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© 2000 American Society for Clinical Oncology Phase I Study of Chimeric Human/Murine Anti–Ganglioside GD2 Monoclonal Antibody (ch14.18) With Granulocyte-Macrophage Colony-Stimulating Factor in Children With Neuroblastoma Immediately After Hematopoietic Stem-Cell Transplantation: A Children’s Cancer Group StudyFrom the Department of Pediatrics, Section of Hematology/Oncology, New York Medical College, Valhalla, NY; Departments of Pediatrics and Human Oncology, University of Wisconsin Medical Center, Madison, WI; Children’s Cancer Group, Operations Office, Arcadia; The Scripps Research Institute, La Jolla; Department of Pediatrics, University of California School of Medicine, San Francisco; Department of Pediatrics, Division of Hematology/Oncology, Childrens Hospital of Los Angeles, University of Southern California School of Medicine, Los Angeles, CA; and Department of Pediatrics, Hematology/Oncology, Childrens National Medical Center, Washington DC. Address reprint requests to M. Fevzi Ozkaynak, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email mehmet_ozkaynak{at}nymc.edu
PURPOSE: Ganglioside GD2 is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-GD2 monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting. PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1,000/µL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 µg/m2/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m2/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated. RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m2/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients. CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m2/d for 4 days when given in this schedule with GM-CSF.
APPROXIMATELY 60% of children with neuroblastoma have high-risk tumors, and conventional therapy rarely results in long-term survival. Recent studies have demonstrated that some high-risk patients achieve long-term, disease-free survival after marrow-ablative chemoradiation therapy and autologous bone marrow transplantation (ABMT).1-4 However, 50% to 60% of these patients will have recurrence after ABMT, which indicates that novel therapies are needed to eradicate minimal residual disease after ABMT. Ganglioside GD2 is strongly expressed on the surface of human neuroblastoma cells, and there is little intra- or intertumor heterogeneity.5,6 A murine monoclonal anti-GD2 antibody (14.G2a) and a chimeric human/murine anti-GD2 antibody (ch14.18) have been tested in clinical studies for neuroblastoma.7-10 14.G2a is a murine immunoglobulin (Ig)-G2a monoclonal antibody (MoAb) that has shown promise for targeted immunotherapy for the following reasons: (1) it is specific for GD2, which is expressed on a variety of tumors but has restricted distribution on normal tissues5,6,11; (2) it (or its molecular derivatives) localizes to human GD2-positive tumors in animal models and in humans7,12,13 (Reuland et al, manuscript submitted for publication); and (3) it activates complement and mediates antibody-dependent cellular cytotoxicity (ADCC) with monocytes, neutrophils, natural killer (NK), and lymphokine-activated killer (LAK) cells.13-16 To improve the potential clinical utility of 14.G2a, Gillies et al17 formed a chimeric construct (ch14.18) using genes for the murine 14.G2a variable region’s heavy and light chains and human constant region genes for IgG1 heavy chain and kappa light chain. Thus ch14.18 has antigen-binding properties comparable to those of the murine MoAb but physical properties and complement- and Fc receptor–binding properties comparable to those of the human Ig chain.17 This human/murine chimeric anti-GD2 MoAb, ch14.18, effectively mediates monocyte, neutrophil, NK, and LAK cell ADCC.13,14,16 Studies in murine models suggest that activation of effector cells in vivo by cytokine administration can increase the antitumor efficacy of tumor-reactive antibodies.18-20 Furthermore, these antitumor effects are best seen in animals bearing minimal residual neoplastic disease.21,22 An initial step in the clinical testing of these hypotheses was this phase I study of escalating doses of ch14.18 with granulocyte-macrophage colony-stimulating factor (GM-CSF) in children with neuroblastoma after hematopoietic stem-cell transplantation (HSCT). It was also hypothesized that the immunosuppression seen immediately after HSCT may allow the administration of ch14.18 without generation of a human antichimeric antibody (HACA) response.
Patients Twenty-two patients with neuroblastoma were treated between January 1995 and September 1997 in six Children’s Cancer Group (CCG) institutions. All patients were treated under the auspices of a protocol approved by the institutional review board at each institution (CCG-0935). Eligibility criteria included age younger than 22 years at initial diagnosis. Patients must have had the diagnosis of neuroblastoma based on tumor histology or bone marrow metastases and elevated urine catecholamine metabolites. Disease status could have been complete response (CR), very good partial response (VGPR), or partial response (PR). Any patient who had prior ch14.18 or 14.G2a therapy was ineligible. Any prior myeloablative chemotherapy or chemoradiotherapy regimen was acceptable. The study began as an autologous bone marrow transplantation (ABMT) protocol; however, investigators were allowed to add or substitute autologous peripheral-blood stem cells instead of ABMT 1 year into the study. Patients were required to have a Lansky performance scale score of 1, 2, or 3, and a life expectancy of more than 2 months. The following organ function criteria were required for eligibility for ch14.18 treatment: left ventricular ejection fraction of more than 47% by radionuclide angiogram or shortening fraction of more than 27% by echocardiogram, creatinine clearance or radioisotope glomerular filtration rate of more than 70 mL/min/1.73 m2, AST and ALT less than 2.5 x normal and total bilirubin less than 1.5 x normal, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry greater than 94%. If pulmonary function tests were performed, forced expiratory volume in 1 second/forced vital capacity had to be more than 60%. Patients with veno-occlusive disease of the liver must have been either stable or improving.
Treatment Program GM-CSF 250 µg/m2/d IV as a 2-hour infusion was continued during the days of ch14.18 infusion and for 3 days afterward. The same dose of GM-CSF could be administered as a subcutaneous injection on an outpatient basis. The ch14.18 infusion was started approximately 1 hour after GM-CSF when both were administered on the same day. ch14.18 was infused IV over 5 hours daily for 4 consecutive days. The initial ch14.18 dose level was 20 mg/m2/d. The subsequent dose levels were 30, 40, and 50 mg/m2/d. There was no intrapatient dose escalation. Patients were premedicated with hydroxyzine 1 mg/kg IV over 10 minutes and acetaminophen 10 mg/kg PO to start 20 minutes before ch14.18 infusion. Also, it was recommended to begin morphine sulfate with a loading dose of 0.1 mg/kg immediately before ch14.18 administration and to continue morphine as a continuous infusion at a rate of 0.05 mg/kg/h. In addition, IV or subcutaneous epinephrine was administered to treat allergic phenomena not controlled by the above premedication regimen. The infusion time of ch14.18 was allowed to be prolonged from 5 to 10 hours, or longer if neuropathic pain was not controlled with appropriate doses of narcotics, or if hypotension, serious allergic toxicity such as extensive urticaria or bronchospasm, or severe peripheral-sensory problems were observed. Patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF in the absence of progressive disease. Second and subsequent treatments were planned to be administered no earlier than every 28 days. The maximum delay allowed in administering the second and subsequent courses was 120 days. Second and subsequent courses of ch14.18 were not mandatory. The HACA test results were not used to determine whether to administer the second or subsequent courses. The following toxicities attributed to GM-CSF required decreasing the dose of GM-CSF at least 50% or discontinuing it: (1) grade 3 or 4 capillary leak syndrome/fluid retention; (2) persistent high (> 39.5°C) fevers with no obvious source of infection and negative blood cultures; (3) persistent or recurrent tachycardia and hypotension.
Measurement of HACA and ch14. ch14.18 enzyme-linked immunosorbent assay. Serum levels of ch14.18 antibody were obtained using a modification of previously published methods.23 Evaluation of HACA. Anti-ch14.18 reactivity in patients’ sera was measured as previously described.24 Negative controls performed with serum specimens from cancer patients never treated with ch14.18 antibody showed no reaction in this assay. Each experiment also included internal standards allowing comparisons between different runs. By this assay, it was not possible to quantitate the amount of HACA in assayed specimens, but only to compare different time points from the same patient. Thus each patient’s cryopreserved serum samples, diluted the same way, were assayed the same day in the same plate, and the obtained optical density values were compared with each other. Although some efforts have been made to quantitate HACA detection,10,25,26 several molecular assumptions are involved in these calculations, and we prefer to report and compare results directly as optical density values.
Definition of Dose-Limiting Toxicity (DLT)
Statistical Analysis
Change in Peripheral-Blood Counts
Course Length
Patient Characteristics Patient characteristics are listed in Table 1. Twenty-three patients with neuroblastoma were entered onto the study. One patient assigned to dose level 2 never received the antibody, because his parents decided against his participation in the study before the first course. On review, three of 22 patients who did receive treatment with ch14.18 and GM-CSF were subsequently deemed ineligible because of protocol treatment violations pertaining only to the timing of the GM-CSF administration before the first treatment course. Two of these three received 48 hours of GM-CSF instead of a minimum of 72 hours, as required by the protocol. In the third patient, GM-CSF was started with the antibody. This report describes the remaining 19 patients. Median age was 4.8 years (range, 2 to 15 years). Fourteen and five patients were in first and second remission before HSCT, respectively (Table 1). Median times from diagnosis to transplantation were 6 (range, 5 to 8) and 19.5 (range, 11 to 48) months for patients treated in first and second remission, respectively. As listed in Table 1, various preparatory regimens were used, but melphalan, carboplatin, and etoposide with local radiotherapy was the most common one.
Timing of the Courses The median time between the day of transplantation and achieving an APC greater than 1,000/µL was 24 days (range, 10 to 62 days). The median time between achieving an APC greater than 1,000/µL and the first course of antibody was 11.5 days (range, 0 to 56 days). The median numbers of days between first and second, second and third, third and fourth, fourth and fifth, and fifth and sixth treatment courses were 31 (range, 21 to 70), 32 (range, 20 to 92), 30 (range, 27 to 70), 28 (range, 26 to 56), and 28 (range, 21 to 34) days, respectively. A total of 79 courses were administered. Two, one, three, six, and seven patients received one, two, three, four, and six courses of therapy, respectively.
Toxicities
Fever with no source of infection was a relatively common complication. The third most common toxicity was nausea and vomiting. Six (32%) of 19 patients experienced nausea/vomiting during the first course. One of six was considered as DLT (Table 3). The patient required readmission for vomiting and dehydration 48 hours after discharge after the first course of therapy. The next most common problem was urticarial eruption. This was observed in seven (37%) of 19 patients during the first course. Two of seven cases were classified as grade 3 (ie, generalized eruption), one of which recurred during the subsequent two courses despite treatment and was declared to be DLT (Table 3). The remaining patients had less than grade 3 skin/allergy toxicity. These patients required hydroxyzine every 4 hours and epinephrine every 6 hours on the days of ch14.18 administration. In addition, the infusion time of ch14.18 was prolonged to minimize these symptoms. Hypotension was observed during 12 of 79 courses, of which five cases were considered to be grade 3 or 4. These patients required infusions of normal saline or albumin. The antibody infusion was completed in all patients experiencing hypotension by prolonging the infusion time. Hypotension was avoided during most of the subsequent courses by continuing with the prolonged ch14.18 infusion. Nine of 79 courses were complicated with mild capillary leak syndrome, two of which occurred during the first course. In six of nine courses, capillary leak was considered to be grade 2 (ie, face swollen, weight gain 5% to 10%, with mild peripheral edema), and the remaining three were grade 1. Dilated pupils were noted during six of 79 courses. In four of six episodes, patients also complained of blurred or double vision. All resolved over a period of days to weeks. Transient motor weakness, mild to moderate paresthesias, and moderate to severe agitation considered to be unrelated to the neuropathic pain were infrequently observed (Table 2). The duration of ch14.18 infusion was increased because of side effects in 10 of 19 patients. The duration was increased to 10 hours in seven patients, 12 hours in one patient, and to 20 and 23 hours in two other patients. The main reasons for prolongation of the duration of infusion were neuropathic pain, hypotension, and allergic skin reactions. The duration was increased in one of three, one of three, four of seven, and four of six patients receiving dose levels 1, 2, 3, and 4, respectively. Once the duration of ch14.18 infusion was increased, these patients received subsequent courses at the same prolonged rate. Complete blood cell counts were obtained before the ch14.18 infusion was started and on the last day of antibody therapy. Declines of WBCs and APC were observed in 43 (56%) of 77 and 40 (56%) of 72 courses with sufficient data reported for analysis, respectively (Table 2). However, the declines in WBCs and APC were not a clinical problem. Similar to WBCs and APC, declines in platelet counts and hematocrit were also observed during therapy. The platelet count decreased in six of seven untransfused patients during the first course. Overall, platelet count declined in 44 (85%) of 52 courses given to untransfused patients during the 4-day therapy period, with a median decline of 25% (range, 2% to 91%). However, none of the courses were complicated with bleeding problems during this transient thrombocytopenic period. Eight significant infectious problems were reported among the 79 courses. Five were herpes zoster, one was staphylococcal infection of the central venous catheter, one was an enterococcus infection of the central venous catheter and urine with bilateral lung infiltrates, and one was apparent sepsis with no organism identified. Transient and insignificant AST/ALT elevations were observed. Pulmonary toxicity was reported in four of 79 courses. Two of four were grade 3, ie, dyspnea with desaturation requiring oxygen. These were separate from the capillary leak syndrome and all resolved quickly. Metabolic problems included hyponatremia in four of 79 courses (grade 2 or less), one case of hypocalcemia (grade 4), and one case of hypokalemia (grade 3). No GM-CSF dose modifications were required during any course, based on toxicities attributed to GM-CSF during the 4 days of ch14.18 therapy or the 3 days afterward.
Serum HACA and ch14. For each course of therapy, serum specimens were required before starting the ch14.18 treatment and on days 3, 7, and 13 after the initiation of ch14.18 treatment. Table 4 presents data collected and analyzed from serum specimens obtained from 18 of the 19 eligible patients. All serum samples obtained were analyzed for ch14.18 level and HACA reactivity. The values for the peak serum level of ch14.18 for the first course of antibody treatment were calculated for each patient and are presented as the mean value for all eligible patients at each dose level. Five (28%) of 18 evaluated patients showed HACA reactivity detectable after two (two patients), five (two patients), and six (one patient) courses of treatment at the dose levels listed in Table 4. No HACA reactivity was found in serum specimens from patients receiving the lowest dose of ch14.18.
Disease Progression Ten of 19 patients experienced disease progression, with a median follow-up of 40 months (range, 25 to 50 months). Eight of 10 patients who experienced disease progression were in first remission (three in first CR, four in first VGPR, and one in first PR) and two were in second CR. Three of eight, who were in first remission, experienced disease progression while on antibody therapy after receiving one, three, and five courses of antibody therapy, respectively. The remaining five of eight patients received one, four, four, six, and four courses, and relapsed 10, 6, 8, 22, and 27 months after the last course of therapy, respectively. Two patients in second remission received one and three courses of antibody therapy and had disease progression 22 and 15 months off therapy, respectively. Progression occurred in the primary site in two patients, in distant sites in seven patients, and in the primary and distant sites in one patient. Two of 10 patients with progressive disease had developed HACA, whereas three of nine patients who did not have disease progression had HACA positivity while on study.
A phase I study of escalating doses of a chimeric human/murine anti-GD2 antibody (ch14.18) with GM-CSF was performed in 19 children with neuroblastoma after HSCT. The MTD of ch14.18 was 40 mg/m2/d for 4 days in this setting. The efficacy of antibody-based immunotherapies in murine models are best demonstrated for animals with small tumor burdens.21,22 Thus our goal was to test ch14.18 in patients with high-risk neuroblastoma who were likely to have minimal residual disease. This state was achieved through induction chemotherapy followed by myeloablative therapy with autologous HSCT.1 However, patients recently completing autologous HSCT might not tolerate ch14.18 with GM-CSF as well as non-HSCT patients. Thus we evaluated the toxicity and MTD of ch14.18 with GM-CSF soon after HSCT when the APC reached 1,000/µL. The choice of GM-CSF was based on preclinical studies that showed enhancement of ADCC against neuroblastoma cells in the presence of anti-GD2 antibody.13,18 In our study, toxicity of ch14.18 was found to be significant but manageable. All the treatments were given on an inpatient basis, because of the anticipated neuropathic pain, allergic skin reactions, and hypotension. In fact, severe neuropathic pain that necessitated the use of continuous infusion of morphine was observed in 68% of the patients during the first course. The etiology of this pain is thought to be recognition of GD2 molecules by ch14.18 on nerve fibers. The main toxicities of pain, fever, urticaria, hypotension, and neurotoxicities encountered in this study have been observed by other investigators7,10,27,28 (Table 5). Several investigators administered ch14.18 alone. Among these, Saleh et al28 observed only the neuropathic pain as the major toxicity among the 13 adult patients with metastatic melanoma treated with ch14.18 alone, eight of whom developed HACA. Handgretinger et al7 reported neuropathic pain, pruritus, urticaria, transient pupillatonia, and no HACA development in nine children with neuroblastoma, whereas Yu et al10 observed neuropathic pain, tachycardia, hypertension, fever, and urticaria in 10 patients with recurrent neuroblastoma and one patient with metastatic osteosarcoma. Yu et al reported HACA development in three of eight patients. The addition of GM-CSF to ch14.18 therapy did not change the above toxicity profile.29,30 Murray et al29 reported their experience with 16 adult patients with metastatic malignant melanoma treated with GM-CSF plus escalating doses of ch14.18 (15 to 60 mg/m2) given as a single injection. Toxicities were pain, hypertension, hypotension, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgia, and weakness. Six of 16 patients developed HACA. Yu et al30 treated 32 patients with refractory or recurrent neuroblastoma with ch14.18 at 50 mg/m2/d for 4 days along with GM-CSF at 10 µg/kg/d for 14 days. The main toxicities were pain, fever, tachycardia, hypertension, hypotension, nausea, vomiting, diarrhea, urticarial rash, and mild thrombocytopenia. In our study, we have observed mild transient decreases of WBCs and APC relatively frequently, despite the administration of GM-CSF; this, however, never became a clinical problem. Similarly, transient thrombocytopenia and anemia were observed in untransfused patients during the first and subsequent courses. Yu et al10 observed a similar transient and mild thrombocytopenia that peaked on day 4 and resolved by day 7. The average decline of platelets was 30%. The pathogenesis of the decline in all three lineages in our patients is unclear. GD2 is not known to be present on hematopoietic cells. The acute decrease of blood counts is compatible with an immune or nonspecific destructive process. Because our patients were treated immediately after HSCT, inadequate and marginal hematopoietic cell production and reserves may have also contributed to the problem.
Peak serum levels of ch14.18 more than 5 µg/mL were consistently observed at all dose levels. In vitro studies have shown that this ch14.18 antibody is effective at mediating ADCC of tumor cells at concentrations as low as 0.01 µg/mL.31 Patients maintained this serum level of ch14.18 for several days and hence had sufficient serum concentrations required for antibody facilitated tumor cell destruction. This chimeric antibody consists primarily of human Ig components but does contain murine variable regions. Thirteen assessable patients showed no HACA response, whereas five patients developed HACA, despite the high-dose chemotherapy they received before treatment with ch14.18. The development of these HACA responses was not noted until after the second course. This suggests that subsequent trials could give two or three courses of ch14.18 with little concern for development of HACA in this setting. It should be noted, however, that different preparative regimens may result in different immunosuppression and hence different HACA production. Ganglioside GD2 is strongly expressed on the surface of tumors of neuroectodermal origin, including neuroblastoma.5,6 This phase I clinical trial in patients with neuroblastoma was based on the encouraging preclinical and clinical data with ch14.18. First, several studies have shown ch14.18 to be very effective in neuroblastoma cell killing mediated by neutrophil, monocyte, NK, and LAK ADCC, as well as complement-dependent cytotoxicity.14-16 Second, objective responses have been observed in at least three clinical trials with ch14.18. Handgretinger et al7 reported two CRs, two PRs, and one minor response among nine heavily pretreated neuroblastoma patients, three of whom were in relapse, whereas six were in partial remission after the primary therapy. Yu et al27 conducted a pilot trial of ch14.18 with GM-CSF in patients with recurrent/refractory neuroblastoma in which 59 courses were administered to 17 patients. There were five patients with CR and three with stable disease. This study led to a phase II study in which 32 patients were treated with a total of 70 courses of ch14.18 at 50 mg/m2/d for 4 days along with GM-CSF at 10 µg/kg/d for 14 days.30 Among 27 patients assessable for response, there were one CR, three PRs, one mixed response, and two cases of stable disease. When analyzed by the site of disease, there were four CRs and one PR in 18 patients with marrow disease and one CR and two PRs in 21 patients with bone involvement. Two of 16 patients with large tumor masses had a PR with 63% and more than 70% reduction in tumor size. Among the five responding patients, four were alive at follow-up of 9, 17, 18, and 20 months, respectively. These results suggest that this approach be further pursued, considering the fact that these patients had received multiagent, multimodality therapy, including bone marrow transplantation in 20 patients. Although this was a phase I study and progression-free survival was not an end point, it is worth noting that the rate of disease progression was not disappointing. Eight of 14 patients in first remission and two of five patients in second remission have experienced disease progression, with a median follow-up of 40 months. Although the numbers are very small, this compares well with a recent study in which only 20% of patients who underwent transplantation after having progressive disease are surviving.32 Several investigators have shown that interleukin-2 augments ADCC, NK, and LAK activity against neuroblastoma cells by anti-GD2 antibodies, including ch14.18.9,15 We are currently exploring the incorporation of interleukin-2 into the above regimen after HSCT. The ultimate study to determine the role of ch14.18 is a phase III trial of antibody versus no antibody after HSCT, which is currently being planned as a Children’s Oncology Group study.
Supported in part by grants from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Also supported in part by the NIH NCRR GCRC grant MO1 RR-43 and the Neil Bogart Memorial Fund of the J.J. Martell Foundation for Leukemia, Cancer and AIDS research (R.C.S.).
Laboratory analyses were performed at the GCRC at Childrens Hospital of Los Angeles, Los Angeles, CA (R.C.S.), and the Children’s Cancer Group Immunotherapy Resource Laboratory in Madison, WI (P.M.S. and J.G.). © 2000 by American Society of Clinical Oncology. 0732-183X/00/1824-4077
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Hank JA, Robinson RR, Surfus J, et al: Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin-2. Cancer Res 50: 5234-5239, 1990 32. Villablanca JG, Reynolds CP, Swift PS, et al: Phase I trial of carboplatin, etoposide, melphalan and local irradiation (CEM-LI) with purged autologous marrow transplantation for children with high risk neuroblastoma. Proc Am Soc Clin Oncol 17: 533a, 1998 (abstr 2045) Submitted February 8, 2000; accepted July 7, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
124 mEq/L) that improves with treatment within 24 hours, (6) grade 3 allergy (eg, moderate bronchospasm) that improves with treatment within 24 hours, (7) grade 3 hypotension and hypertension, or (8) grade 3 hepatic toxicity that returns to grade 1 before the time for the next ch14.18 treatment course. 
