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703.Full.Pdf Vol. 9, 703–710, February 2003 Clinical Cancer Research 703 Phase I Clinical and Pharmacologic Study of Weekly Cisplatin and Irinotecan Combined with Amifostine for Refractory Solid Tumors1 Abdul-Kader Souid, Ronald L. Dubowy, Conclusion: The combination of cisplatin and irinote- Susan M. Blaney, Linda Hershon, Jim Sullivan, can administered weekly for 4 weeks in children with re- Wendy D. McLeod, and Mark L. Bernstein1 fractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >30% dose escalation for Departments of Pediatric Hematology/Oncology, State University of irinotecan, when administered in a combination regimen New York Upstate Medical University, Syracuse, New York 13210 [A-K. S., R. L. D.]; Texas Children’s Cancer Center, Houston, Texas with cisplatin. However, effective antiemetics and calcium 77030 [S. M. B.]; Sainte-Justine Hospital, H3T 1C5, Canada [L. H., supplementation are necessary with the use of amifostine. M. L. B.]; and the Statistical Office, Children Oncology Group, Further escalation of irinotecan dosing, using these precau- Gainesville, Florida 32601 [J. S., W. D. M.] tions for amifostine administration, may be possible. ABSTRACT INTRODUCTION Purpose: This Phase I study was designed primarily to Irinotecan (Camptosar, CPT-11, 7-ethyl-10-[4-(1-piper- determine the maximum tolerated dose (MTD) and dose- idino)-1-piperidino]carbonyloxycamptothecin) is a water-solu- limiting toxicities (DLTs) of irinotecan and cisplatin with ble derivative of camptothecin, an alkaloid extracted from the and without amifostine in children with refractory solid Chinese tree Camptotheca accuminata (1). Its therapeutic effect tumors. is mediated by the active metabolite SN-38 (7-ethyl-10- Patients and methods: Cisplatin, at a fixed dose of 30 hydroxycamptothecin), which is generated in the plasma and mg/m2, and escalating doses of irinotecan (starting dose, 40 tissues (e.g., the liver, bowel mucosa, and tumors) by the cata- mg/m2) were administered weekly for four consecutive lytic activity of carboxylesterase that cleaves the water-solubi- weeks, every 6 weeks. After the MTD of irinotecan plus lizing dipiperidino side chain (2). SN-38, in turn, interferes with cisplatin was determined, additional cohorts of patients were the nicking-ligation reaction of topoisomerase I (a nuclear en- enrolled with amifostine (825 mg/m2) support. Leukocyte zyme involved in DNA transcription, replication, and repair), DNA-platinum adducts and pharmacokinetics of cisplatin preventing DNA ligation (3). Irinotecan was approved by the and WR-1065 (amifostine-active metabolite) were also de- United States Food and Drug Administration in 1996 for termined. the treatment of colorectal cancers refractory to 5-fluorouracil. Results: Twenty-four patients received 43 courses of The drug also has a broad spectrum of activity against pediatric 2 therapy. The MTD for irinotecan administered in combina- solid tumors (4, 5). The DLTs of irinotecan are myelosuppres- tion with cisplatin (30 mg/m2) was 50 mg/m2. The DLTs of sion and diarrhea (produced by the effect of SN-38 on intestinal this combination were neutropenia and thrombocytopenia. motility; Refs. 4 and 5). High doses of loperamide control With the addition of amifostine, at an irinotecan dose of 65 diarrhea in most patients (6). mg/m2 and cisplatin dose of 30 mg/m2, the DLT was hy- Cisplatin, cis-diamminedichloroplatinum (II), exerts its an- pocalcemia. Although no objective responses were observed, titumor activity through binding to cellular DNA (7). When six patients received at least three courses of therapy. The cisplatin enters the cell, it aquates, producing cationic species amounts of platinum adducts (mean ؎ SD) were 10 ؎ 20 that bind to nitrogen atoms on the bases of DNA (8). Cisplatin molecules/106 nucleotides. The maximum plasma concentra- binding alters the structure of DNA, affects its ability to act as a template in transcription, and promotes cell death by apoptosis ؎ tions (Cmax) for free cisplatin and WR-1065 were 4.5 1.6 ␮ ϳ ؎ ␮ (9, 10). Cisplatin also has a broad spectrum of antitumor activity M and 89 10 M, respectively. The half-life (t1/2) for and is included in standard front-line treatment regimens for a ؎ free plasma cisplatin was 25.4 5.4 min. The initial t1/2 for ϳ ϳ variety of adult and pediatric solid tumors. Cisplatin toxicities plasma WR-1065 was 7 min and terminal t1/2 24 min. are cumulative. The primary DLTs of cisplatin are nephrotox- icity, peripheral neuropathy, and ototoxicity. Amifostine [WR-2721, S-2-(3-aminopropylamino)ethyl phosphorothioic acid] is used to ameliorate some renal and bone Received 7/1/02; revised 9/24/02; accepted 10/1/02. 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 To whom requests for reprints should be addressed, at Department of 2 The abbreviations used are: DLT, dose-limiting toxicity; ANC, abso- Pediatric Hematology/Oncology, Sainte-Justine Hospital, 3175 Chemin lute neutrophil count; Pt, platelet; G-CSF, granulocyte colony-stimulat- Cote Ste Catherine, Montreal, Quebec, Canada H3T 1C5. Phone: ing factor; SGPT, serum glutamic pyruvic transaminase; nt, nucleotide; (514) 345-4969; Fax: (514) 345-4792; E-mail: bernstm@magellan. CNS, central nervous system; SD, stable disease; MTD, maximum umontreal.ca. tolerated dose. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2003 American Association for Cancer Research. 704 Cisplatin and Irinotecan with Amifostine Support Table 1 Treatment strata, irinotecan dose escalation, and treatment courses Irinotecan Cisplatin No. of Total no. of Total no. of Stratum (mg/m2) (mg/m2) patients courses started courses completed I 40 30 3 6 2a (heavily pretreated without amifostine) II 40 30 6 13 12 (less heavily pretreated without amifostine) 50 30 4 6 6 65 30 6 11 8b III 65 30 5 7 6 (less heavily pretreated with amifostine) Total 24 43 34 a One course was completed at a irinotecan dose of 32 mg/m2. b Two courses were completed at a irinotecan dose of 50 mg/m2. marrow toxicities (11). The drug is activated in the blood by tumors); (i) no anticancer therapy for Ն3 weeks before entry (6 alkaline phosphatase, producing the free thiol metabolite WR- weeks for nitrosoureas); (j) no local radiation for Ն2 weeks 1065 [WR-SH, S-2-(3 aminopropylamino)ethanethiol], which before entry; (k) no craniospinal or Ն50% pelvic radiation for enters the cell by passive diffusion. The side effects of amifos- Ն6 months before entry; (l) no autologous or allogeneic bone tine include hypotension, hypocalcemia, nausea, and vomiting marrow transplantation (without total body irradiation) for Ն6 (12). Guidelines for amifostine dosing, administration, and man- months before entry; (m) no graft-versus-host disease; (n) agement of hypocalcemia are reported (13–15). ANC Ն 1,000/mm3; hemoglobin concentration Ն 8 grams/dl; The different mechanisms of action, the lack of overlap- (o) Pt count Ն100,000/mm3;(p) bilirubin Յ 1.5 mg/dl; (q) ping DLTs, and the broad spectrum of antitumor activity re- SGPT less than or equal to twice the upper limit of normal; and sulted in clinical trials to determine the MTD and DLTs of the (r) normal serum creatinine for age, or glomerular filtration rate. combination of cisplatin and irinotecan administered to adults Specific exclusion criteria were pregnancy, breast feeding, with refractory solid tumors (16–22). These studies demon- and therapy with anticonvulsants. For less heavily pretreated strated that the combination was well tolerated and effective. patients, the exclusion criteria also included more than two The DLTs were neutropenia, diarrhea, and cisplatin neph- previous chemotherapy regimens, central axis radiation, bone ropathy. marrow involvement with cancer, and previous bone marrow Because cisplatin is widely used in pediatric tumors and the transplantation. initial results of preclinical and early Phase I clinical studies The study was approved by the institutional review board suggest that irinotecan may have antitumor activity in a variety of each participating institution. Written informed consent was of pediatric solid tumors (1), we initiated a pediatric Phase I trial obtained for each patient before study entry. of this combination with and without amifostine. Cisplatin and Pretreatment evaluation included medical history, physical irinotecan were given weekly for 4 weeks, followed by a 2-week examination, performance status, tumor size, chest roentgeno- 2 rest. The cisplatin dose was fixed at 30 mg/m , and the irino- gram, complete blood count, serum electrolytes, creatinine, cal- ϳ tecan dose was escalated in increments of 30% (20). After the cium, magnesium, phosphate, bilirubin, SGPT, total protein, MTD of cisplatin plus irinotecan was determined, additional albumin, and urinalysis. The same tests were done at least 2 cohorts of patients were enrolled with amifostine (825 mg/m ) weekly thereafter. Complete blood count was done two to three support. The study also included an estimation of the levels of times per week during myelosuppression. Tests of measurable leukocyte DNA-Pt adducts, the pharmacokinetics of cisplatin, disease, appropriate roentgenograms, bone marrow examination and the pharmacokinetics of WR-1065. (if infiltrated), and audiogram were done before and every 6 weeks during treatment. PATIENTS AND METHODS Treatment Plan. Cisplatin and irinotecan were adminis- Patient Population. Patients between 1 and 22 years of tered weekly for four consecutive weeks, every 6 weeks. age with confirmed malignant solid tumors refractory to stand- Courses were repeated every 6 weeks if there was no unaccept- ard therapy were eligible for this trial. Other eligibility criteria able toxicity or evidence of disease progression. The three included: (a) Karnofsky score Ն 50% for patients Ͼ10 years old treatment strata, irinotecan dose escalation schema, and treat- and Lansky play scale Ն 50% for patients Յ10 years old; (b) ment courses are shown in Table 1.
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