Abstract
Purpose: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. Methods: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80±10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. Results: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level −1; n=3) and 9 (level −2; n=3) mg/m2/day, and topotecan-TSE was reduced to 60±10 ng*h/ml (level −3; n=2). DLTs were neutropenia (n=8), typhlitis (n=5), and skin rash (n=1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6–76.2) l/h/m2 and 27.6 (14.7–55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. Conclusion: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.
Similar content being viewed by others
References
Athale UH, Stewart C, Kuttesch JF, Moghrabi A, Meyer W, Pratt C, Gajjar A, Heideman RL (2001) Phase I study of combination topotecan and carboplatin in pediatric solid tumors. J Clin Oncol 20:88–95
Bertrand R, O’Connor PM, Kerrigan D, Pommier Y (1992) Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells. Eur J Cancer 28A:743–748
Blaney SM, Needle MN, Gillespie A, Sato JK, Reaman GH, Berg SL, Adamson PC, Krailo MD, Bleyer WA, Poplack DG, Balis FM (1998) Phase II trial of topotecan administered as a 72-hour continuous infusion in children with refractory solid tumors: a collaborative pediatric branch, national cancer institute, and children’s cancer group study. Clin Cancer Res 4:357–360
Blaney S, Berg SL, Pratt C, Weitman S, Sullivan J, Luchtman-Jones L, Bernstein M (2001) A Phase I study of irinotecan in pediatric patients: a pediatric oncology group study. Clin Cancer Res 7:32–37
Cheng MF, Chatterjee S, Berger NA (1994) Schedule dependent cytotoxicity of topotecan alone and in combination chemotherapy regimens. Oncol Res 6:269–279
Chu XY, Suzuki H, Ueda K, Kato Y, Akiyama S, Sugiyama Y (1999) Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. J Pharmacol Exp Ther 288:735–741
Coggins CA, Elion GB, Houghton PJ, Hare CB, Keir S, Colvin OM, Binger DD, Friedman HS (1998) Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41:485–490
Creemers GJ, Gerrits CJ, Schellens JH, Planting AS, van der Burg ME, van Beurden VM, de Boer-Dennert M, Harteveld M, Loos W, Hudson I, Stoter G, Verweij J (1996) Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J Clin Oncol 14:2540–2545
Crews KR, Stewart CF, Jones-Wallace D, Thompson SJ, Houghton PJ, Heideman RL, Fouladi M, Bowers DC, Chintagumpala MM, Gajjar A (2002) Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clin Cancer Res 8:2202–2209
Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418
D’Argenio DZ, Schumitzky A (1979) A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 9:115–134
Furman WL, Baker SD, Pratt CB, Rivera GK, Evans WE, Stewart CF (1996) Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia. J Clin Oncol 14:1504–1511
Furman WL, Stewart CF, Poquette CA, Pratt CB, Santana VM, Zamboni WC, Bowman LC, Ma MK, Hoffer FA, Meyer WH, Pappo AS, Walter AW, Houghton PJ (1999) Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815–1824
Gottleib JA, Luce JK (1972) Treatment of malignant melanoma with camptothecin (MSC-100880). Cancer Chemother Rep 56:103–105
Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723–3725
Hare CB, Elion GB, Houghton PJ, Houghton JA, Keir S, Marcelli SL, Bigner DD, Friedman HS (1997) Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 39:187–191
Hoki Y, Fujimori A, Pommier Y (1997) Differential cytotoxicity of clinically important camptothecin derivatives in P-glycoprotein-overexpressing cell lines. Cancer Chemother Pharmacol 40:433–438
Holcombe RF, Kong KM, Wimmer D (2003) Combined topoisomerase I inhibition for the treatment of metastatic colon cancer. Anti-Cancer Drugs 15:569–574
Houghton JA, Cheshire PJ, Hallman JD, Lutz L, Luo X, Li Y, Houghton PJ (1996) Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma. Clin Cancer Res 2:107–118
Houghton PJ, Cheshire PJ, Myers L, Stewart CF, Synold TW, Houghton JA (1992) Evaluation of 9-dimethylaminomethyl-10-hydrocamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31:229–239
Houghton PJ, Cheshire PJ, Hallman JD, Bissery MC, Mathieu-Boue A, Houghton JA (1993) Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10(4-[1-piperidino]-1-piperidino)carboxyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomehtyl-10-hydroxycamptothecin. Cancer Res 53:2823–2829
Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, Houghton JA (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low doses in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393–403
Hsiang YH, Liu LF (1998) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726
Jansen WJ, Zwart B, Hulscher ST, Giaccone G, Pinedo HM, Boven E (1997) CPT-11 in human colon-cancer cell lines and xenografts: characterization of cellular sensitivity determinants. Int J Cancer 70:335–340
Jansen WJ, Hulscher TM, van Ark-Otte J, Giaccone G, Pinedo HM, Boven E (1998) CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein. Br J Cancer 77:359–365
Kaufmann SH (1991) Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. Cancer Res 51:1129–1136
Kehrer DFS, Sparreboom A, Vermeij J, de Bruijn P, Nierop CA, van de Schraaf J, Ruijgrok EJ, de Jonge MJA (2001) Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7:1136–1141
Knab AM, Fertala J, Bjornsti MA (1993) Mechanisms of camptothecin resistance in yeast DNA topoisomerase I mutants. J Biol Chem 268:22322–22330
Kretschmar C, Kletzel M, Murray K, Joshi V, Smith E, Pao PV, Castleberry R (1995) Upfront phase II therapy with taxol (Txl) and topotecan (Topo) in untreated children (>365 days) with disseminated (INSS stage 4) neuroblastoma (NB). A pediatric oncology group (POG) study. Med Pediatr Oncol 25:243a
Lokich J (2001) Phase I clinical trial of weekly combined topotecan and irinotecan. Am J Clin Oncol 24:336–340
Ma J, Maliepaard M, Nooter K, Loos WJ, Kolker HJ, Verweij J, Stoter G, Schellens JH (1998) Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line. Br J Cancer 77:1645–1652
Masuda N, Kudoh S, Fukuoka M (1996) Irinotecan (CPT-11): pharmacology and clinical applications. Crit Rev Oncol/Hematol 24:3–26
Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG (1972) Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 56:95–101
Mugishima H, Matsunaga T, Yagi K, Asami K, Mimaya J, Suita S, Kishimoto T, Sawada T, Tsuchida Y, Kaneko M (2002) Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol Oncol 24:94–100
Nitschke R, Parkhurst J, Sullivan J, Harris MB, Bernstein M, Pratt C (1998) Topotecan in pediatric patients with recurrent and progressive solid tumors: a pediatric oncology group phase II study. J Pediatr Hematol Oncol 20:315–318
Ohe Y, Sasaki Y, Shinkai T, Eguchi K, Tamura T, Kojima A, Kunikane H, Okamoto H, Karato A, Ohmatsu H (1992) Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion. J Natl Cancer Inst 84:972–974
Owens TS, Dodds H, Fricke K, Hanna SK, Crews KR (2003) High-performance liquid chromatographic assay with fluorescence detection for the simultaneous measurement of carboxylate and lactone forms of irinotecan and three metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 788:65–74
Pappo AS, Lyden E, Breneman J, Wiener E, Teot L, Meza J, Crist W, Vietti T (2001) Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19:213–219
Pawlik CA, Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Danks MK (1998) Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays. Clin Cancer Res 4:1995–2002
Pratt CB, Stewart CF, Santana VM, Bowman L, Furman W, Ochs J, Marina N, Kuttesch JF, Heideman R, Sandlund JT, Avery L, Meyer WH (1994) Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539–543
Rodriguez-Galindo C, Radomski KM, Stewart CF, Furman W, Santana VM, Houghton PJ (2000) Clinical use of topoisomerase I inhibitors in anticancer treatment. Med Pediatr Oncol 35:385–402
Saleem A, Ibrahim N, Patel M, Li XG, Gupta E, Mendoza J, Pantazis P, Rubin EH (1997) Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning. Cancer Res 57:5100–5106
Santana VM, Zamboni WC, Kirstein MN, Tan M, Liu T, Gajjar A, Houghton PJ, Stewart CF (2003) A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633–640
Saylors RL, Stine KC, Sullivan J, Kepner JLBM, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ (2001) Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a pediatric oncology group (POG) phase II study. J Clin Oncol 19:3463–3469
Stewart CF, Baker SD, Heideman RL, Jones D, Crom WR, Pratt CB (1994) Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. J Clin Oncol 12:1946–1954
Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1996) Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 56:3752–3757
Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E et al (1998) Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats. Cancer Chemother Pharmacol 42:280–286
Thompson J, Zamboni WC, Cheshire PJ, Lutz L, Luo X, Li Y, Houghton JA, Stewart CF, Houghton PJ (1997) Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clin Cancer Res 3:423–431
Thompson J, Guichard SM, Cheshire PJ, Richmond LB, Poquette CA, Ragsdale ST, Webber B, Lorsbach R, Danks MK, Houghton PJ (2001) Development, characterization and therapy of a disseminated model of childhood neuroblastoma in SCID mice. Cancer Chemother Pharmacol 47:211–221
Tubergen DG, Stewart CF, Pratt CB, Zamboni WC, Winick N, Santana VM, Dryer ZA, Kurtzberg J, Bell B, Grier H, Vietti TJ (1996) Phase I and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a pediatric oncology group study. J Pediatr Hematol Oncol 18:352–361
Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM (2004) Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res 10:840–848
Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA (1966) The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 88:3888–3889
Wang LF, Ting CY, Lo CK, Su JS, Mickley LA, Fojo AT, Whang-Peng J, Hwang J (1997) Identification of mutations at DNA topoisomerase I responsible for camtothecin resistance. Cancer Res 57:1516–1522
Wells RJ, Reid JM, Ames MM, Mares WL, Krailo MD, Seibel NL, Mosher R, Reaman GH, Wiersma SR (2002) Phase I trial of cisplatin and topotecan in children with recurrent solid tumors: children’s cancer group study 0942. J Pediatr Hematol Oncol 24:89–93
Zamboni WC, Stewart CF, Cheshire PJ, Richmond LB, Hanna SK, Luo X, Poquette C, McGovren JP, Houghton JA, Houghton PJ (1998) Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models. Clin Cancer Res 4:743–753
Zamboni WC, Stewart CF, Thompson J, Santana VM, Cheshire PJ, Richmond LB, Luo X, Poquette C, Houghton JA, Houghton PJ (1998) Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90:505–511
Zamboni WC, Gajjar AJ, Heideman RL, Beijnen JH, Rosing H, Houghton PJ, Stewart CF (1998) Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 4:783–789
Zamboni WC, Bowman LC, Tan M, Santana VM, Houghton PJ, Meyer WH, Pratt CB, Heideman RL, Gajjar AJ, Pappo AS, Stewart CF (1999) Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454–460
Author information
Authors and Affiliations
Corresponding author
Additional information
Contract grant sponsor: National Institutes of Health; Contract grant numbers P30 CA 21765 and CA 23099; Contract grant sponsor: American Lebanese Syrian Associated Charities (ALSAC).
Rights and permissions
About this article
Cite this article
Rodriguez-Galindo, C., Crews, K.R., Stewart, C.F. et al. Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. Cancer Chemother Pharmacol 57, 15–24 (2006). https://doi.org/10.1007/s00280-005-0030-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-005-0030-7