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Suramin in Patients with Metastatic Colorectal Cancer Pretreated with Fluoropyrimidine-Based Chemotherapy A Phase I1 Study

Alfredo Falcone, M.D.,* Elisabeffa Pfanner, M.D.," Claudia Cianci, M.D.," Romano Danesi, M.D.,t lsa Brunefti, M.D.," Mario Del Tacca, M.D.,$ and Pier Franco Confe, M.D.*

Background. The results of conventional chemother- apy in metastatic colorectal cancer are discouraging, making it a logical target for new treatment approaches a necessary consideration. Suramin is a polysulfonated naphthylurea that binds to several cellular growth fac- tors and has in vitro activity against human colorectal cancer cells. Therefore, this Phase I1 study of patients with metastatic colorectal cancer was conducted to eval- uate its clinical activity.

Methods. Suramin was administered as a 6-day con- tinuous infusion every week for 8 consecutive weeks by using a computer-assisted dosing of Bayesan pharmaco- kinetics to maintain suramin plasma concentrations of 200-250 pg/ml. Twenty patients with metastatic colorec- tal cancer who were not responsive or in progression within 6 months after completing fluoropyrimidine- based chemotherapy entered the study.

Results. Toxicities included mostly Grade 1 and 2 fa- tigue, nausea and vomiting, peripheral neurotoxicity, creatinine elevation, and proteinuria. No objective re- sponses were observed, but three of three patients who received 5-fluorouracil plus folinic acid after suramin achieved a partial response.

Conclusions. These results indicate that suramin is inactive in patients with metastatic colorectal cancer pre- treated with fluoropyrimidines. Pretreatment with sura- min may have changed the biology of the tumor, sensitiz- ing it to fluoropyrimidines. Studies to investigate this pos- sibility are in progress. Cancer 1995; 75:440-3.

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From the *Uniti Operativa Oncologia Medica, Ospedale S. Chi- ara, the tScuola Superiore di Perfezionamento e dell'universita s. Anna, and the SIstituto Farmacologia Medica Universita, Pisa, Italy.

Supported in part by a grant from the Associazione Italiana Ric- erca Cancro.

Address for reprints: Alfredo Falcone, M.D., U.O. Oncologia Medica, Osp. S. Chiara, Via Roma, 67, 56126 Pisa, Italy.

Received June 22, 1994; revision received September 19, 1994; accepted September 23,1994.

Key words: suramin, metastatic colorectal cancer, Phase 11, fluoropyrimidines.

Metastatic colorectal cancer no longer responsive to fluoropyrimidine-based chemotherapy is infrequently sensitive to further cytotoxic therapy, and survival is poor.' Suramin is a polysulfonated naphthylurea origi- nally synthesized in Germany in 1916 and is used in treating trypasonomiasis, onchocerciasis, and acquired immune deficiency syndrome.'r3 More recently, the drug has received new attention as a potential antineo- plastic agent because of its capacity to disrupt several systems important to tumor proliferation; in particular, it binds several cellular growth factors such as platelet- derived growth factor, basic fibroblast growth factor, transforming growth factor-beta, insulin-like growth factor I, and with less potency, epidermal growth factor, antagonizing their proliferative e f f e ~ t . ~ - ~ Suramin also has shown significant inhibitory effects on cell prolifer- ation and colony formation of many human tumor cell lines9-13 and clinical activity against prostate, adreno- cortical, and ovarian carcinomas and low grade non- Hodgkin's 1ymph0rnas.'~- l6 Recently, because of the multiautocrine loops described in colorectal cancer in- volving growth factors that are inactivated by sura- min,l7-I9 we have evaluated the drug's antiproliferative activity in vitro against five human colorectal tumor cell lines"; these studies found significant suramin activity at clinically achievable concentrations. We have, there- fore, conducted a Phase I1 trial to evaluate if suramin has clinical activity in patients with metastatic colorectal cancer pretreated with conventional fluoropyrimidine- based chemotherapy.

Patients and Methods

Patients with a hystologically proven diagnosis of colorec- tal cancer, measurable metastatic disease, and who are not

Suramin in Colorectal Cancer/Falcone et al.

responsive or in progression within 6 months from the end of fluoropyrimidme-based chemotherapy were con- sidered eligible for the study. Other inclusion criteria in- cluded an Eastern Cooperative Oncology Group perfor- mance status I 2, a life expectancy 2 3 months, leukocyte count 2 3000 mm3, creatinine level I 1.5 mg/dl, b i h b i n level < 1.5 mg/dl, and coagulation test results in the range of normal values. Patients with bleedmg dlathesis, brain metastases, or severe neuropathy were excluded. Ap- proval for the study was obtained from the local Ethical Review Committee; patients were informed of the nature of the study and provided an oral informed consent. Sur- amin was purchased from Bayer (Leverkusen, Federal Re- public of Germany) as 1-g vials and was administered as a 6-day continuous infusion every week through a central venous implantable catheter and an external volumetric pump (Pharmacia CADD-1, Pharmacia Deltec Inc., St. Paul, MN). The initial daily dose during the first 6 days of therapy was 350 mg/mq. Thereafter, doses for each weekly infusion of 6 days were determined using a com- puter-assisted dosing system that used Bayesian pharma- cokmetics (MW/Pharm 3.03; Medi/ware, Groningen, the Netherlands) to maintain suramin plasma concentrations of 200-250 ug/ml. Treatment was continued for a maxi- mum of 8 weeks and was repeated after a 6-8-week in- terval (to allow recovery from toxicities) if no progression or dose-limiting toxicities had occurred. All patients re- ceived 25 mg of cortisone acetate orally at 8 a.m. and 8 p.m. daily as therapy began and thereafter, and 10 mg/ weekly of vitamin K intramuscularly during suramin in- fusion. The baseline evaluation included medical history, results from physical examination, hematology study, blood chemistry, carcinoembryonic antigen level assess- ment, electrocardiogram , chest X-ray, abdominal com- puted tomography scan and/or ultrasound, and from any other test to measure dsease sites. During treatment, pa- tients underwent physical examination, measurement of blood cell counts, and assessment of blood chemistry in- cluding renal and coagulation tests. Assessment of plasma suramin levels were initiated on Day 7 of treatment and thereafter were repeated every 7 days until the end of sur- amin a h i s t r a t i o n . Plasma concentrations of suramin were assayed by the reverse-phase ion-pairing high per- formance liquid chromatography method previously de- scribed.” Responses were evaluated every 8 weeks. Tox- icity and responses were evaluated according to standard World Health Organization criteriaz1; also, patients who progressed rapidly or died, presumably because of meta- static disease before the first planned revaluation (8 weeks), were considered as having progressed.

Results

Twenty patients with metastatic colorectal cancer en- tered the study. All patients were pretreated for meta-

441

Table 1. Patient Characteristics

Characteristic ~~

No. of patients Male/female

Median Range

Median Range

Primary Colon Rectum

5-FU + folinic acid 5-FU continuous infusion Floxuridine (intrahepatic) 5-FU + folinic acid + interferon 5-FU + levamisole 5-FU + methotrexate 5-FU + azidothymidine

1 Multiple

Site of disease Liver Lung Abdominal Others

1 Multiple

Median Ranee

Age (yr)

ECOG Performance Status

Prior chemotherapy

No. of previous chemotherapies

No. of metastatic sites

Time from metastases to study entry (mo)

No.

20 12/8

60 43-69

1 0-2

15 5

10 8 4 3 3 1 1

11 9

14 9 6 2

12 8

12 3-48 ~~ m - ~~~~

5-FU: 5-fluorouracil.

static disease and were not responsive or in progression within 6 months from the end of fluoropyrimidine- based chemotherapy, and their characteristics are sum- marized in Table 1. Plasma suramin levels of 200-250 ug/ml were reached after 6-13 days, and these concen- trations remained within this range during most (>90%) of each cycle of therapy and never exceeded 300 ug/ml or decreased to less than 150 ug/ml. Median duration of therapy was 8 weeks (range, 1-22 weeks), and the median number of cycles administered was 1 cycle (range, 1-2 cycles). Nineteen patients were evalu- able for toxicity (one patient who had not experienced side effects refused further therapy after only 6 days of treatment), which included mostly Grade 1-2 nausea, vomiting, fatigue, peripheral neuropathy, creatinine el- evation, proteinuria, fever, cutaneous rash (Table 2). Prolonged prothrombin and/or partial thromboplastin times developed in 14 patients, but only one patient re-

442 CANCER January 25,2995, Volume 7 5 , No. 2

Table 2. Overall Toxicity: 19 Patients Evaluable

WHO erade WO)

Adverse event 1 2 3 4

Fatigue* 26 10 5 0 Nausea/vomiting 26 10 0 0 Peripheral neurotoxicity 31 21 0 0 Creatinine elevation 10 0 0 0 Proteinuria 74 0 0 0 Fever 16 5 0 0 Cutaneous rash 16 0 0 0 Stomatitis 5 10 0 0 Diarrhea 5 10 0 0

* 1: mild: 2: moderate: 3: severe.

quired temporary treatment discontinuation because of hypocoagulation. No hemorrhage, sepsis, or toxic death occurred in any patient. Seventeen patients were eval- uable for response (3 patients were lost to follow up be- fore response could be assessed), and no objective re- sponses were observed. Four patients had stable disease lasting a median of 3.5 months (range, 3-8.5 months), and 13 progressed. The four patients with stable disease had liver only (l), liver and lymph node (l), lymph node and colon (l), and lung (1) disease localizations. One patient classified as having stable disease with lymph node involvement and liver metastases achieved a par- tial response in the lymph nodes (overall reduction of tumor area of less than 50%). Of interest, three of three patients who received 5-fluorouracil(5-FU) plus folinic acid after suramin achieved a partial response and were still alive at this writing after 14.5+, 16+, and 16.5+ months from when suramin therapy began; of these, one had progressive disease during continuous infusion 5-FU, another had progressive disease after 5 months of continuous infusion 5-FU that he received for meta- static, nonevaluable disease, and one had progressive disease in lungs after 3 months of intrahepatic floxuri- dine. Overall actuarial median survival for all 20 pa- tients was 28 weeks.

Discussion

The results of conventional chemotherapy in patients with metastatic colorectal cancer who are resistant to fluoropyrimidine are discouraging, making it a logical target for new treatment approaches.' Suramin has re- ceived new interest as a potential anticancer agent in treating this disease because of its ability to bind and inactivate several growth factors involved in the growth of colorectal carcinoma cell^,^-^,'^-'^ and recent in vitro studies also have demonstrated that suramin possesses significant activity, at clinically achievable concentra-

tions, against human colorectal cells.'-" These results provided the experimental basis for clinical evaluation of suramin in metastatic colorectal cancer in the present study. Unfortunately, our results show that suramin used as a single agent is inactive in treating patients with metastatic colorectal cancer pretreated with flu- oropyrimidine-based chemotherapy and also exemplify the failure of in vitro evaluation of potential anticancer drugs. This observation does not exclude suramin's pos- sible activity in patients with a smaller tumor burden who previously were untreated with chemotherapy; however, we believe that the possibility that suramin will have significant activity in this more favorable situ- ation is unlikely. It also can be speculated that if plasma suramin levels were maintained at higher levels (250- 300 ug/ml), objective responses may have occurred; however suramin at concentrations of 200-250 ug/ml has clinical activity in metastatic prostate cancer, and higher plasma concentrations are not associated with greater activity, but only with greater toxicities.'' The combination of suramin with agents that enhance in vi- tro its antiproliferative effect like alpha-interferon" may be able to improve its clinical activity; and these studies are presently ongoing. Of interest is our clinical observation that three of three patients pretreated with fluoropyrimidines responded to 5-FU plus folinc acid after suramin administration. Although these patients had not previously received 5-FU plus folinic acid and one patient experienced a lung relapse after intrahe- patic floxuridine, and, therefore, did not have a sys- temic chemotherapy failure, it is possible that suramin changed the biology of the tumor, making it sensitive to modulated fluoropyrimidines. Interestingly, also in patients with hormone-refractory prostate cancer, re- sponses to additional hormonal manipulations have been observed after suramin treatment.23 We are, there- fore, planning experimental and clinical studies to in- vestigate the possibility that suramin can overcome re- sistance to fluoropyrimidines.

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