Suramin for breast and prostate cancer: A pilot study of intermittent short infusions without adaptive control

Annals of Oncology 5: 597-600, 1994. © 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Suramin for breast and prostate cancer: A pilot study of intermittent short infusions without adaptive control P. J. Woll,1 M. Ranson,1 J. Margison,2 Y. Thomson,2 L. van der Water,1 N. George3 & A. Howell1 1

CRC Department of Medical Oncology and 2 Department of Clinical Pharmacology, Christie Hospital, Manchester; 3 Department of Urology, Withington Hospital, Manchester, UK

Summary

Background: Suramin has shown promising activity against prostate and breast cancer but is severely neurotoxic. Complex adaptive pharmacokinetics have previously been used to adjust doses. We have undertaken a pilot study to assess the feasibility of administering suramin to outpatients with advanced cancer, using simple peak and trough monitoring. Patients and methods: Nine patients with cancer refractory to conventional therapy were studied, eight with breast cancer and one with prostate cancer. Two received continuous infusions of suramin 350 mg/mVday through an indwelling central venous catheter. Both sustained axillary vein thromboses. Subsequent patients received suramin 500 mg/ m2 as a one hour intravenous infusion thrice weekly until a

Introduction Suramin is a polysulphonated naphthylurea that was developed for the treatment of human trypanosomiasis and onchoceriasis over 70 years ago. It has multiple biological properties, including inhibition of RNA virus reverse transcriptase. Testing in AIDS patients indicated some activity against HTV-related tumours and suggested a potential role as an anticancer agent. Whilst suramin is growth inhibitory to a wide range of human cancers in vitro, hormone-resistant prostate cancer has been the subject of most clinical studies because responses were seen in these tumours during phase I testing. In the three phase II studies in prostate cancer published in full, response rates of 0%, 35% and 50% were seen, with biochemical responses (>50% reduction in prostate specific antigen) in 44%, 55% and 77% [1-3]. An intermittent dosing schedule may be associated with better response rates and less toxicity than continuous infusions [4]. Suramin is a highly charged polyanionic compound which exhibits extensive protein binding. This contributes to its many biological effects, including inhibition of 1. binding of polypeptide growth factors such as platelet derived growth factor, epidermal growth factor, basic fibroblast growth factor, and transforming growth

trough serum level of 200 ng/ml was achieved. Treatment was repeated at 8 week intervals. Serum suramin levels were checked before and after each dose. Results: Suramin treatment was well tolerated. Despite peak serum levels of up to 506 (ig/ml, no serious toxicity was seen. No tumour responses were seen. Conclusions: We conclude that suramin can be safely and conveniently administered to outpatients by intermittent infusion without using complex adaptive dosing strategies. Suramin merits further study in less heavily pretreated breast cancer patients. Key words: breast cancer, pharmacokinetics, prostate cancer, suramin

factor-p to their cell-surface receptors; 2. cell migration and adhesion; 3. angiogenesis; 4. adrenal steroidogenesis; 5. signal transduction pathways; 6. cellular enzymes such as DNA polymerase, ATP-ase, trypsinase and DNA topoisomerase; 7. mitochondrial function; and 8. accumulation of tissue and circulating glycosaminoglycans [5]. Which of these mechanisms are involved in the antitumour effects of suramin are unknown. In view of its diverse biological effects, it is perhaps unsurprising that early clinical studies with suramin were complicated by multiple and severe toxicities [6]. These included proteinuria, liver dysfunction, vortex keratopathy, adrenal insufficiency, clotting disorders and peripheral neuropathy. Severe neurological toxicity has been observed at plasma suramin levels >300 ng/ml but no clear correlation between plasma levels and toxicity has been demonstrated [5, 7, 8]. As suramin has a prolonged plasma half-life and levels of >150 ng/ml are probably required for antitumour activity, the drug has a narrow therapeutic window. Several investigators have advocated the use of complex adaptive dosing strategies to optimise dosing [3,7-9]. Polypeptide growth factors such as epidermal growth factor, insulin-like growth factors and fibroblast growth factors can stimulate the growth of breast cancer cell lines. Breast cancer is therefore an interesting

598 candidate for suramin treatment [10]. Suramin has been shown to inhibit the growth of breast cancer cell lines in vitro at concentrations achievable in vivo, although growth stimulation was seen at lower suramin concentrations [11-13]. We have tested the safety and efficacy of suramin given to patients with far advanced breast and prostate cancer as outpatients, with simple pharmacological monitoring.

tified by comparison to a standard curve comprising blank serum spiked with 0-500 ng suramin. An internal control consisting of 200 u.g/ml suramin in blank serum was included in every series of samples. The three compartment population pharmacokinetic parameters determined by a two stage method [9] were used to supplement serum concentration data and a Bayesian algorithm to estimate the serum concentration profiles for each patient retrospectively.

Results Patients and methods

Patient characteristics

Patients with histologically proven breast or prostate cancer and locally recurrent or metastatic disease refractory to conventional hormonal and chemotherapy were eligible for the study if they had evaluable disease, WHO performance status <2, adequate hepatic and renal function, and a life expectancy of at least 3 months. Written informed consent was obtained. The study was approved by the District Ethics Committee. Baseline evaluation included routine haematological, coagulation and biochemical screening (with acid phosphatase and prostate specific antigen in prostate cancer patients). Chest X-ray and radiographs of bony metastases were performed. Twenty-four hour urine collections were sent for creatinine clearance, protein excretion and glycosaminoglycans estimations. A tetracosactrin test was performed at entry and every four weeks during treatment. The first two patients enrolled received suramin (Bayer) 350 mg/ mVday by continuous intravenous infusion through an indwelling central venous catheter. Both patients sustained axillary vein thromboses and subsequent patients received suramin 500 mg/m2 as a one hour infusion thrice weekly until a trough serum level of 200 u.g/ml was attained. Treatment was then discontinued and serum suramin levels were monitored twice weekly. Treatment was repeated at 8 weeks. Patients received prednisolone 10 mg daily thoughout the study. Vitamin K was not given routinely. Disease responses were evaluated using UICC criteria. Suramin levels were measured before and after each suramin infusion and weekly between cycles of therapy. The assay used was a modification of the HPLC method of Klecker and Collins [14). 50 ul samples of serum were extracted using 1 ml of methanol containing 50 mM tetrabutylammonium dihydrogen phosphate (TBAP). After centrifugation, 25 \i\ aliquots of the supernatant were injected onto a C8-spherisorb analytical column and eluted with 50% acetonitrile/ 50% 10 mM ammonium acetate pH 6.5, 5 mM TBAP at a flow rate of 1 ml/min. Detection was by UV absorbance at 240 run and retention time was 4 min. Samples were assayed in duplicate and quan-

Nine patients were studied, 8 with breast cancer and 1 with prostate cancer (Table 1). They were of median age 59 years (range 44-69 years) and a median of 42 months (range 25-122 months) from diagnosis. They had received a median of 2 (range 1-3) prior hormonal treatments and 2 (range 0-3) prior chemotherapy treatments. Baseline creatinine clearance and tetracosactrin tests were normal. Suramin administration Details of the drug administration and serum suramin levels achieved are shown in Table 2. The serum concentration profile in a representative patient is shown in Fig. 1. Toxicity The most commonly reported side effect was mild lethargy (Table 3). Six treatment cycles were associated with an itchy rash that responded to treatment with chlorpheniramine. No serious haematological toxicity was attributable to suramin. Axillary vein thromboses necessitating treatment to be discontinued occurred in the two patients treated by continuous infusion. One patient complained of persistent vaginal bleeding. No patient had deranged thrombin or prothrombin times. Mild blurring of vision was described by three patients

Table 1. Patient characteristics. Number of prior hormone treatments

Number of prior chemotherapies

Sites of disease

Treatment continuous/ intermittent

42

2

2

continuous

breast

27

1

2

skin, nodes, lung, bone lung, bone

F

breast

122

3

3

F F M F F F

breast breast prostate breast breast breast

92 39 25 81 47 38

2 1 1 3 1 2

3 3 0 2 3 2

Patient

Age, years

Gender

Disease

1

49

F

breast

2

53

F

3

65

4 5 6 7 8 9

59 44 59 58 68 69

Months from diagnosis

skin, lung, pleura skin skin, bone bone skin, nodes skin, nodes skin, nodes, pleura

continuous/ intermittent intermittent intermittent intermittent intermittent intermittent intermittent intermittent

599 Table 2. Suramin treatment administration. Peak measured suramin levels are shown in ng/ml, with calculated duration above 150 and 350 Hg/ml. Patient

Cycle 2

Cycle 1

1 2 3 4 5 6 7 8 9

Number of infusions

Peak suramin levels

Hours > 350 ug/ml

days > 150 ug/ml

51 5' 6 6 6 6 5 4 4

213 243 354 434 462 397 443 431 413

0 0 1 4 9 2 2 5 3

2 4 4 17 18 15 9 10 13

Number of infusions

Peak suramin level

Hours > 350 ug/ml

Days> 150 ug/ml

4

467

15

20

4 3 4 5 4 5

444 506 377 359 412 452

5 8 4 5 9 9

19 20 21 17 14 30

Denotes number of days of continuous intravenous infusion. Table 3. Toxicity of suramin given by intermittent infusion (14 cycles in 8 patients). WHO Grade

400

Leucopenia Anaemia Thrombocytopenia Bleeding Lethargy Rash Vision

0

1

2

3

4

11 8 14 12 1 8 10

3 4 0 0 13 1 4

0 2 0 2 0 5 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

longed tissue half life and slow intercompartmental rate constants have led to the development of complex Day] pharmacokinetic approaches using adaptive control Fig. 1. Serum suramin concentration in patient 6. Intravenous infu- and feedback. As a result, the population pharmacosions of suramin 500 mg/m2 were given thrice weekly until a trough kinetics are now well understood. A simpler approach serum level of 200 ug/ml was achieved. Treatment cycles were repeated at 8 week intervals. ( • ) , measured serum concentration; (-), to administering the drug safely is needed for phase II calculated concentration/time curve using population pharmaco- studies. kinetic parameters of Cooper et al. (9] and Bayesian algorithm. Although continuous infusion has the advantage of more rapid attainment of target drug concentration (4 cycles). No mucositis, nausea, vomiting, diarrhoea, than intermittent bolus administration, it carries the constipation or alopecia was observed. No neurological risk of side effects such as catheter-related sepsis and thrombosis. In addition, pump malfunction can cause toxicity occurred. difficulties in determining the dose given by continuous infusion. Drug administration by intermittent bolus or Responses short infusion is simpler and less invasive. In this study, axillary vein thrombosis was observed No rumour responses were seen. The patient with prostate cancer described some improvement in bone pain in two breast cancer patients treated by continuous and a reduction in serum alkaline phosphatase was suramin infusions. This complication has not been reobserved after each treatment cycle but there was no ported in studies in prostate cancer patients. Suramin is significant change in serum acid phosphatase or pros- known to generate an anticoagulated state, but clotting studies were normal in both our patients. Breast cancer tate specific antigen. is associated with a thromboembolic tendency and it is possible that this, combined with the endothelial protein binding capacity of suramin, led to thromboses at Discussion the site of the central venous catheters in these patients. The dosing strategy subsequently adopted involved Suramin has notable activity in advanced prostate cancer and merits evaluation in breast cancer. Its pro- one hour infusions of 500 mg/m2 repeated thrice

600 weekly, until through suramin levels exceeded 200 ml. Detailed studies have resulted in good understanding of the pharmacokinetics of suramin [3, 7-9]. Consistent with these, our data were best fitted by a three compartment model. The early studies of suramin in cancer patients, in which the drug was given by continuous infusion, were attended by severe, sometimes fatal toxicity at serum levels >350 ng/ml [5]. In the present study, peak serum levels exceeded this in all patients treated by intermittent intravenous infusions. Furthermore, serum levels exceeded 350 jig/nu" for 8-15 hours in 4 patients. No severe toxicity and no neurotoxicity were seen. This suggests that prolonged exposure to such levels, causing saturation of tissue suramin binding, is required for the development of neurotoxicity. The role of binding to serum proteins may also be important in determining its distribution and activity [15], although this appears to be clinically important only in patients with hypoalbuminaemia [9]. Serum suramin levels are probably a poor surrogate for tissue levels. We cannot therefore be complacent about the lack of toxicity seen in this study because more toxicity may be seen when more than two treatment cycles are given. We recommend that further studies use intermittent intravenous infusions with monitoring of peak and trough suramin levels, so that treatment cycles can be repeated when the serum levels fall below 175 ng/ml. If this is done, adaptive dosing strategies [3] may not be necessary. This approach will require evaluation in a larger study to demonstrate its safety. Our patients had far advanced breast and prostate cancer refractory to all conventional treatments. Seven had cutaneous breast cancer en cuirasse that is notoriously difficult to control. It is not surprising that no tumour responses were seen. In view of the useful antitumour effects seen in breast cancer in vitro [11-13] and cogent arguments for its testing [10], we believe that phase II studies of suramin are merited in breast cancer patients with disease responses to prior treatment and a maximum of one line of prior chemotherapy. Acknowledgements We thank Jean Miller and Nora Whelan for their help with this study.

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