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A Pharmacokinetically Guided Phase II Study of Carboxyamido-triazole in Androgen-independent Prostate Cancer¹

Medicine Branch [K. S. B., W. D. F., J. M. H., V. D., J. M. P., E. R.], Biostatistics and Data Management Section [S. M. S.], and Urological Oncology Branch [W. M. L.], Division of Clinical Sciences, National Cancer Institute, NIH, and Radiology Department, NIH Clinical Center [E. C. J., A. P.], Bethesda, Maryland 20892

	ABSTRACT

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We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing.

Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 µg/ml would be maintained.

Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed.

CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases. Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed.

	INTRODUCTION

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CAI³ is an inhibitor of non-voltage-gated calcium-mediated signal transduction. In vitro and in vivo studies have shown CAI to possess anti-invasive, antimetastatic, and antiangiogenic properties (1 , 2) . Preclinical activity of CAI was demonstrated in human melanoma and human ovarian cancer in nude mouse xenograft experiments (1 , 3) . CAI has also demonstrated in vitro activity in a number of tumor types, including breast, prostate, and glioblastoma (4, 5, 6) In the prostate cancer cell line LNCaP, CAI has also been shown to decrease PSA secretion at concentrations having minimal cell killing effect (4) .

CAI has also been extensively studied in the Phase I clinical setting. Several formulations of CAI have been used in Phase I clinical trials. In early investigations of this compound, either a liquid or a liquid gel cap preparation was used. A Phase I study at the NCI demonstrated a 49% (24 of 49) rate of disease stabilization using these formulations (7) . In a concurrent Phase I investigation using these preparations of CAI at UW, one partial response in a prostate cancer patient was noted (8) . However, these formulations were not well tolerated, and due to compliance-limiting gastrointestinal toxicity, an encapsulated micronized powder formulation was prepared. In a Phase I study at the NCI using the micronized formulation, 10 of 21 patients (47%) experienced disease stabilization, and the formulation was found to be generally well tolerated but with dose-limiting toxicities of cerebellar ataxia and confusion (9) . These dose-limiting toxicities occurred at a CAI dose of 350 mg/m²/day, and thus, the maximum tolerated dose was determined to be 300 mg/m²/day (9) .

Several patients receiving CAI at UW experienced some degree of vision disturbance.⁴ All patients experiencing this toxicity were noted to have CAI concentrations of >6.0 µg/ml at the time of toxicity, and vision returned to baseline levels several weeks after discontinuation of CAI. On the basis of the antiproliferative and antimetastatic activity of CAI in prostate cancer cell lines in vitro and the observed disease stabilization and partial response in patients on the UW trial, we proceeded with this prostate cancer-specific Phase II clinical trial. Due to the apparent concentration related vision loss, this trial was designed such that the CAI dose was determined using patient-specific pharmacokinetic analysis.

	MATERIALS AND METHODS

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Patients and Study Design.
Patients with histologically documented stage D2 adenocarcinoma of the prostate were generally eligible. Eligibility criteria included: clinical progression for at least 1 month following antiandrogen withdrawal; measurable soft tissue metastases; life expectancy of >3 months; Eastern Cooperative Oncology Group performance statue of 0, 1, or 2; granulocyte count of 1,000 cells/mm³; platelet count of 75,000 cells/mm³; hemoglobin level of 9.0 g/dl; serum creatinine level of 1.5 mg/dl or 24-h creatinine clearance of 60 ml/min; serum bilirubin level of 1.5 mg/dl; alanine aminotransferase and aspartate aminotransferase levels that were 2.5 times the upper limit of normal; serum testosterone in the range expected for castrated males (<50 ng/dl); age of 18 years; and signed informed consent. All patients must have recovered from any toxicity related to prior therapy, including surgery. Prior chemotherapy must have ceased at least 4 weeks (6 weeks for mitomycin C or nitrosoureas) before treatment. All patients that had not undergone surgical castration continued to receive an luteinizing hormone-releasing hormone agonist. Patients were excluded if they had any concurrent nonskin malignancy, liver metastases comprising greater than one-third of the total liver volume, active infection (including positive serology for HIV), history of brain metastases, recent history (within 6 months) of myocardial infarction or unstable or newly diagnosed angina pectoris, New York Heart Association class II–IV congestive heart failure, chronic obstructive pulmonary disease requiring oxygen, uncontrolled seizure activity, type I diabetes mellitus, grade II clinically detectable peripheral neuropathy, or noncancer life-threatening illness.

Prior to enrollment, a complete medical history was documented, physical and ophthalmological examinations were performed, and an echocardiogram was recorded for each patient. Physical examinations and blood indices were repeated at 1, 2, and 4 weeks and repeated every 4 weeks after initiation of therapy. Ophthalmological exams were repeated as necessary.

Treatment Plan.
CAI was initiated at a p.o. dose of 250 mg/m²/day, rounded down to the nearest 50-mg increment. Drug was administered in the morning, under fasting conditions, for 7 days. On day 8, patients began taking the medication at a dose calculated to maintain a maximum steady-state plasma concentration of CAI between 2.0 and 5.0 µg/ml. The maximum daily dose could not exceed 350 mg/m²/day. The daily dose was modified upon reassessment of pharmacokinetic parameters if the predicted steady-state maximum concentration was determined to be outside the range of 2.0–5.0 µg/ml. Patients experiencing NCI grade III or IV toxicity (or NCI grade II–IV CNS toxicity) at CAI plasma concentrations of <5.0 µg/ml had their dose held for at least 1 week. Upon resolution of symptoms, therapy was resumed at a dose calculated to achieve a steady-state maximum concentration of one-half that present at the time of toxicity. Patients were not eligible to resume therapy if their toxicity did not resolve within 1 month.

Clinical Evaluation.
Patients were evaluated for toxicity according to the NCI common toxicity criteria on days 7, 14, and 28 and every 4 weeks thereafter. Additionally, patients were evaluated for response by CT and ⁹⁹Tc bone scintigraphy (bone scan) approximately every 8 weeks. Complete response to therapy was defined by the disappearance of all evidence of tumor for at least two measurement periods, separated by 4 or more weeks. Partial response was defined as a decrease of 50% in the sum of the longest bidimensional products of measurable soft tissue lesions with no new lesion formation, lasting at least 4 weeks. Disease progression consisted of either an increase of >25% in the sum of the products of all measurable lesions, the appearance of new lesions, or the development of urethral, ureteral, or spinal cord obstruction secondary to tumor. Stable disease was defined as any situation that did not fit the criteria of response or disease progression, which was maintained for at least 6 months. A 6-month disease stabilization was considered a clinically meaningful finding due to the fact that disease progression can be relatively slow in a small number of stage D prostate cancer patients.

Pharmacokinetic Analysis.
Blood samples were obtained in heparinized tubes during the first week of therapy. Samples were collected prior to treatment and at 4, 8, 12, 24, 30, 36, 48, 54, 60, 72, 80, and 96 h after the first dose or at 2, 8, 14, 24, 30, 36, 48, 49.5, 58, 72, 76, and 96 h after the first dose. During maintenance therapy, samples were collected at 1, 2, and 4 weeks after initiation of therapy and then every 4 weeks thereafter. The blood samples were centrifuged at 1250 x g for 7 min, and the plasma was then collected and stored at -80°C until time of analytical analysis. The concentration of CAI in plasma was determined using an high-performance liquid chromatography assay, with a lower limit of quantitation of 0.02 µg/ml (10) . All samples were assayed in duplicate, and the mean CAI concentration was used for pharmacokinetic analysis. Pharmacokinetic parameters were calculated using ADAPT II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA) with the use of the maximum a posteriori Bayesian estimator (11) .

Pharmacokinetic parameters and variances reported in a previously published Phase I study of CAI (9) , in addition to new data obtained prior to this study, were used as Bayesian prior estimates. A one-compartment open linear model was fit to the data. The pharmacokinetic parameters estimated include: total oral clearance (Cl/F), apparent volume of distribution (V/F), elimination rate constant (k_e), rate constant of absorption (k_a), and elimination half-life (t_1/2). Pharmacokinetic parameter estimates and associated SDs used as Bayesian priors for this analysis were: V/F, 801.7 ± 496.4 liters; k_a, 0.203 ± 0.202 h^-1; and k_e, 0.0191 ± 0.0111 h^-1. The pharmacokinetic parameters determined from each patient’s plasma concentration time data were used to determine the maintenance dose of CAI. The maintenance dose was estimated using the expression C_ss = (dose per 24 h)/Cl, rounded down to the nearest 50 mg, and then verified using each patient’s specific pharmacokinetic parameters to simulate maintenance dosing to steady state using ADAPT II.

Pharmacodynamic Evaluation.
Blood samples were obtained in evacuated tubes without additives prior to initiation of therapy and on days 7, 14, and 28 and every 4 weeks thereafter following the start of CAI administration. These samples were centrifuged at 1250 x g for 7 min, the serum was then collected and stored at -80°C until the time of analysis. Serum samples were analyzed for VEGF and bFGF concentration using the Quantikine Human VEGF and Human bFGF Immunoassays (R&D Systems, Minneapolis, MN).

Statistical Considerations.
This study was originally designed using a one-stage design in which 36 patients were required. If 10 or fewer patients survived progression free at 6 months, then the treatment was to be rejected. Otherwise, with 11 or more patients exhibiting 6-month progression free survival, the treatment was to be considered promising. Under this design, at 6 months, a frequency of 40% disease-free patients was considered desirable, and a frequency of 20% was considered unacceptably low, with a 10% probability of false-positive and false-negative errors.

A comparison between day 0 and day 28 serum VEGF concentrations was determined using a paired t test on the data of patients at both time points. This analysis was performed after verifying that the differences were consistent with data arising from a normally distributed population.

An analysis was performed to assess the association between grade of neurological toxicity and the CAI concentration at the time of the toxicity. Because multiple instances of the same type of toxicity were reported for some individuals, they were interpreted as continuing reports of the same episode, and a rule was devised to select the toxicity and concentration values included in the analysis. The first reported instance of a particular grade and type of toxicity was included when there were two or more cases with the same type and grade of toxicity. When there were multiple instances of the same type of toxicity but varying grades, the highest grade for a particular type of toxicity (and its associated concentration) was analyzed. Because only one patient experienced a grade III toxicity, this event was included with the grade II toxicity data, and thus, CAI concentrations associated with episodes of grade II and III toxicity together were compared with concentrations associated with episodes of grade I toxicity. The two-sample t test was used to determine the significance of the difference of the concentrations between the two groups of episodes of neurological toxicity, assuming that unrelated types of toxic events within the same individual were statistically independent from one another. All Ps reported here are two-tailed (denoted by P₂).

	RESULTS

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Patient Evaluation.
Fourteen of the 15 patients enrolled onto this study were evaluable for response (Table 1) . One patient was taken off study after only 2 weeks of therapy due to grade II peripheral neuropathy, which did not resolve within 1 month following discontinuation of CAI (Table 2) . The plasma CAI concentration at that time was 2.09 µg/ml. Although the study originally called for enrolling 36 patients, when the first 14 evaluable patients exhibited rapid progression, it was determined that the study should stop accrual. The probability of eventually obtaining 11 or more patients of 36 with a successful avoidance of disease progression by 6 months was <1%, given that the true probability of "success" was apparently no greater than 20% and the fact that 11 of the next 22 patients would have needed to exhibit acceptable disease stabilization in order for this to occur. Thus, the study was stopped after a total of 15 patients were enrolled.

Pharmacokinetics.
A pharmacokinetic assessment of data obtained during the first 5 days of daily treatment with 250 mg/m²/day CAI was performed. Approximately 24 h after the fourth daily dose of CAI, the final blood sample was obtained. On study days 5, 6, and 7, plasma samples were analyzed for CAI concentration and individual patients’ CAI pharmacokinetic parameter estimates were used to determine their specific daily dose. Following the initial assessment period, nine patients required an increase, two patients required a decrease, and four patients needed no change from the initial dose of 250 mg/m²/day. Each patient began treatment with his pharmacokinetically determined dose on study day 8. Individualized patient doses are listed in Table 3 . Data from pharmacokinetic analyses using only the assessment period are listed in Table 4 ; additionally, parameter estimates using all of the plasma concentrations obtained are also listed. Using a Bayesian approach, we fit the data to a one-compartment open linear model with first-order absorption; this model fit the data well. Fig. 1 shows a representative concentration-time curve for a patient during the initial assessment period and during the entire time on study. Fig. 2 is the simulated concentration-time profile of this patient using the pharmacokinetic parameters determined during the initial assessment to predict plasma concentrations during maintenance therapy with CAI. Fourteen of 15 patients enrolled onto the study reached the targeted concentration range following the initial assessment period. One patient (Table 3 , patient 7) was not dose-adjusted following the initial assessment period due to toxicity he was experiencing at the time of the expected dosage adjustment. Although this patient’s pharmacokinetically determined dose was estimated to be 700 mg/day, this patient was maintained at 500 mg/day for the duration of the study, This was due to grade II fatigue at the time of the expected dose adjustment and grade II nausea and grade I vomiting at subsequent assessments.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Plasma concentration versus time curve for a representative patient. Model-fitted CAI concentrations () and measured CAI concentration (•) are shown. A, data obtained during the pharmacokinetic assessment period; B, data from the entire study duration.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Plasma concentration versus time curve for a representative patient. Simulated CAI concentrations using the pharmacokinetic parameters obtained during the pharmacokinetic assessment period () and measured CAI concentration (•) are shown.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Individual patient plasma VEGF concentrations prior to CAI treatment and at the 28-day assessment (n = 10).

	DISCUSSION

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Patient enrollment was limited to patients with measurable soft tissue disease. This was due to the demonstrated ability of CAI to inhibit the production of PSA by LNCaP cells. At CAI concentrations of 2.125 and 4.25 µg/ml, the LNCaP PSA secretion, adjusted for cell number, was decreased by 25 and 60%, respectively (4) . Therefore, we did not use PSA as a marker for disease progression. As can be seen in Table 3 , all of the evaluable patients progressed at the 8-week assessment. One patient received CAI for 80 days. However, this was due to the patient’s 8-week follow-up visit being delayed by 2 weeks. This patient was shown to have progressed by CT scan at that time. Another patient received therapy for 89 days. Although this patient showed a slight improvement on CT scan at the 8 week follow-up, 1 month thereafter, this patient developed CNS carcinomatosis and bone metastases and was withdrawn from the study. Thus, CAI does not possess clinical activity in patients with androgen-independent prostate cancer with soft tissue metastases. If this agent does possess activity in patients with prostate cancer it is likely that only patients with early-stage or organ-confined disease would benefit.

Ninety-three % of the patients enrolled onto the study achieved CAI concentrations within the desired range after the initial assessment period (Table 3) . Therefore, we conclude that pharmacokinetically guided dosing in this investigation was successful. One patient did not achieve the minimum desired concentration of 2.0 µg/ml. This patient was experiencing toxicity that, in the judgment of the investigators, precluded the recommended dosage increase. Despite the pharmacokinetic success, this method of dose determination did not succeed at its primary goals, to prevent drug-related toxicity and toxicity-related withdrawal from the study. Although relatively tight control of plasma concentrations within the theorized therapeutic range was achieved, one patient was withdrawn from study for persistent grade II peripheral neuropathy (CAI concentration, 2.09 µg/ml), and another patient experienced grade III peripheral neuropathy (CAI concentration, 4.73 µg/ml). Of note, the plasma concentrations of CAI in these patients were at opposite ends of the therapeutically accepted range.

In a Phase I clinical trial conducted at the NCI, it appeared that no association could be made between CAI plasma concentration and either toxicity or disease stabilization (9) . Additionally, a pharmacokinetic study of CAI reported the plasma protein binding of this compound to be 99.6% at the concentrations studied (13) . There was a lack of association observed between total plasma concentrations and clinical effect and toxicity in a previous study as well (9) . The data suggest that variability in unbound CAI concentration may be responsible for variability in clinical effect. At present, the lower limit of detection for CAI in human plasma is 20 ng/ml, which is insufficient for the determination of free concentrations in vivo.

Although a positive clinical effect was not achieved, we have demonstrated a significant decrease in serum concentration of VEGF following chronic treatment with CAI. We have demonstrated a 27.7% decrease in serum VEGF concentration following CAI administration to these patients. Although this significant decrease was revealed, no clear interpatient pattern emerged. If further investigation with CAI reveals a disease state for which this compound shows efficacy, it may be possible to demonstrate an association between CAI treatment, VEGF concentration, and clinical effect or toxicity. Thus, VEGF could theoretically be used as a surrogate marker for unbound CAI concentration in a pharmacodynamic assessment. This report demonstrates the feasibility of pharmacokinetically guiding the dose of CAI within a specified range. However, the design used here is labor-intensive and costly. Given the relative lack of success at preventing toxicity, we question the practical value of a pharmacokinetically guided dosing scheme for this drug.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was funded by the United States Government.

² To whom requests for reprints should be addressed, at National Cancer Institute, Building 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 402-3622; Fax: (301) 402-8606; E-mail: wdfigg{at}helix.nih.gov

³ The abbreviations used are: CAI, carboxyamido-triazole; PSA, prostate-specific antigen; NCI, National Cancer Institute; UW, University of Wisconsin; CNS, central nervous system; CT, computed tomography; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor.

⁴ G. Wilding, personal communication.

Received 3/22/99; revised 6/17/99; accepted 6/24/99.

	REFERENCES

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