
A number of other agents with antiangiogenic activity are currently undergoing evaluation in metastatic RCC, a disease of interest for testing this antitumor approach because of its distinct vascular nature and probable development related to loss of von-Hippel Lindau gene control and up-regulation of hypoxia-inducible factors and vascular endothelial growth factor (VEGF).15–17 Carboxyamidotriazole (CAI), an agent originally developed as an antiparasitic drug approximately 80 years ago, is 1 such agent being tested in patients with refractory malignancies. CAI has been investigated in Phase I trials at the University of Wisconsin and at the National Cancer Institute.18, 19 The mechanism of action is inhibition of voltage-dependent calcium channels, which is believed to affect a number of downstream functions including angiogenesis. In an endothelial cell model, CAI inhibits inositol 1,4,5-trisphosphate (IP3) formation, nitric oxide (NO) release, and VEGF-A–induced proliferation.20 Calcium signaling is necessary for VEGF-A–induced proliferation. Therefore, it appears that the inhibition of angiogenesis via VEGF-A produced by CAI may be explained by inhibition of IP3 formation and possibly via reduced NO release. This could lead to inhibition of tumor cell growth by interfering with the vascular development.
Two formulations of CAI have been evaluated in Phase I clinical trials. An early study using a PEG-400 gelcap formulation produced neurocerebellar toxicity at the maximum tolerated dose (MTD), with nausea, emesis, and fatigue predominating at lower doses.21 Berlin et al.19 evaluated micronized CAI, and reported the MTD to be 150 mg/m2. In the micronized CAI trial, neurotoxicities (including visual loss and peripheral neuropathy) were observed after dose escalation to 300 mg/m2 and were dose limiting. Predictable neurotoxicity including peripheral sensory neuropathy and visual changes as well as nausea and emesis were noted at lower dose levels. Coadministration of CAI with food increased absorption by 29%. Given that micronized CAI was available in 50-mg capsules, and that a moderate amount of intrapatient pharmacokinetic variability was noted, a fixed dose of 250 mg was adopted for subsequent Phase II trials. The combined Phase I experience included 19 patients with previously treated RCC. Nine of these patients had prolonged periods of SD (i.e., ≤ 40 months).19 In the earlier CAI gelcap study, 2 of 6 patients with RCC had SD for > 1 year, with 1 of these patients remaining stable for nearly 3 years.
The current ECOG Phase II study was designed to evaluate the ability of CAI to stabilize metastatic RCC, using an end point of 6-month freedom from disease progression. It was noted that the noncytotoxic mechanism of this agent predicted a low objective response rate. The study employed a two-stage design with early stopping guided by a stochastic curtailment algorithm.
MATERIALS AND METHODS
Patients were required to have histologically confirmed advanced RCC defined as locally recurrent disease or metastatic lesions not amenable to curative resection. All patients were age ≥ 18 years of age and able to provide informed consent. Evidence of recent progressive disease (PD) (defined as a 25% increase from last measurement to prestudy measurement or new lesions) was required. In addition, patients must have received previous immunotherapy defined as at least one (but no more than two) previous biologic regimen(s) including IL-2, IFN-α, or the combination of both. A regimen was defined as ≥ 8 weeks of treatment. Treatment must have ended > 4 weeks before registration and all toxicities had to be resolved. Previous treatment with granulocyte-macrophage—colony-stimulating factor was not considered a previous biologic therapy. Patients could not have received any previous chemotherapy. Previous treatment with hormonal agents (i.e., megestrol or tamoxifen) must have ended > 4 weeks before registration and all toxicities must have resolved. Indicator lesions must not have been previously treated with radiation therapy (RT). Previous RT must have been completed ≥ 4 weeks before registration and the patient must have completely recovered from any acute toxicities associated with RT. Patients may have undergong previous nephrectomy provided they met all other eligibility criteria. Patients must have adequately recovered from any surgery. Patients were required to have bidimensionally measurable disease; an ECOG performance status of 0, 1, or 2; and adequate bone marrow, liver, and renal function, as indicated by the following laboratory values, obtained 2 weeks before registration: a leukocyte count > 3000/mm3 or an absolute neutrophil count > 1500/mm3, a platelet count > 100,000/mm3, a bilirubin level < 1.5 mg/dL, transaminases (aspartate aminotransferase and/or alananine aminotransferase) < 2 times the institutional upper limit of normal, and a creatinine level < 2.0 mg/dL. Patients with a history of previous malignancy were eligible provided they were treated with curative intent and had been disease free for 5 years. No serious concurrent medical illness or active infection should have been present which would jeopardize the ability of the patient to receive the chemotherapy outlined in this protocol with reasonable safety. No current or previous history of brain metastases was permitted. In addition, female patients must not have been pregnant or breast-feeding due to the unknown effects of CAI on a fetus or infant. Sexually active patients were required to use an effective form of birth control consistently while participating in the current study. The study was approved by the institutional review boards for human subject research at each participating institution and written informed consent was obtained from all participants.
Micronized CAI at a dose of 250 mg was administered daily. Fifty-milligram capsules were provided and were to be taken at bedtime ≥ 2 hours after eating. Patients were asked to complete a pill calendar at home and to keep a record of the number of pills taken per day. Pill counts also were made by a study monitor at each follow-up visit. Patients were treated until there was unacceptable toxicity or evidence of disease progression. One treatment cycle equaled 28 days. Response evaluation was to be performed after every 2 cycles (56 days). Patients with SD could continue to receive the protocol beyond six cycles, provided CAI was well tolerated. If a patient's disease had progressed by 50%, then the protocol treatment was discontinued.
Dose withholding and possible reductions were specified for treatment-related toxicity, including NCI CTC Grade ≥ 2 neurotoxicity, Grade ≥ 2 nausea/emesis, Grade ≥ 2 ocular toxicity, or Grade 4 leukopenia. Patients were initially managed symptomatically and by withholding the drug, and were rechallenged at the original dose level. If toxicity recurred, dose reductions to 200 mg/day and to 150 mg/day were allowed. Further toxicity required withdrawing the drug.
The study was initially designed with a 2-stage design plan and called for early stopping after the 6-month evaluation of the first 21 patients if < 3 patients were disease progression free. However, full accrual of 57 patients was completed before reaching the primary evaluation point of the Stage I accrual goal. Statistical goals for the complete study required that ≥ 8 of the 50 eligible patients be free of disease progression at 6 months, to enable a conclusion that some activity was being demonstrated. Using this design, the probability of concluding that the treatment was effective was 90–95% if the true disease progression-free rate at 6 months was 25%. If 8 of 50 eligible patients were observed to be disease progression free at 6 months, the 2-stage, 90% confidence interval (90% CI) would have been approximately 8–27%. If 10 of 50 eligible patients were observed to be free of disease progression, the 2-stage 90% CI would have been approximately 12–36%.
Descriptive statistics were used to characterize patients at the time of study entry. The Kaplan–Meier method22 was used to characterize time to disease progression and overall survival. Exact 2-sided binomial 90% CIs were computed for the response and 6-month disease progression-free rates. A Cox proportional hazards model was used to evaluate survival by Motzer risk category.23
Criteria for response employed measurement criteria of the World Health Organization, in which bidimensional measurements were used. A complete response was defined as the complete disappearance of all clinically detectable malignant disease for ≥ 4 weeks. For patients with bidimensionally measurable disease, a partial response (PR) was defined as a ≥ 50% decrease in tumor area (multiplication of the longest dimension by the greatest perpendicular dimension), or as a 50% decrease in the sum of the products of the perpendicular dimensions of multiple lesions in the same organ site for ≥ 4 weeks, with no appearance of new malignant lesions. Response was required to be confirmed at 4 weeks. Patients were considered to have SD if they did not experience a significant change in measurable or evaluable disease for ≥ 4 weeks (12 wks for bony metastases). This included no increase in the size of any known malignant tumors, no appearance of new areas of malignant disease, or a decrease in malignant disease of < 50%, or an increase in malignant disease of < 25% in any site, with stable performance status. PD was defined as a significant increase in the size of lesions present at the initiation of therapy or after a response, or the appearance of new metastatic lesions known not to be present at the beginning of therapy, or stable objective disease associated with a deterioration in ECOG performance status of ≥ 1 level related to malignancy. Specifically, PD occurred in patients with measurable disease when there was a ≥ 25% increase in the area of any malignant lesions > 2 cm2 or in the sum of the products of the individual lesions in a given organ site.
A total of 57 patients were accrued between study activation on March 4, 2000 and October 3, 2000. At the time of this analysis, four patients were determined to be ineligible due to an unacceptably short interval from previous therapy. Patient characteristics at the time of study entry for the 53 eligible and treated patients are shown in Table 1. The median age of the patients was 57 years. The majority of patients (66%) were male and most (91%) were white. The majority of patients (74%) had received previous nephrectomy in addition to immunotherapy required for study entry.
|Factor||No. of patients (%)|
|Median age in yrs (range)||57 (36–75 yrs)|
|Histology as reported|
|Clear cell||33 (65)|
|Sarcomatoid features||1 (2)|
|ECOG performance status|
|Metastatic disease symptoms|
|Night sweats||5 (9)|
|Weight loss > 10%||4 (8)|
|Sites of metastatic disease|
|Lymph nodes||27 (51)|
|Renal bed||6 (11)|
|Biopsy only||17 (32)|
|Lymph node dissection||9 (17)|
|Palliative, < 50% of body||13 (25)|
|Gene therapy||2 (4)|
|Hormone therapy||5 (9)|
|Motzer risk category|
Of the 53 patients, 10 had received only 1 cycle, 4 of whom were withdrawn from treatment for PD and 6 for intolerance. Fourteen patients had received only 2 cycles, with 10 being withdrawn from treatment because of PD. Of the 14 patients receiving 3, 4, or 5 cycles, all but 1 discontinued therapy due to PD. Fifteen patients continued for > 5 cycles, 13 of whom eventually discontinued treatment because of PD. Therefore, 39 patients discontinued treatment due to PD, and 4 patients each because of treatment toxicity or patient request. Four patients discontinued treatment for other reasons, including clinical circumstances consistent with PD (deterioration in performance status, pathologic fractures, and gastrointestinal bleeding attributed to PD).
The majority of toxicities noted were Grade 1. Thirty-seven patients had Grade 1 or 2 toxicities as their worst degree of toxicity, 16 patients had Grade 3 toxicities as their worst degree, and 4 patients had Grade 4 toxicities as their worst degree. Four patients each discontinued treatment either due to documented toxicity or at patient request. The most common drug-related toxicities were fatigue, nausea, emesis, sensory neuropathy, and hyponatremia. Additional toxicity related to the gastrointestinal system included dyspepsia (2 patients), dysphagia (3 patients), stomatitis (2 patients), constipation (6 patients), anorexia (14 patients), diarrhea (3 patients), and gastrointestinal bleeding (3 patients). Abnormal liver function was noted occasionally, but was more likely related to the underlying disease process. Similarly, although anemia and an altered serum creatinine level were common, these more likely reflected disease-related effects rather than an effect from CAI. A summary of the Grade 3 and 4 toxicities experienced by all 57 patients that were considered to be possibly, most likely, or definitely treatment related is provided in Table 2.
|Toxicity||Grade 3||Grade 4|
Proportion of Patients Free of Disease Progression at 6 Months
Six of the 53 patients included in the current analysis were alive and free of disease progression at 6 months from the initiation of treatment with CAI after PD after immunotherapy. This corresponds to a rate of 11.3% (90% exact 2-sided binomial CI, 5.0–21.1%). This interval does not exclude the null rate of 10% specified in the protocol design.
Forty-seven of the 53 patients included in the current analysis were evaluable for response. Six patients were unevaluable for response because there were no posttreatment disease assessments, but are part of the denominator used in calculating the response rate. Table 3 summarizes their response to treatment. There was 1 PR, a rate of 1.9% (90% exact 2-sided binomial CI, 0.1–8.6%). The duration of response was 172 days for the patient who responded. Nineteen patients had SD before disease progression (median duration of 5.1 mos; range, 3.2–10.8 mos) and 27 patients had PD as the best response.
|Best response||No. of patients (%)||Median duration in mos|
|Partial response||1 (2)||5.6|
|Stable disease||19 (36)||5.1|
|Disease progression||27 (51)|
|Time to disease progression in mos||2.9||1.9–3.5|
|Overall survival in mos||12.5||8.3–15.8|
Time to Disease Progression
All 47 patients who were evaluable for response had experienced PD at the time of last follow-up. Time to disease progression was defined as the time from registration onto the study until evidence of PD. Six patients who were unevaluable for disease progression were censored at the date they were last known to be free of disease progression. The median time to disease progression was 2.3 months (95% CI, 1.9–3.5 mos).
Overall survival was defined as the time from registration until death from any cause. Thirty-nine of the 53 patients had died at the time of last follow-up. The median survival period was 12.5 months (95% CI, 8.3–15.8 mos).
Motzer Criteria Analysis
Motzer et al.24 have identified prognostic factors for survival in patients with advanced RCC. Although we were unable to duplicate those factors exactly, we considered each of the following to constitute a risk factor: an ECOG performance status poorer than 0 (fully active), no previous nephrectomy, an abnormal (low) hemoglobin level, and an abnormal (elevated) serum calcium level. Calcium levels were not corrected because serum albumin was not collected as part of the study. Patients with no risk factors were considered to be in the favorable-risk category, those with one risk factor were considered to be in the intermediate-risk category, and those with more than one risk factor were considered to be in the poor-risk category. Because lactate dehydrogenase was not collected for patients in the current study, risk levels may have been underestimated compared with those described by Motzer et al. Table 1 shows the distribution of patients into these risk categories. The median survival periods among favorable-risk, intermediate-risk, and poor-risk patients were 16.2 months, 20.9 months, and 5.8 months, respectively. The differences were not found to be statistically significant (P = 0.27 for intermediate risk vs. favorable risk; P = 0.06 for poor risk vs. favorable risk), but the study was not powered to detect such differences. These data define patients entering second-line clinical trials, and demonstrate a better prognosis than previously believed. This also has been demonstrated in a recent randomized Phase III trial.25, 26
The current Phase II clinical trial evaluated the novel antineoplastic agent CAI in patients with advanced RCC. CAI has been evaluated in Phase I trials and a number of treated patients with RCC had prolonged periods of SD while receiving treatment.19 In the current study, all patients had PD despite the receipt of previous standard immunotherapies. Although a classic Phase II study design was used in the current trial, the primary endpoint was the disease progression-free rate at 6 months rather than the response rate. It was expected that an agent such as CAI, which is not cytotoxic but appears to suppress growth, would produce a low response rate. There is concern that the testing of novel agents such as CAI by classic clinical trial designs based on objective tumor regression might cause many of these agents to be considered inactive, when tumor stabilization is occurring.27, 28 This is the rationale for evaluating the proportion of patients who are free of disease progression at 6 months. In the current trial, only one objective response was observed. However, 11.3% of patients were free of disease progression after 6 months of therapy. Six recent trials of novel agents demonstrating clinical activity in patients with advanced RCC have demonstrated that the time to disease progression and the percentage of patients who are free of disease progression at 6 months are feasible response outcomes for agents that are not directly cytotoxic (Table 4).29–35 However, in all these trials, there was a low level of objective response (range, 5–25%) (Table 4).29–35
|Novel agent||Response||% PF at 6 mos||Reference|
|CAI–ECOG||1/53 (1.9%) PR||6/53 11.3%||Friedland et al., 200227, this study|
|CAI–CALGB||5/374 (1%) PR||< 18%||Stadler et al., 200328 Stadler et al 200536|
|Bevacizumab||4/39 (10%) PR||42%||Yang et al., 200329 and Elaraj et al., 200430|
|CCI-779||7% PR/CR||50%||Atkins et al., 200431|
|SU-011248||15/63 (23%) PRa||50%||Motzer et al, 200432|
|BAY-43-9006||25/63 MR/PR (5-10%)a||50%||Ratain et al., 200433|
|Bev/OSI-774||10/40 (25%) PR||71%||Hainsworth et al., 200434|
|PTK||1/37 (2.8%) PR||42%||George et al., 200335|
The median survival period of 12.5 months noted in the cohort in the current study was comparable to historical data regarding the expected survival of newly diagnosed patients with RCC.24 Recently, however, the survival of patients with metastatic RCC in second-line clinical trials has been evaluated in a randomized, placebo-controlled study.25, 26 Although intuitively one might expect a shorter survival for patients treated in a second-line trial, Escudier et al. recently reported the outcome of a placebo-controlled study of Neovastat/AE-941 (Aeterna Laboratories, Quebec City, Quebec, Canada) in previously treated patients with RCC and found that the placebo-treated group had a median survival of 12 months, which was 33% greater than the original assumption in the study design.25, 26 Therefore, patients who enter second-line trials with adequate performance status and organ function status actually have a more prolonged median survival than initially assumed, reflecting the indolent nature of RCC in some patients and the more prolonged natural history. In light of these new data, the median survival observed in the current Phase II trial appears to be comparable to that observed in the Neovastat trial25, 26 and does not appear to reflect a treatment effect from CAI. Patients with poor risk assessed by the Motzer criteria demonstrated substantially shorter median survival.
Stadler et al.36 have reported the results of a randomized discontinuation Phase II trial design of CAI in metastatic RCC in which 374 patients were entered. The goal of that study was to utilize trial design to evaluate the role of this noncytotoxic agent, by discontinuing the CAI in approximately half of the treated patients at 16 weeks and assessing disease progression of patients receiving the study drug or placebo for the next 16 weeks. In this study, 5 patients (1%) experienced an objective response, and only 18% of patients were able to enter the randomized portion of this study. Fifty-one percent of patients demonstrated disease progression at 16 weeks, the first evaluation period. Of 53 patients in this study, 38 had developed disease progression by 16 weeks.
Therefore, in both our classic Phase II trial of 53 patients, using an endpoint of percentage of patients with disease progression at 6 months (which is currently being evaluated in many additional noncytotoxic therapeutic trials) and in the randomized discontinuation design, utilizing 374 patients, the agent CAI has not been demonstrated to have an impact on the natural history of RCC in patients who have developed disease progression after treatment with cytokine therapy. We are fortunate to have the Neovastat placebo-controlled study to provide a new baseline for survival evaluation in studies of second-line treatments, putting the results of these two CAI studies into perspective.
CAI is an interesting compound with a complex mechanism of action. However, it does not appear to alter the natural history of advanced RCC, and in fact demonstrates minimal to no activity in this disease. The novel study design used in the current trial may serve as a template for the evaluation of noncytotoxic agents that might be inappropriately discarded based on response rates alone.
- 12Phase II study of thalidomide in advanced refractory metastatic renal cell cancer: a single institution experience [abstract]. Proc Am Soc Clin Oncol. 2001; 20: 265a., , , .
- 14Low dose interferon-α2b + thalidomide in patients with previously untreated renal cell cancer. Improvement in progression-free survival but no quality of life or overall survival. A phase III study of the Eastern Cooperative Oncology Group (E2898) [abstract]. Proc Am Soc Clin Oncol. 2004; 23: 384., , , et al.
- 21National Cancer Institute. Investigator Brochure. National Cancer Institute, Clincial Trials Evaluation Program, 1996.
- 23Regression models and life tables. J R Stat Soc B. 1972; 34: 181–220..
- 25Phase III trial of Neovastat in metastatic renal cell carcinoma patients refractory to immunotherapy [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 211., , , et al.
- 26Prognostic factors in metastatic renal cell carcinoma after failure of immunotherapy: lessons from a large phase III trial [abstract]. Proc Am Soc Clin Oncol. 2004; 23: 392., , , et al.
- 27Carboxyamidotriazole (CAI) in patients with advanced renal cell cancer (RCC) refractory to immunotherapy: an ECOG phase II trial [abstract]. Proc Am Soc Clin Oncol. 2002; 21: 152b., , , , , .
- 28Successful implementation of the randomized discontinuation trial design (RDTD) with the putative antiangiogenic agent carboxyaminoimidazole (CAI) in renal cell carcinoma (RCC). A Cancer and Leukemia Group B (CALGB) Study [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 193a., , , , , .
- 32SU011248, a novel tyrosine kinase inhibitor, shows anti-tumor activity in second-line therapy for patients with metastatic renal cell carcinoma: results of a phase 2 trial [abstract]. Proc Am Soc Clin Oncol. 2004; 23: 381., , , et al.
- 33Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial [abstract]. Proc Am Soc Clin Oncol. 2004; 23: 381., , , et al.
- 34Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma [abstract]. Proc Am Soc Clin Oncol. 2004; 23: 381., , , et al.
- 35Phase I study of PTK787/ZK 222584 in metastatic renal cell carcinoma [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 385., , , et al.