Investigational New Drugs 9: 269-272, 1991. (cid:14)9 1991 Kluwer Academic Publishers. Printed in the Netherlands. Phase II study of echinomycin in patients with advanced breast cancer: A report of cancer and leukemia group B protocol 8641 Richard L. Schilsky, David Faraggi, Ann Korzun, Nicholas Vogelzang, John Ellerton, William Wood and I. Craig Henderson Cancer and Leukemia Group B, Lebanon, NH 03766, USA Key words: echinomycin, breast cancer Summary Twenty-five women with advanced histologically documented stage IV recurrent or inoperable breast cancer were enrolled on a phase II study of echinomycin administered at a dose of 1.2 mg/m 2 intravenously over 30 minutes weekly for 4 weeks followed by a two week rest period. Seventy-six percent of patients had visceral dominant disease at study entry and all patients had previously received chemotherapy. One of 21 eligible patients had a partial response lasting 147 days. The median survival for this group of patients was 5.9 months and the median time to treatment failure was 1.7 months. Nausea and vomiting was the primary toxic effect and was severe or life-threatening in 43 % of patients. Transient elevation of liver enzymes occurred in 30% of patients. Bone marrow suppression was not significant. Echinomycin as employed in this study did not demonstrate significant antitumor activity in previously treated patients with advanced breast cancer. Echinomycin (NSC 526417) is one of a family of quinoxaline antibiotics originally isolated from Streptomyces echinatus [1,2]. It is thought to act as a bifunctional intercalator in DNA thereby result- ing in inhibition of DNA-directed RNA synthesis. The drug's interaction with DNA is due to the polar quinoxaline chromophores located on opposite sides of the cyclic peptide which can intercalate at two sites on the same DNA molecule or on separate DNA molecules resulting in intra- or intermolecular cross-linking [3,4]. In the National Cancer Institute pre-clinical screening systems, echinomycin demonstrated sig- nificant antitumor activity against P388 leukemia and B16 melanoma [5]. It was not effective, how- ever, against a number of other tumors including L1210 leukemia, Lewis lung carcinoma, the CD8F1 mammary tumor, the colon 38 tumor or against human colon, lung or mammary xenografts in im- mune-deficient mice. In the human tumor stem cell assay, the drug demonstrated a 24% response rate for breast cancer, 25% for colorectal cancer and 38070 for sarcoma [6]. Pre-clinical toxicology studies in mice and dogs demonstrated gastrointestinal toxicity, mild bone marrow suppression and histologic evidence of liver damage as the primary toxic effects of echinomycin [5]. Several phase I clinical trials using different dose schedules have been conducted [7-9]. The dose limiting toxicity in all studies was severe and often protracted nausea and vomiting. Mild throm- bocytopenia, elevation of liver enzymes and hyper- sensitivity reactions were also noted. This paper reports the results of a phase I1 trial of echinomycin conducted by the Cancer and Leu- kemia Group B (CALGB) in women with advanced breast cancer.
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`270 Patients and methods Patient selection Women with histologically documented stage IV recurrent or inoperable adenocarcinoma of the breast were eligible for this study provided they had measurable disease, a performance status of 0-2 (CALGB scale), a life expectancy of at least 2 months, treatment with no more than 1 prior chemotherapy program for metastatic disease and recovery from the toxic effects of all prior therapy. All patients had acceptable bone marrow (granulo- cytes > 1800/#1, platelets > 100,000/#1), renal (BUN < 1.5 x normal, creatinine < 1.8 mg/dl), and hepatic (total bilirubin < 1.5 (cid:141) normal, SGOT/SGPT < 1.5 (cid:141) normal) function prior to entry on protocol. All patients provided written in- formed consent for participation in this study. Treatment plan Echinomycin 1.2 mg/m 2 was administered intra- venously once a week for 4 consecutive weeks fol- lowed by a 2 week rest period. Cycles were repeated every 6 weeks. Patients received at least 2 cycles of chemotherapy unless severe toxicity or rapid dis- ease progression occurred. The drug was provided as a sterile lyophilized powder and was reconstitut- ed by mixing with Diluent 12 composed of equal parts of polyethoxylated castor oil and ethanol. Once dissolved, the drug was diluted in normal sa- line and the desired dose was administered as a 30 minute infusion in 150 cc normal saline. Aggressive antiemetic therapy was encouraged although the specific antiemetic regimen employed was left to the discretion of the treating physician. Most pa- tients received combination antiemetic therapy in- cluding metaclopropamide, prochlorperazine, lo- razepam or diphenhydramine. Criteria of response and toxicity Response to therapy was assessed using standard criteria. Complete response was defined as the dis- appearance of all measurable disease, signs, symp- toms and biochemical changes related to the tu- mor for at least 4 weeks. Partial response was de- fined as at least a 50~ reduction in the sum of the products of the perpendicular diameters of all measurable lesions lasting at least 4 weeks during which no new lesions could appear. Stable disease was defined as less than a 50070 reduction or less than a 25~ increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions for at least 8 weeks. Progressive disease was defined as an in- crease in the product of two perpendicular diam- eters of a measured lesion by at least 25~ or the ap- pearance of new metastases. Toxicity was graded according to the CALGB toxicity scale. Statistical methods Survival time was defined as the time from registra- tion on study to the date of death from any cause. Time to treatment failure was defined as the time from registration on study to the date of tumor progression or to the date of death without progres- sion or to the date last seen. Survival curves were computed according to the method of Kaplan and Meier [10]. Results Twenty-five patients were enrolled on this study be- tween April and November, 1986 of whom 4 were deemed ineligible due to absence of measurable dis- ease (2), abnormal liver function (1), or excessive prior chemotherapy (1). Characteristics of the 21 eligible patients are summarized in Table 1. Seventy- six percent of patients had visceral dominant dis- ease at study entry and all had previously received either adjuvant chemotherapy (6), chemotherapy for metastatic disease (11) or both (4). One patient had a partial response lasting 147 days. Twenty of the 21 patients have died. The me- dian survival was 5.9 months and the median time to treatment failure was 1.7 months. The toxicity of echinomycin as used in this study is summarized in Table 2. Nausea and vomiting was
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`Table 1. Characteristics of eligible patients No. of patients enrolled 25 No. of eligible patients 21 Median age (range) y 56 Dominant site of disease at entry Visceral dominant 16 Osseous dominant 5 Menopausal status Premenopausal 5 Perimenopau sal 1 Postmenopausal 14 Unknown 1 Performance status 0 7 1 10 2 4 Prior therapy Any hormonal therapy 11 Any chemotherapy 21 Any radiation therapy 12 (27 to 69) the primary toxic effect and was severe or life- threatening in 43% of patients. Four patients were unable to complete the planned four doses per cycle due to severe nausea and vomiting. Transient eleva- tion of liver enzymes occurred in 30% of patients while bone marrow suppression was not significant except for two individuals who developed severe thrombocytopenia. Discussion Echinomycin, as employed in this study, did not demonstrate significant antitumor activity in pa- tients previously treated with chemotherapy for ad- vanced breast cancer. This schedule of drug ad- ministration was particularly difficult to administer because of severe and sometimes protracted nausea and vomiting despite aggressive anti-emetic thera- py. Similar toxicity had been observed by Pazdur and colleagues [8] using this schedule of echinomy- cin administration in a phase I study. Other toxici- ties were generally mild and reversible. The relative lack of bone marrow toxicity of echinomycin makes it an attractive agent for combination with other drugs. Further clinical evaluation of echinomycin may be possible with the availability of new effec- tive antiemetics such as ondansetron [11]. Table 2. Toxicity 271 Toxic effect No. of patients (%) with grade: 1 2 3 4 5 Leukopenia 3(14) 0(0) 0(0) 0(0) 0(0) Thrombocytopenia 3(14) 0(0) 1(5) 1(5) 0(0) Anemia 3(14) 2(10) 0(0) 0(0) 0(0) Hemorrhage 0(0) 1 (5) 0(0) 0(0) 0(0) Infection 3(14) 1(5) 0(0) I(5) 0(0) Hepatic 1(5) 2(10) 2(10) 1(5) 0(0) Nausea/vomiting 1(5) 6(29) 7(33) 2(10) 0(0) Diarrhea 0(0) 1(5) 1(5) 0(0) 0(0) Hypersensitivity 0(0) 0(0) 0(0) 0(0) 0(0) Acknowledgements This study was conducted by the Cancer and Leuke- mia Group B and was supported by Public Health Service Grants from the National Cancer Institute, National Institutes of Health, the Department of Health and Human Services and by a grant from the T.J. Martell Foundation. The following mem- bers participated in this study: University of Chicago Medical Center, Chicago, IL, Nicholas Vogelzang (CA-41287) University of California at San Diego, San Diego, CA, Mark Green (CA-11789) New York Hospital - Cornell Medical Center, New York, NY, Richard T. Silver (CA-07968) Long Island Jewish Medical Center, New Hyde Park, NY, Kanti Rai (CA-11028) Massachusetts General Hospital, Boston, MA, Robert W. Carey (CA-12449) Columbia University, New York, NY, Rose Ruth Ellison (CA-12011) Upstate Medical Center at Syracuse, Syracuse, NY, Arlan Gottlieb (CA-21060) Bowman-Gray School of Medicine, Winston- Salem, NC, Robert Cooper (CA-03927) McGill Cancer Center, Montreal, Canada, Bernard Cooper (CA-31809) University of Tennessee, Memphis, TN, Alvin M. Mauer (CA-47555) Harvard School of Public Health, Boston, MA, James R. Anderson (CA-33601)
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`272 References 1. Martin DG, Mizsak SA, Biles C, Stewart JC, Baczynskyj L, Meulman PA: Structure of quinomycin antibiotics. J An- tibiot (Tokyo) 28:332-336, 1975 2. Foster B J, Clagett-Carr K, Shoemaker DD, Suffness M, Plowman J, Trissel LA, Grieshaber CK, Leyland-Jones B: Echinomycin: the first bifunctional intercalating agent in clinical trials. Invest New Drugs 3:403-410, 1985 3. Wakelin LPG, Waring M J: The binding of echinomycin to deoxyribonucleic acid. Biochem J 157:721-740, 1976 4. Waring M J, Wakelin LPG: Echinomycin: a bifunctional intercalating antibiotic. Nature 252:653-657, 1974 5. Clinical Brochure, Echinomycin, Division of Cancer Treat- ment, National Cancer Institute, December, 1981 6. Lathan B, Von Hoff DD: Cytotoxic activity of echinomycin in a human tumor cloning system. Cancer Drug Deliv 1:191-198, 1984 7. Harvey JH, McFadden M, Andrews WG, Byrne P J, Ahl- gren JD, Wooley PV: Phase I study of echinomycin ad- ministered on an intermittent bolus schedule. Cancer Treat Rep 69:1365-1368, 1985 8. Pazdur R, Haas CD, Baker LH, Leichman CG, Decker D: Phase I study of echinomycin. Cancer Treat Rep 71:1217-1219, 1987 9. Kuhn J, Von Hoff D, Hersh M, Melink T, Clark GM, Weiss GR, Coltman CA: Phase I trial of echinomycin (NSC- 526417), a bifunctional intercalating agent, administered by 24 hour continuous infusion. Eur J Can Clin Oncol 25:797-803, 1989 10. Kaplan EL, Meier P: Nonparametric estimation from in- complete observations. J Am Stat Assoc 53:457-481, 1958 11. Einhorn LH, Nagy C, Werner K, Finn AL: Ondansetron: a new antiemetic for patients receiving cis-platin chemothera- py. J Clin Oncol 8:731-735, 1990 Address for offprints: R.L. Schilsky, Section of Hematology- Oncology, Box 420, Univesity of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
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