Irinotecan Or Topotecan) Plus High-Dose Cyclophosphamide As Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma

84 Vol. 10, 84–87, January 1, 2004 Clinical Cancer Research

Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma

Brian H. Kushner, Kim Kramer, Shakeel Modak, blocked by neutralizing antibodies, consistent with the and Nai-Kong V. Cheung desired immunosuppressive effect of high-dose cyclophosphamide. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York Conclusions: CTV and C/I require transfusional and antibiotic support but otherwise entail tolerable morbidity. They have modest antineuroblastoma activity in heavily ABSTRACT treated patients and are good preparative regimens for pas- Purpose: We used high-dose cyclophosphamide plus sive immunotherapy with monoclonal antibodies. topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma. The aim was to use a regimen INTRODUCTION with little risk to major organs to (a) achieve or consolidate The camptothecin analogs topotecan and irinotecan hold remission in heavily treated patients and to (b) induce an great promise in the treatment of neuroblastoma (NB) for sev- immunological state conducive to passive immunotherapy eral reasons. First, they have impressive activity against NB cell with the murine 3F8 antibody. lines resistant to standard anti-NB agents (1–5); this finding Experimental Design: CTV and C/I included cyclophos- implies that they may provide a novel non-cross-resistant che- phamide 140 mg/kg (ϳ4200 mg/m2). With CTV, topotecan 2 motherapeutic addition to the standard drug armamentarium for mg/m2 was infused i.v. (30 min) on days 1–4 (total, 8 mg/m2), NB. Second, their nonhematological toxicity (mucositis/topote- and vincristine 0.067 mg/kg was injected on day 1. With C/I, can, Refs. 6 to 11; diarrhea/irinotecan, Refs. 12 to 16) is man- irinotecan, 50 mg/m2 was infused i.v. (1 h) on days 1–5 (total, ageable and transient, major consideration in NB patients who 250 mg/m2). Mesna and granulocyte colony-stimulating fac- often undergo nephrectomy and who are treated with cardio- tor were used. toxic (doxorubicin) and nephrotoxic (platinum compounds, if- Results: Twenty-nine patients received 38 courses of osfamide) agents, as well as with total body or local irradiation. CTV, and 26 patients received 38 courses of C/I. All patients Third, cytotoxicity occurs at relatively nonmyelosuppressive had previously received topotecan, a hemopoietic stem-cell dosages (6–8, 13–15, 17, 18), which suggests that they can be transplant, and/or high-dose cyclophosphamide. CTV and safely given with other anticancer drugs. C/I caused myelosuppression of comparably prolonged du- Camptothecin analogs target topoisomerase I, which is ration as follows: absolute neutrophil counts <500/␮l lasted involved in DNA replication; hence, their cytotoxicity may be 5–12 days in patients who had not previously received trans- mainly S-phase specific (19). The mechanism of action suggests plant and 7–21 days in patients who were post-transplant. that their optimal use might be with alkylators, which also Other significant toxicities included typhlitis (two CTV- obstruct DNA activity. In fact, combined use of topotecan 3.75 treated patients, one C/I-treated patient) and hemorrhagic mg/m2 and cyclophosphamide 1250 mg/m2 (relatively low dos- cystitis (one C/I-treated patient). Major responses were seen ages of each agent) has become standard treatment for resistant in 4 (15%) of 26 CTV and 4 (17%) of 24 C/I-treated patients NB (20). In contrast, there have been no detailed reports on with assessable disease. Bone marrow disease resolved in 5 irinotecan used with other agents in children or with cyclophos- (28%) of 18 CTV-treated patients and in 4 (27%) of phamide in any age group (21). 15 C/I-treated patients. 3F8 after CTV or C/I was not We combined these camptothecin analogs with high-dose cyclophosphamide, which has well-known anti-NB and immunosuppressive activity, spares hemopoietic stem cells, and has modest nonhematological toxicity. The aim was to use a regi- Received 8/5/03; revised 9/3/03; accepted 9/5/03. men that poses little risk to major organs to (a) achieve or Grant support: Partially supported by grants from the National Cancer consolidate remission in heavily treated NB patients and to (b) Institute (CA61017, CA72868), Bethesda, Maryland; Hope Street Kids, induce an immunological state conducive to passive immuno- Alexandria, VA; the Justin Zahn Fund, New York, New York; the Katie’s Find A Cure Fund, New York, New York; and the Robert Steel therapy with the murine anti-GD2 monoclonal antibody 3F8 Foundation, New York, New York. (22–24). Optimal use of 3F8 involves multiple two-week cycles, The costs of publication of this article were defrayed in part by the but that is not possible if there is early development of human payment of page charges. This article must therefore be hereby marked antimouse antibody. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Brian H. Kushner, Department of Pediatrics, MATERIALS AND METHODS Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Phone: (212) 639-6793; Fax: (212) 717-3239. Patients with relapsed or refractory (i.e., incompletely re- E-mail: [email protected]. sponding) NB were assessed in this Memorial Sloan-Kettering

Cancer Center retrospective study. Patients needed to have Table 1 Patient characteristics satisfactory cardiac (normal echocardiogram), hepatic (normal CTVa (n ϭ 29) C/I (n ϭ 26) serum bilirubin, serum liver enzymes 1–1.5ϫ the upper limits of Age at study entry normal), and renal (normal serum creatinine) status. Informed Range 1 y 10 m–14y6m3y5m–11y8m written consents for treatments were obtained in accordance Median 5y9m 7y3m with hospital policy after guardians understood the investiga- Male:female 14:15 19:7 tional nature of the treatments, the potential life-threatening Stage 4 disease 26 (90%) 25 (96%) Prior therapy with: risks to be expected, the known side effects of each agent, and Irinotecan 3 (10%) 4 (16%) the possibility of unforeseen life-threatening toxicities. Topotecan 10 (34%) 23 (88%) Both CTV and C/I included 70 mg/kg cyclophosphamide Stem-cell transplantation 13 (45%) 20 (77%) infused i.v. over6hondays 1 and 2 (total ϭ 140 mg/kg, i.e., High-dose 18 (62%) 18 (69%) ϳ 2 cyclophosphamide 4200 mg/m ), with hydration using D5/1/2 normal saline plus Disease status at study entry 30 meq/l potassium chloride and 10 mg/l furosemide at 150 1° refractory/PD 15 4 ml/m2/h. Mesna (70 mg/kg) was started on days 1 and 2 along 1st relapse 8 7 with the cyclophosphamide but was infused over 24 h. 2° refractory/PD 4 8 Ն With CTV, 2 mg/m2 topotecan was infused i.v. over 30 min 2nd relapse 0 5 2 CR2 2 2 on days 1–4 (total: 8 mg/m ) and 0.067 mg/kg vincristine was a given by i.v. bolus on day 1. CTV, cyclophosphamide plus topotecan/vincristine; C/I, cyclo- 2 phosphamide plus ironotecan; PD, progressive disease; CR, complete With C/I, 50 mg/m irinotecan was infused i.v. over1hon remission. days 1–5 (total ϭ 250 mg/m2). Granulocyte colony-stimulating factor was used after com- pletion of chemotherapy. Disease status was assessed by computed tomographic (n ϭ 12). In contrast, only 4 (15%) of the 26 C/I-treated patients scans, 99mTc-bone scan, 131I- or 123I-metaiodobenzylguanidine were treated for a poor response to induction, whereas 22 (85%) scan, urine catecholamine measurements, histological examina- were treated after at least one relapse. tions of bone marrow biopsy specimens and aspirates from Toxicity. CTV and C/I were routinely given on an out- bilateral iliac crests. patient basis because acute toxicities such as emesis, hematuria, Disease status was defined by the International Neuroblas- and hyponatremia were readily preventable. There was one toxic toma-Response Criteria (25) as follows: complete response, no death (from infection). evidence of disease; very good partial response, volume of CTV and C/I caused grade 4 myelosuppression of compa- primary mass reduced by 90%–99%, no evidence of distant rably prolonged duration. In patients who had not received disease (including normal metaiodobenzylguanidine) except for hemopoietic stem-cell transplants previously, absolute neutro- skeletal residua, catecholamines normal; partial response (PR), phil counts Ͻ500/␮l lasted 5–12 days, and platelet count recov- Ͼ50% decrease in measurable disease and Յ1 positive bone ery to Ͼ75,000/␮l occurred by day 21–28. Five previously marrow site; mixed response, Ͼ50% decrease of any lesion with transplanted patients with poor bone marrow reserve received Ͻ50% decrease in any other; no response, Ͻ50% decrease but CTV (n ϭ 2) or C/I (n ϭ 3), which was followed 48 h later by Ͻ25% increase in any lesion; and progressive disease, new infusion of hemopoietic stem cells to minimize myelosuppres- lesion or Ͼ25% increase in an existing lesion. sion. In the other 27 post-transplant patients, absolute neutrophil Human antimouse antibody was measured using an ELISA counts Ͻ500/␮l lasted 7–21 days and platelet count recovery to as described previously (22). Ͼ75,000/␮l occurred by day 17–40ϩ. Blood-borne bacterial Toxicity was graded using the National Cancer Institute infections were documented in eight patients, one of whom died Common Toxicity Criteria. of septic shock. Two other patients had clinical sepsis and Eligibility criteria to start treatment with 3F8 included pneumonia, respectively, but no organisms were identified. refractory but nonprogressing disease and no bulky masses. Major nonhematological toxicities included suspected typhlitis in two CTV-treated patients (concomitant with bacterial sepsis) and in one C/I-treated patient. Grade 2 mucositis RESULTS occurred in three CTV-treated patients but not with those treated Patient Characteristics. Twenty-nine patients received with C/I. Diarrhea was grade Յ2. One CTV-treated patient had 38 courses of CTV, and 26 patients received 38 courses of C/I grade 3 generalized pain attributable to vincristine, and one (Table 1). All patients had previously received topotecan, an C/I-treated patient developed hemorrhagic cystitis. No signifi- autologous hemopoietic stem-cell transplant, and/or high-dose cant renal, cardiac, or hepatic dysfunction was seen. cyclophosphamide. Topotecan or stem-cell transplants had been 3F8 was used after CTV in 13 patients and after C/I in used previously in 34% and 45% of the CTV-treated patients, seven patients. These patients received a median of three cycles respectively, versus 88% and 77% of the C/I-treated patients. of 3F8 (range, 1–8) over a median period of 4.5 months (range, Two-thirds of the patients had prior exposure to high-dose 1–12 months) without developing persistent human antimouse cyclophosphamide. Fifteen (52%) of the 29 CTV-treated pa- antibody, consistent with the desired immunosuppressive effect tients had NB that was refractory to, or progressed during, of high-dose cyclophosphamide, except in one patient who was induction that included topotecan (n ϭ 5) and/or high-dose treated with CTV followed by infusion of autologous stem cells cyclophosphamide combined with doxorubicin and vincristine that had been collected after relatively low-dose chemotherapy.

Table 2 Responses in patients with assessable diseasea effect when topotecan and vincristine were used together (26). Response CTVb (n ϭ 26) C/I (n ϭ 24) The choice of topotecan daily dosage and infusion time was based on the absence of undue toxicity with 30-minute daily CR/VGPR/PR 4 (15%) 4 (17%) ϫ 2 2 MR 2 (8%) 5 (19%) infusions 5 days of topotecan 2–2.4 mg/m (i.e., 10–12 mg/m NR 15 (58%) 11 (46%) per cycle; Refs. 17 and 27) and the fact that daily dosages of 1–2 PD 5 (19%) 4 (17%) mg/m2 correlated with efficacy against topotecan-sensitive ma- a Three CTV and two C/I patients were not assessable for response. lignancies (17, 26–29). We increased the dosage of topotecan to b CTV, cyclophosphamide plus topotecan/vincristine; C/I, cyclo- 8 mg/m2 because of the lack of nonhematological toxicity in the phosphamide plus ironotecan; CR, complete response; VGPR, very earlier study with 6 mg/m2 (11). good partial response; PR, partial response; MR, mixed response; PD, Uncertainty exists regarding the optimal dosage and sched- progressive disease; NR, no response. ule of irinotecan. Preclinical studies using xenografts of pediatric solid tumors, including NB, favor 5- or 10-day schedules, and the few published clinical reports support that timing. Thus, Responses. Bone marrow disease resolved in 5 (28%) of in pediatric phase I studies, (12–14) and in small pilot studies 18 CTV-treated patients and in 4 (27%) of 15 C/I-treated pa- (15, 18), irinotecan administered at 50–200 mg/m2/day ϫ3 days tients. These bone marrow responses left three patients in com- (14), at 30–65 mg/m2/day ϫ5 days, (12, 18), or at 20–29 plete response/very good partial response, two patients in PR mg/m2/day ϫ10 days (13, 15) produced favorable results in 123 with improved but still abnormal I-metaiodobenzylguanidine patients with NB or other solid tumors. In contrast, the sole scans, one patient in PR with slightly high urine catecholamine phase II trial of irinotecan for NB reported to date used a single levels, and three patients with mixed response attributable to dose of 600 mg/m2 every 3 weeks but, despite the higher dosage 123 persistence of I-metaiodobenzylguanidine uptake in a single than in the 3-, 5-, or 10-day regimens, yielded “no clinically skeletal site or soft tissue. useful activity” (16). For C/I, we chose the 5-day schedule with CTV achieved no major responses of soft tissue disease irinotecan 50 mg/m2/day because myelosuppression from irino- present in 11 patients, although gross total resections were tecan would coincide with that caused by the high-dose cyclo- subsequently performed in five of these patients. C/I produced phosphamide. PR of retroperitoneal and/or thoracic NB in three of nine pa- CTV and C/I have modest anti-NB activity in heavily tients with assessable soft tissue disease and was followed by treated patients, immunomodulatory effects conducive to anti- gross total resections in seven of nine patients. body-mediated immunotherapy, and modest toxicity to major Overall, among patients with assessable disease, major nonhematological organs. Other aspects of CTV and C/I worthy responses (PR or better) were achieved in 4 (15%) of 26 CTV- of note include the activity of camptothecins as radiation sen- treated patients and in 4 (17%) of 24 C/I-treated patients sitizers, (30) evidence that the camptothecins may be less af- (Table 2). fected by P-glycoprotein multidrug resistance mechanisms when compared with doxorubicin and etoposide, (7, 31) the DISCUSSION excellent penetration into the central nervous system of topote- Based on past experience with each agent individually in can (32) though not of irinotecan (33), and the absence of altered the dosages and schedules applied, combined use of camptoth- pharmacokinetics with combined use of cyclophosphamide and ecin analogs and high-dose cyclophosphamide in a large series topotecan (Refs. 34 and 35; no report to date on this issue of heavily treated NB patients had few unexpected side effects. regarding irinotecan). 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Brian H. Kushner, Kim Kramer, Shakeel Modak, et al.

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