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Randomized Study of Three Different Doses of Suramin Administered With a Fixed Dosing Schedule in Patients With Advanced Prostate Cancer: Results of Intergroup 0159, Cancer and Leukemia Group B 9480

From the Comprehensive Cancer Center, University of California, San Francisco; Arroyo Grande Community Hospital, Arroyo Grande, CA; Duke University, Durham, NC; University of Chicago Medical Center, Chicago, IL; Wayne County Memorial Hospital, Detroit, MI; University of Wisconsin Comprehensive Cancer Center, Madison, WI; Columbia Presbyterian Medical Center, New York, NY.

Address reprint requests to Eric J. Small, MD, University of California, San Francisco, UCSF Comprehensive Cancer Center, 1600 Divisadero St, Third Floor, San Francisco, CA 94115; email: smalle{at}medicine.ucsf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent.

PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m², respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated.

RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P = .49). The objective response rate was 9%, 7%, and 15%, respectively (P = .10). PSA response rates were 24%, 28%, and 34%, respectively (P = .082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity.

CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.

	INTRODUCTION

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PROSTATE CANCER IS the most common cancer and the second leading cause of death due to cancer in North American men.¹ Although androgen deprivation results in stabilization or regression of disease in approximately 80% of patients with metastatic disease, all patients ultimately develop hormone-refractory prostate cancer (HRPC).² The median survival for this group of patients is less than 1 year, and to date, no agent has been shown to prolong survival in HRPC patients.^3,4 Novel therapeutic agents for the treatment of HRPC are urgently required.

Suramin is a highly charged polysulfonated naphthylurea that is capable of binding a number of proteins, including a variety of growth factors such as basic fibroblast growth factor. However, it is not clear to what degree the antitumor effects of suramin are mediated by this mechanism.^5-11 A double-blind, placebo-controlled phase III trial comparing the efficacy of suramin plus hydrocortisone (HC) with placebo plus HC in patients with symptomatic HRPC was recently reported.¹² Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank-sum P = .0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P = .001), and the duration of pain response was longer for suramin-treated patients (median, 240 v 69 days; P = .0027). The time to disease progression was longer (relative risk, 1.5; 95% confidence interval [CI], 1.2 to 1.9) and the proportion of patients with a more than 50% decline in prostate-specific antigen (PSA) was higher (33% v 16%; P = .01) in patients who received suramin. There was no difference in overall survival, with a median survival of 10.2 months for the suramin-treated patients and 9.9 months for the placebo-treated patients.¹² Although this study suggested the possibility of a clinical advantage of suramin over placebo, there were concerns with the complex administration schedule required with potential toxicity, in particular dose-dependent neurotoxicity.

During the time period that the suramin plus HC versus placebo plus HC trial was conducted, investigators at the University of Chicago developed a simplified suramin dosing regimen.⁸ A fixed-dose schema was used to test the hypothesis that a pharmacokinetically based empiric dosing scheme was both feasible and safe. The delivery of intermittent doses of suramin by a 1-hour infusion on days 1, 2, 8, and 9 of a 28-day cycle provided a smooth approach to the steady state. Given the long elimination half-life of suramin, doses were incrementally decreased throughout the course of therapy to avoid high peak plasma concentrations.

The hypothesis that higher doses of cytotoxic agents result in improved outcome in patients with HRPC has not been tested in a prospective randomized trial. Phase I/II data from the University of Chicago had suggested that there might be a higher likelihood of a decline in PSA in patients who achieve higher day 1 peak suramin levels.⁸ Of note, PSA levels decreased by more than 50% in 5% of patients receiving 1,440 mg/m² of suramin but in 53% of patients receiving more than 1,440 mg/m² of suramin on day 1. Although these data were of interest, no conclusions regarding the relative efficacy of various suramin dose levels could be made on the basis of this phase I trial.

The hypothesis of Cancer and Leukemia Group B (CALGB) 9480 was that the efficacy and toxicity of suramin in the treatment of chemotherapy-naive HRPC patients was dose dependent. The University of Chicago schedule was used because it was the only schedule that had been studied at the three proposed levels. The first level corresponded to the lowest dose level on the University of Chicago regimen at which activity was observed, with 3.192 g/m² of suramin administered. The total suramin dose delivered on the intermediate dose level was 5.32 g/m² and approximated the total dose delivered by most other schedules.^6,9,12 The high-dose level (1,440 mg/m²) was designed to deliver a total dose of 7.661 g/m² of suramin. The purpose of this study was to compare the response rates across the three different doses of suramin.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Eligibility Criteria
Eligible patients had histologically confirmed adenocarcinoma of the prostate. Patients had metastatic prostate cancer with progressive disease by conventionally defined objective evidence of tumor growth, or, for patients with bone scan abnormalities only, a minimum PSA level of 10 ng/mL that had increased by at least 50% over baseline on at least two occasions at least 2 weeks apart. Progressive disease despite androgen deprivation was required; antiandrogen withdrawal for at least 4 weeks was mandated in those patients receiving an antiandrogen. Other criteria included an Eastern Cooperative Oncology Group performance status of 2 and an expected survival of at least 3 months. Required laboratory parameters included serum creatinine 2.0 times the upper limit of normal (ULN); AST and ALT 2.5 times the ULN; bilirubin less than the ULN; hemoglobin 9 g/dL; platelets more than 100,000/µL; absolute neutrophil count 1,200/µL; and normal prothrombin time, partial thromboplastin time, and fibrinogen level. Exclusion criteria included requirements for systemic corticosteroids, any prior nonhormonal systemic therapy, radiation therapy within 28 days, radiopharmaceutical administration within 90 days, or prior malignancy. Patients with a requirement for treatment with heparin or warfarin were not eligible. All patients provided written, informed consent before study enrollment.

Study Design
Patients without prior orchiectomy continued receiving gonadal suppression with a luteinizing hormone–releasing hormone agonist. Patients were stratified according to performance status (0 to 1 v 2), presence or absence of soft tissue disease, and number of prior hormonal treatments (1 or 2 v 3). Patients were randomized with equal probability to receive suramin at a low dose (3.192 g/m² total dose), intermediate dose (5.320 g/m² total dose), or high dose (7.661 g/m² total dose), with incremental decreases in dosing over 10 weeks as listed in Table 1. All patients received HC, 25 mg orally (PO) each morning and 15 mg PO each afternoon, throughout suramin treatment. Patients randomized to the high-dose arm also received fludrocortisone 0.1 mg PO every other day. Adrenal function testing (adrenocorticotropic hormone stimulation testing) was undertaken at completion of therapy and every 12 weeks thereafter if results were abnormal. HC and fludrocortisone taper was permitted after week 12 only if a physiologic response to adrenocorticotropic hormone testing was obtained. PSA levels were measured weekly during treatment, then monthly after treatment ended. Measurable lesions were assessed at baseline, at week 12, and then every 3 months. Toxicity was graded according to CALGB expanded common toxicity criteria. If grade 3 or 4 toxicity occurred, dosing was interrupted until the toxicity resolved to grade 1 or baseline. Patients who experienced any persistent ( 4 weeks) or recurrent grade 3 or 4 toxicity without significant antitumor response were considered to have reached dose-limiting toxicity and were removed permanently from study treatment.

Statistical Design and Data Analysis
This trial was designed to compare response rates across the three levels of suramin. The target sample size was 378 patients, allowing for a 10% unassessable rate. The trial was designed to have 115 patients per group to detect, with 90% power and a two-sided alpha level of 0.05, response rates of 25%, 30%, and 45% in the low-, intermediate-, and high-dose arms, respectively. The study was monitored by CALGB and the Data Safety Monitoring Board. The Lan and DeMets analog of the O’Brien-Fleming sequential boundary was used to maintain the overall significance level of alpha = 0.05 while interim analyses of this study were conducted.¹⁴ CALGB Statistical Center personnel were responsible for quality assurance for all the data submitted by the participating institutions. Data were analyzed by using an intent-to-treat approach. Pearson ² tests and the F test were used to compare treatment arms on demographic and clinical variables and response rates (PSA and objective rates). Exact CIs based on the binomial distribution were used to estimate the 95% CI for response rates. The Kaplan-Meier product-limit estimator¹⁵ was used to estimate the overall survival and progression-free survival across the three treatment arms, and the log-rank test statistics were used to compare the three treatment arms. The proportional hazards model was used to assess variables that were predictive of survival time. To minimize lead-time bias, landmark analyses¹⁶ at 8, 12, and 16 weeks after randomization were performed. In these analyses, survival duration was defined as the time between the landmark and death. All tests were performed with a two-sided alpha of 0.05.

Pharmacokinetics
Relationships between plasma suramin concentrations and response (PSA and clinical), toxicity, and survival were evaluated. Plasma samples drawn on days 2, 8, 9, and 29 were assayed for suramin concentrations, as previously described.⁸ The concentrations on days 2 and 9 represent residual suramin taken approximately 24 hours after a dose of suramin. The other 2 days’ concentrations are trough concentrations taken after the most recent dose of the drug (see Table 1 for the treatment schedule). Logistic regression was used to examine relationships between dichotomous outcomes and concentration and the proportional hazards regression model for survival. For toxicity, the outcome was the risk of grade 3 or higher nonhematologic toxicity and the risk of grade 4 or higher hematologic toxicity. The toxicity analyses included the worst toxicity reported at any time during the treatment period, as well as during the first two cycles of therapy (ie, the first 6 weeks). Treatment arm was included in the regression models to stratify the analysis accordingly, to see whether pharmacokinetic variation within each treatment group further explained variation (or predicted response) compared with using the treatment group by itself. All quoted P values are two sided.

	RESULTS

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Patient Characteristics
From December 1995 to December 1996, 390 patients were enrolled onto the study: 131 in the low-dose arm, 129 in the intermediate-dose arm, and 130 in the high-dose arm. All patients enrolled were included in an intent-to-treat analysis. The three groups of patients were balanced regarding age, race, performance status, percentage with measurable disease, number of prior hormonal therapies, PSA level, hemoglobin level, and alkaline phosphatase level (Table 2).

View larger version (14K): [in this window] [in a new window]   Fig 1. Survival by treatment arm (CALGB 9480).

View larger version (15K): [in this window] [in a new window]   Fig 2. Time to disease progression (CALGB 9480).

View larger version (13K): [in this window] [in a new window]   Fig 3. CALGB 9480: landmark analysis at 20 weeks by 50% prostate-specific antigen reduction.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

This is the first randomized study in HRPC patients that has evaluated a dose-response question. Although high-dose suramin was associated with a higher objective response rate and possibly PSA response rate, these were not statistically significant, and overall no dose-response relationship was observed for survival or progression-free survival. Similarly, the measured suramin concentration did not correlate with survival, PSA response, or objective response.

The correlation of PSA decline with survival remains debated,^17-20 although in another suramin series, a PSA decline of more than 50% correlated with survival, time to objective progression, and time to pain progression.²⁰ In this series, a PSA decline of more than 50% also correlated with prolonged survival. Other predictors of survival in a proportional hazards model included alkaline phosphatase, PSA, lactate dehydrogenase, and the requirement for opioid analgesics.

Although dose level did not correlate with clinical efficacy, there clearly was increased toxicity on the higher dose level. Adverse events paralleled the toxicity reported in earlier trials. The higher levels of cardiac and neurologic toxicity and asthenia make the high-dose level on this schedule impractical. By contrast, patients treated on the low-dose level experienced quite modest toxicity, making it the preferred arm on this study.

The lack of a dose-response relationship and the toxicity profile observed raise questions as to the utility of suramin, and in particular high-dose suramin, as administered on this schedule. These results stand in contradistinction to the recently published trial of suramin plus HC versus placebo plus HC,¹² in which toxicity seemed to be manageable and in which there was evidence of a modest anticancer effect. This discrepancy may reflect differences in the dosing schedule, a patient selection bias, or both. Because there was not a dose-response relationship with this schedule, a low dose of suramin that provides a modest anticancer effect with lower toxicity is the preferred dose. Whether this effect is superior to that seen with HC alone was not addressed by this trial. The optimal therapy, if any, for HRPC patients with disease progression after front-line chemotherapy is unknown. A relatively well-tolerated agent, such as low-dose suramin, could be considered for testing as second-line therapy, given its modest efficacy in the front-line setting. Of perhaps greater interest is the observation that in a preclinical prostate cancer model, low-dose suramin alone did not have significant anticancer activity, but its addition to paclitaxel significantly enhanced the activity of single-agent paclitaxel therapy.²¹ Thus, although high-dose suramin clearly has a less favorable therapeutic index than currently used taxane-based regimens, evaluation of low-dose suramin, with its attendant improved toxicity profile, either in combination with other agents or as salvage therapy, could be considered.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The appendix of participating investigators is available online at www.jco.org.

The following investigators participated in the study: Stephen George, PhD (supported by CA33601), CALGB Statistical Office, Durham, NC; Lee S. Schwartzberg, MD (supported by CA71323), Baptist Cancer Institute Community Clinical Oncology Program (CCOP), Memphis, TN; Irving M. Berkowitz, DO (supported by CA45418), Christiana Care Health Services, Inc, CCOP, Wilmington, DE; Jeffrey Kirshner, MD (supported by CA45389), Community Hospital–Syracuse CCOP, Syracuse, NY; George P Canellos, MD (supported by CA32291), Dana-Farber Cancer Institute, Boston, MA; Marc S. Ernstoff, MD (supported by CA04326), Dartmouth Medical School–Norris Cotton Cancer Center, Lebanon, NH; Jeffrey Crawford, MD (supported by CA47577), Duke University Medical Center, Durham, NC; H. James Wallace Jr, MD (supported by CA35091), Green Mountain Oncology Group CCOP, Bennington, VT; Jonathan A. Polikoff, MD (supported by CA45374), Kaiser Permanente CCOP, San Diego, CA; Marc Citron, MD (supported by CA11028), Long Island Jewish Medical Center, Lake Success, NY; Michael L. Grossbard, MD (supported by CA12449), Massachusetts General Hospital, Boston, MA; Lewis R. Silverman, MD (supported by CA04457), Mount Sinai School of Medicine, New York, NY; Louis A. Leone, MD (supported by CA08025), Rhode Island Hospital, Providence, RI; Ellis Levine, MD (supported by CA02599), Roswell Park Cancer Institute, Buffalo, NY; James N. Atkins, MD (supported by CA45808), Southeast Cancer Control Consortium, Inc, CCOP, Goldsboro, NC; John Ellerton, MD (supported by CA35421), Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV; Stephen L. Graziano, MD (supported by CA21060), State University of New York Upstate Medical University, Syracuse, NY; Clara D Bloomfield, MD (supported by CA77658), The Ohio State University Medical Center, Columbus, OH; Robert Diasio, MD (supported by CA47545), University of Alabama Birmingham, Birmingham, AL; Stephen L. Seagren, MD (supported by CA11789), University of California at San Diego, San Diego, CA; Alan P. Venook, MD (supported by CA60138), University of California at San Francisco, San Francisco, CA; Gini Fleming, MD (supported by CA41287), University of Chicago Medical Center, Chicago, IL; Jeffrey A. Sosman, MD (supported by CA74811), University of Illinois MBCCOP, Chicago, IL; David Van Echo, MD (supported by CA31983), University of Maryland Cancer Center, Baltimore, MD; Bruce A. Peterson, MD (supported by CA16450), University of Minnesota, Minneapolis, MN; Michael C. Perry, MD (supported by CA12046), University of Missouri/Ellis Fischel Cancer Center, Columbia, MO; Anne Kessinger, MD (supported by CA77298), University of Nebraska Medical Center, Omaha, NE; Thomas C. Shea, MD (supported by CA47559), University of North Carolina at Chapel Hill, Chapel Hill, NC; Harvey B. Niell, MD (supported by CA47555), University of Tennessee Memphis, Memphis, TN; Hyman B. Muss, MD (supported by CA77406), Vermont Cancer Center, Burlington, VT; David D. Hurd, MD (supported by CA03927), Wake Forest University School of Medicine, Winston-Salem, NC; John C. Byrd, MD (supported by CA26806), Walter Reed Army Medical Center, Washington, DC; and Michael Schuster, MD (supported by CA07968), Weill Medical College of Cornell University, New York, NY.

	ACKNOWLEDGMENTS

 
Supported in part by National Cancer Institute grant no. CA31946 to the Cancer and Leukemia Group B. Also supported in part by a CaPCURE Young Investigator Award, The Aurthur and Linda Gelb Center for Translational Research at the Dana-Farber Cancer Institute, and The T.J. Martell Foundation for Leukemia, Cancer and AIDS Research.

	NOTES

 
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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6. Eisenberger MA, Sinibaldi VJ, Reyno LM, et al: Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer. J Clin Oncol 13: 2174-2186, 1995[Abstract/Free Full Text]

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13. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17: 3461-3467, 1999[Abstract/Free Full Text]

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Submitted October 9, 2001; accepted April 29, 2002.

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