Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer.

BACKGROUND: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE: We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS: In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, soft-tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of soft-tissue disease. CONCLUSIONS: Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS: On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.

A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer.

Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.

Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein.

The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human alpha1-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to alpha1-acid glycoprotein.

Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin.

PURPOSE: To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin. METHODS: Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks). RESULTS: Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL. CONCLUSION: Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.

Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms.

PURPOSE: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. PATIENTS AND METHODS: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling. RESULTS: Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred. CONCLUSION: The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms.

PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target.

Cyclin-dependent kinases (CDKs) have been recognized as key regulators of cell cycle progression. Alteration and deregulation of CDK activity are pathogenic hallmarks of neoplasia. Therefore, inhibitors or modulators would be of interest to explore as novel therapeutic agents in cancer, as well as other hyperproliferative disorders. Flavopiridol is a semisynthetic flavonoid that emerged from an empirical screening program as a potent antiproliferative agent that mechanistic studies demonstrated to directly inhibit CDKs 1, 2, and 4 as a competitive ATP site antagonist. Initial clinical trials have shown that concentrations that inhibit cell proliferation and CDK activity in vitro can be safely achieved in humans, and additional clinical trials will establish its clinical potential. To address the need for additional chemotypes that may serve as lead structures for drugs that would not have the toxicities associated with flavopiridol, compounds with a similar pattern of cell growth inhibitory activity in the National Cancer Institute's in vitro anticancer drug screen have been recognized by the computer-assisted pattern recognition algorithm COMPARE and then screened for anti-CDK activity in a biochemical screen. The benzodiazepine derivative NSC 664704 (7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one) was revealed by that approach as a moderately potent (IC50 0.4 microM) inhibitor of CDK2, which in initial experiments shows evidence of causing cell cycle redistribution in living cells. NSC 664704 is, therefore, a candidate for further structural optimization, guided in part by understanding of the ATP-binding site in CDK2. This approach represents one way of combining empirical screening information with structure-based design to derive novel candidate therapeutic agents directed against an important cellular target.

A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer.

Micromolar concentrations of tamoxifen inhibit the activity of protein kinase C and were recently shown to inhibit prostate cancer cell growth in preclinical studies. Because micromolar concentrations can be attained with high-dose therapy, the clinical activity of high-dose tamoxifen was evaluated in patients with metastatic adenocarcinoma of the prostate. Between December 1993 and February 1997, 30 patients with hormone-refractory metastatic adenocarcinoma of the prostate were continuously administered tamoxifen at 160 mg/m2/day. Therapy was continued until disease progression. All study patients had failed prior treatment with combined androgen blockade, had castrate levels of testosterone, and were heavily pretreated, having received a median of three prior regimens. The average steady-state plasma concentration of tamoxifen was 2.96+/-1.32 microM (mean +/- SD). Grade 3 neurotoxicity was observed in 29% of patients and was rapidly reversible and readily managed with dose modification. Otherwise, grade 3 toxicities were rare. One partial response (80% decline in prostate-specific antigen) was observed (3.3%), whereas disease stabilization was observed in six patients (20%), for a combined partial response/stable disease response rate of 23%. Median time to progression was 2.1 months, and median survival time was 10.5 months. High-dose tamoxifen therapy was well tolerated and associated with micromolar concentrations of tamoxifen in human plasma, and it demonstrated activity, albeit limited, in a heavily pretreated patient cohort with hormone-refractory prostate cancer. These findings suggest that further investigation of the role of protein kinase C modulation in prostate cancer is warranted.

Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal.

Management of prostate cancer progression after failure of initial hormonal therapy is controversial. Recently, the activity of the simple discontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal suppression (i.e., aminoglutethimide and hydrocortisone). Furthermore, suramin has generated considerable interest following reports of response rates ranging from 17 to 70%. More recently, suramin response rates of 18 and 22% have been reported when the potential confounding variables of flutamide withdrawal and hydrocortisone were prospectively controlled. On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those with simultaneous antiandrogen withdrawal compared to those who had previously discontinued antiandrogen therapy). Eighty-one evaluable patients were enrolled in this study between June 1992 and November 1994. Patients were a priori divided into two cohorts, those receiving prior antiandrogen withdrawal (n = 56) and those receiving simultaneous antiandrogen withdrawal (n = 25) at the time the patients were enrolled into the trial. For the group that discontinued antiandrogen prior to enrolling in therapy, the partial response rate (> 50% decline in PSA for > 4 weeks) was 14.2%, whereas the partial response was 44% for those patients who discontinued their antiandrogen at the time of starting suramin and aminoglutethimide. The median time to progression was 3.9 months in patients failing prior antiandrogen withdrawal and 5.5 months in those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference). The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [95% confidence interval (CI), 11-32.9%]. For those patients who experienced antiandrogen withdrawal simultaneous with the treatment, the progression-free survival estimates at 1 and 2 years were 27.1 (95% CI, 13.2-47.6%) and 4.5% (95% CI, 0.8-21.6%). The median survival time for those patients having prior antiandrogen withdrawal was 14.2 months, whereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In conclusion, the partial response rate of 44% for those who had concomitant flutamide withdrawal with adrenal suppression was consistent with that of other reports using a similar maneuver. Although this study was not randomized and thus we should not over-interpret the results, flutamide withdrawal plus adrenal suppression appears to have greater activity than flutamide withdrawal alone. Furthermore, these data suggest that suramin adds little to the response rate observed for other adrenal suppressive agents in the presence of antiandrogen withdrawal. This interpretation is in agreement with those studies controlling for adrenal suppression and flutamide withdrawal prior to suramin administration, which noted modest activity of short duration. Given that antiandrogen withdrawal is now accepted as an active maneuver for a subset of patients progressing after maximum androgen blockade, we propose that future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.

A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma.

This study used an 8-day continuous infusion regimen of a 1:1 mixture of two immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA; Combotox) in a Phase I trial involving 22 patients with refractory B cell lymphoma to determine the maximum tolerated dose, clinical pharmacology, and toxicity profile and to characterize any clinical responses. Adult patients received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No intrapatient dose escalation was permitted. Patients with > or =50 circulating tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345 ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that included two deaths probably related to the IT. Additionally, patients exhibited a significant potential for association between mortality and a history of either autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and between mortality and a history of radiation therapy (P2 = 0.036). In patients with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37-dgA. In addition, HD37-dgA thawed at the study site tended to contain significant particulates, which were not apparent in matched controls stored at the originating site. This suggests that a tendency to aggregate may have resulted from shipping, storage, and handling of the IT that occurred prior to preparation for administration. It is not clear to what extent, if any, the aggregation of HD37-dgA IT was related to the encountered clinical toxicities; however, the potential to aggregate does suggest one possible basis for problems in our clinical experience with HD37-dgA and leads us to the conclusion that non-aggregate-forming formulations for these ITs should be pursued prior to future clinical trials.

Hypothyroidism associated with aminoglutethimide in patients with prostate cancer.

OBJECTIVE: The administration of aminoglutethimide and hydrocortisone is a second-line hormonal maneuver commonly prescribed for the treatment of metastatic prostate cancer. We determine the incidence of aminoglutethimide-induced primary hypothyroidism in an elderly population who have prostate cancer. DESIGN: Prospective evaluation. PATIENTS: Twenty-nine men with stage D2 prostate cancer who were treated at the National Cancer Institute, Bethesda, Md, in 1992. RESULTS: Clinical and biochemical evidence of hypothyroidism (thyrotropin levels greater than 10 mU/L) was noted in nine of 29 patients treated following the initiation of aminoglutethimide (250 mg four times daily). The elevation in thyrotropin and the clinical symptoms of hypothyroidism were reversed by the administration of levothyroxine (n = 4). CONCLUSION: Hypothyroidism should be included in the differential diagnosis of lethargy in elderly patients who are receiving aminoglutethimide for prostate cancer. Furthermore, patients who are receiving this agent at a dosage of 1000 mg/d or greater should have their serum thyrotropin levels monitored, and replacement therapy with levothyroxine should be initiated when abnormally elevated levels are noted.

Adaptive control with feedback strategies for suramin dosing.

Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of suramin was initially motivated by an association between acute neurologic toxicity and plasma suramin concentrations in excess of 350 micrograms/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics.

Suramin-induced neutropenia.

This paper presents a retrospective review of 6 cases of severe neutropenia attributed to suramin, the response to granulocyte-colony stimulating factor (G-CSF) and the possible mechanism. Plasma suramin concentrations, G-CSF, platelet-derived growth factor-AB (PDGF-AB) and fibroblast growth factor basic (FGF basic) levels were measured and correlated with neutropenic course. The time course of neutropenia was unpredictable and occurred both during and following discontinuation of suramin. Neutropenia rapidly resolved with G-CSF. Neither the measured growth factor levels nor plasma suramin concentrations correlated with neutropenia. We conclude that neutropenia secondary to suramin is unpredictable and responds to G-CSF administration permitting further suramin therapy. The mechanism remains unknown.

Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine.

Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 +/- 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (+/- SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 +/- 0.07, 0.88 +/- 0.10, and 0.92 +/- 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2-33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 mumol/L) and exhibited saturable elimination (Km = 34.1 +/- 18.1 micrograms/mL and Vmax = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 +/- 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer: toxicity and response.

INTRODUCTION: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. OBJECTIVE: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 microg/ml. METHODS: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 microg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. RESULTS: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 microg/ml for 4 or more weeks. A single patient treated at 215 microg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 microg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 microg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. CONCLUSIONS: In summary, although plasma suramin concentrations were maintained below 300 microg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 microg/ml for 4 or more weeks. Therapy at 215 and 175 microg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin's activity in hormone-refractory prostate cancer.

Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models.

UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.

Anaphylactoid reaction with suramin.

Suramin, a drug used to treat parasitic diseases, is currently being investigated as a treatment for metastatic prostate cancer. A 73-year-old man had an anaphylactoid reaction following the first dose of suramin. It was treated successfully with epinephrine, diphenhydramine, and hydrocortisone. Investigators should be aware of the possibility of such a reaction with parenteral administration of this drug.

Similar clinical outcomes in African-American and non-African-American males treated with suramin for metastatic prostate cancer.

African-American males have a higher incidence of prostate cancer than non-African-American males and an overall poorer prognosis. Environmental factors such as socioeconomic status and biological factors such as an increased frequency of androgen receptor mutation have been identified as causal. As androgen ablation therapy is ubiquitous in the treatment of metastatic prostate cancer, little information is available on clinical outcome independent of hormone therapy. Our experience at the Warren G. Magnusson Clinical Center, National Institutes of Health with the anticancer agent, suramin, offers the opportunity to study clinical outcome in patients treated with an agent whose tumoricidal activity is not dependent on androgen receptor function. Clinical outcome was examined retrospectively in 43 patients treated on a single suramin-based protocol and evaluated as a function of ethnic background. No significant difference in time to disease progression or survival was observed between African Americans (n = 4) and the other 39 patients. These findings are consistent with the hypothesis that therapies that work through mechanisms independent of the androgen receptor may result in similar outcomes across ethnic groups.

Acute renal toxicity associated with suramin in the treatment of prostate cancer.

The use of suramin, a polysulfonated naphthylurea, in the treatment of advanced prostate cancer currently is being investigated. A 52-year-old man developed acute renal dysfunction after receiving nine doses of suramin. His suramin therapy was discontinued, but his serum creatinine level continued to rise to 10.8 mg/dl during the next 6 days. The patient was not rechallenged with suramin, and his renal function returned to baseline within the next 3 weeks. Future investigators of this drug should be aware of the possibility of such a reaction with parenteral administration.

A phase I study of the somatostatin analogue somatuline in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Somatuline, a somatostatin analogue, has proven to be effective in several animal models of prostate cancer. Preliminary clinical studies also have suggested antitumor activity in patients with prostate cancer. The authors conducted a dose-escalation trial of 25 patients with metastatic hormone-refractory prostate cancer. METHODS: Dosages of 4, 7, 10, 13, 18, and 24 mg/day were administered by continuous intravenous infusion for at least 28 days. RESULTS: Plasma levels of insulin-like growth factor-I (IGF-I), but not those of IGF-II, declined modestly during therapy. Toxicities included grade I diarrhea, bloating, infection, nausea, and flatus. The gastrointestinal side effects were typically self-limiting and occurred during the initial portion of treatment cycles. In addition, three patients experienced grade II catheter-related infections. No clinical response was noted by either radiographic or tumor marker criteria. The maximally tolerated dose of somatuline was not determined. CONCLUSION: A continuous intravenous infusion of 24 mg/day of somatuline is well tolerated and could be evaluated in other types of cancer or possibly in less advanced prostate cancer, but no clinical activity was noted at this dose in patients with advanced metastatic hormone-refractory prostate cancer.