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Clinical Trials |
Department of Medicine, University of Chicago, Chicago, Illinois 60637 [G. F. F., R. L. S., M. J. R.]; Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [N. J. M.]; Cancer and Leukemia Group B Statistical Center, Duke University, Durham, North Carolina 27710 [G. L. R., D. R. H.]; The Ohio State University Medical Center, Columbus, Ohio 43210 [W. E. C., M. C., R. P.]; Washington University School of Medicine, St. Louis, Missouri 63110 [J. M.]; and University of Maryland Cancer Center, Baltimore, Maryland 21201 [K. T.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m2 (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m2 (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m2 after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines.
Results: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response.
Conclusions: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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NK cells comprise approximately 15% of PBMCs and are the only lymphocytes that constitutively express functional IL-2 receptors (7)
. Ten percent of NK cells constitutively express high-affinity IL-2 receptors in addition to intermediate-affinity IL-2 receptors (8)
. Activation of the high-affinity receptor with picomolar concentrations of IL-2 provides a proliferative stimulus, without augmenting cytotoxicity. Binding to the intermediate-affinity receptor requires nanomolar concentrations of IL-2 and results in augmented effector cell cytotoxicity, with little effect on proliferation. These effects are time dependent, with prolonged stimulation producing more pronounced effects. NK cells expanded in vivo with low-dose IL-2 commonly express a low-affinity Fc-
receptor (CD16) and participate in ADCC (9
, 10)
. Thus, we hypothesized that the NK cell population could be expanded with low-dose IL-2 and subsequently stimulated to lyse antibody-coated tumor cells after administration of intermediate-dose IL-2.
Meropol et al. (11) demonstrated that daily s.c. IL-2 administration to cancer patients at doses ranging from 0.4–1.75 million IU/m2 (yielding peak levels of 10–100 pM) resulted in 154–530% expansion of NK cell numbers above baseline. The maximum tolerated dose was 1.25 million IU/m2 daily. In an effort to stimulate the cytotoxic mechanism in this expanded cell population, they then added 10-fold higher doses of IL-2 as outpatient "pulses" s.c. for 3 days every 2 weeks in patients receiving daily low doses. This resulted in further expansion of NK cell numbers, and the maximum tolerated "intermediate-dose pulse" was 15 million IU/m2 (12) . Dose-limiting toxicities with both the low-dose IL-2 and the intermediate-dose pulsing were largely constitutional, with fever, chills, and fatigue predominating.
The current Phase I study was designed to combine the IL-2 regimen developed by Meropol et al. (12) with escalating doses of trastuzumab to develop a treatment program suitable for future Phase II testing. In vitro ADCC assays using patient PBMCs and HER2-overexpressing target cell lines were performed to see whether results of these assays correlated with response. The effects of IL-2 on the expansion of the NK cell compartment were also evaluated via flow cytometric analysis of patient PBMCs for CD56+ cells.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Other eligibility criteria included age 
18 years, measurable or evaluable disease, Cancer and Leukemia Group B performance status 0 or 1, life expectancy 3 months, and adequate end-organ function as defined by an absolute granulocyte count 1,500/µl, platelet count 100,000/µl, blood urea nitrogen 
1.5 x ULN, creatinine 1.5 x ULN, bilirubin 1.5 x ULN, and serum glutamic oxalic acid transferase and alkaline phosphatase both 5 x ULN. Toward the end of the trial, the requirement for a LVEF of 45% was added due to reports that trastuzumab can induce cardiomyopathy. Patients were excluded for known central nervous system metastases, pregnancy or nursing, underlying immunological disease such as HIV infection or autoimmune disorder, concomitant treatment with corticosteroids or other immunomodulators, psychiatric conditions that would interfere with informed consent or treatment compliance, and any other serious medical illness including active uncontrolled infection, uncontrolled or severe cardiac disease, and known seropositivity for viral hepatitis. At least 4 weeks were to have elapsed since major surgery, radiotherapy, or chemotherapy, and 6 weeks were to have elapsed since any treatment with nitrosoureas, melphalan, or mitomycin C. Initially, any prior therapy with IL-2 or trastuzumab was prohibited; toward the end of the trial, this restriction was removed to facilitate accrual. All patients signed written informed consent in accordance with federal and institutional guidelines. Consent was signed before having tumor samples centrally tested for HER2 overexpression.
Treatment Regimen and Dose Escalation
The treatment plan is shown schematically in Fig. 1
. Patients received low-dose IL-2 as a daily s.c. injection starting on day 1 of protocol therapy and continuing without planned interruption, except that low-dose IL-2 was not given on days of intermediate-dose IL-2 administration. On the first (21-day) cycle, trastuzumab was given on day 7 as a 90-min infusion, and intermediate-dose IL-2 was given as a daily s.c. injection on days 8, 9, and 10. This was to help distinguish any acute (occurring within hours of infusion) toxicities due to trastuzumab from those due to intermediate-dose IL-2. On all subsequent (14-day) cycles, trastuzumab was given as a 90-min infusion on the same day as and just before the first intermediate-dose IL-2 injection.
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Trastuzumab was supplied by the Division of Cancer Treatment and Diagnosis Division, NCI, either as a liquid formulation or as a lyophilized formulation. The liquid formulation was supplied in 10-ml vials designed to deliver 5 mg/ml and was formulated in sodium acetate, sodium chloride, polysorbate 20, and water for injection USP. These vials did not contain preservative and were suitable for single use only. The lyophilized preparation was a freeze-dried preparation at a nominal content of 400 mg/vial. The formulation included histidine, trehalose, and polysorbate 20. Each vial was reconstituted with 20 ml of bacteriostatic water for injection, USP (containing 1.1% benzyl alcohol). The reconstituted solution was designed for multiple use within 28 days after reconstitution. The appropriate trastuzumab dose was added to 250 ml of 0.9% sodium chloride injection, USP, and infused over 90 min.
The low dose of IL-2 was initially fixed at 1.25 million IU/m2, and the intermediate dose of IL-2 was 15 million IU/m2. Because of IL-2-related toxicity, this was reduced after the first 18 patients to a low dose of 1.0 million IU/m2 and an intermediate dose of 12 million IU/m2. Trastuzumab was escalated through five antibody dose levels, 1, 2, 4, and 8 mg/kg biweekly and 8 mg/kg weekly. The biweekly schedule was tested so that trastuzumab doses would coincide with the intermediate-dose IL-2 pulses. The weekly cohort was added because that was the usual dosing schedule for trastuzumab. Escalation beyond a dose of 8 mg/kg was not planned because this dose was believed to provide adequate receptor saturation (1 , 13) . On the weekly antibody schedule, intermediate-dose IL-2 pulses remained at every-other-week intervals.
At least six patients were to be enrolled at each dose level at which excessive toxicity was not observed. Eligible patients with centrally documented HER2 overexpression who had already signed consent were guaranteed enrollment without waiting for the next dose level, and dose levels could be expanded accordingly. An antibody dose level was felt to be tolerable if fewer than two of the first six patients experienced a dose-limiting toxicity that was determined to be related to either antibody alone or the combination of antibody with IL-2. Toxicities related to IL-2 alone might require treatment modification but did not limit antibody dose escalation. A total of 12–18 patients were to be entered on the highest tolerated biweekly dose to better characterize the toxicity profile.
Toxicity considered a priori to be dose-limiting included grade 3–4 nonhematological toxicity, grade 4 hematological toxicity, and intolerable (persistent for 4 weeks) grade 2 constitutional toxicities, such as fever, chills, or fatigue that were believed to be related to low-dose IL-2. Protocol therapy was also to be stopped if LVEF declined by 15 absolute percentage points or to a value 40%.
Patient Monitoring
Baseline evaluation included a history, physical exam, tumor measurements, urinalysis, electrocardiogram, chest X-ray, complete blood count with platelet and differential count, and serum chemistries. In the latter part of the study, a multigated angiocardiogram or echocardiogram was also required to assess LVEF. Physical examination, toxicity assessment, blood count with platelet count, and serum chemistries were repeated on day 7 of cycle 1 and on day 1 of all subsequent cycles. LVEF was to be repeated every 2 months. Tumor measurements were repeated after the first four cycles and then every five (2-week) cycles.
The study was monitored by weekly conference calls attended by a representative from each participating center with a patient on active therapy, the study chair, and the study statistician, who jointly made decisions about toxicity attributions and management. Dose reductions were performed as follows. Low-dose IL-2 was held for grade 3–4 or intolerable grade 2 toxicity felt to be related to low-dose IL-2 and reinstituted at a 25% dose reduction after resolution of toxicity. If toxicity recurred after one dose reduction, the patient was removed from protocol therapy. Intermediate-dose IL-2 was held for grade 3–4 toxicity other than grade 3 fever or fatigue/malaise occurring within 24 h of an intermediate-dose pulse. It was reinstituted with a 25% dose reduction after resolution of toxicity. If toxicity recurred after one dose reduction, then the patient was removed from protocol therapy. Toxicities related to multiple components, such as low- and intermediate-dose IL-2 were managed by dose reductions of both components. Trastuzumab was held for grade 3–4 toxicity related to antibody and could be reinstituted with a 25% dose reduction. This dose reduction was not applied when toxicities were felt to be typical of a first-dose reaction that was not likely to recur. Patients were also removed from study treatment for PD or patient desire to discontinue protocol therapy.
Responses were recorded using the following criteria. CR required disappearance of all signs and symptoms of disease. PR was a >50% reduction in the sum of the products of the perpendicular diameters of all measured lesions. The category of PR did not apply to patients without measurable disease. PD was an increase in the sum of the products of the perpendicular diameters of all measured lesions by >25%, any new lesion, or (for evaluable disease) any definite increase in tumor size. SD was disease fitting none of the above criteria.
Correlative Studies
Blood for correlative studies was drawn at baseline, on day 1 of cycle 3 (immediately before antibody administration), and on day 4 of cycle 3 (24 h after the third intermediate-dose IL-2 administration). Blood was drawn in cycle 4 if cycle 3 samples could not be obtained. Additional samples were obtained from later cycles in some patients. Heparinized blood was sent at room temperature by overnight mail to a central laboratory for processing. PBMCs were viably procured from heparinized blood samples using Ficoll-Hypaque density centrifugation, cryopreserved per protocol, and stored in liquid nitrogen for later analysis (14)
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Flow Cytometry.
Frozen PBMCs were thawed (viability was routinely >90%), counted, and stained for cell surface expression of CD56 (NK cell marker) and CD16 (FcRIII) with phycoerythrin-labeled anti-CD56 mAb and FITC-labeled anti-CD16 mAb, respectively (BD PharMingen, San Diego, CA). After the addition of mAbs, samples were incubated in flow buffer (PBS + 5% fetal bovine serum) for 30 min at 4°C and washed twice with flow buffer before fixation in 1% formalin. Stained PBMCs were analyzed via two-color flow cytometry using a Coulter Elite XL Flow Cytometer. Ten thousand events were analyzed using standard lymphocyte gates (15)
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51Chromium Release ADCC Assay.
Patient PBMCs were viably thawed, enumerated, and plated at a density of 1 x 105, 5 x 104, 2.5 x 104, and 1.25 x 104 cells/well in 96-well, V-bottomed plates in RPMI 1640 supplemented with 10% human AB serum and antibiotic/antimycotic solution (Life Technologies, Inc., Calsbad, CA) with or without 1 or 10 ng/ml recombinant human IL-2 and incubated for 18 h at 37°C. SKBR3 (human HER2-positive breast adenocarcinoma) and MDA-468 (human HER2-negative adenocarcinoma) cells were washed and labeled with either Herceptin or control human IgG antibody for 30 min on ice, washed again, and then labeled with 100 µCi 51Cr/million cells. 51Cr-labeled SKBR3 or MDA-468 tumor targets were washed three times and then added (4 x 103 cells/well) for effector (patient PBMC) to target (E:T) ratios of 100:1, 50:1, 25:1, and 10:1, respectively (8)
. Plates were incubated at 37°C for 4 h, at which time cells were pelleted by centrifugation, and the supernatant was harvested for quantification of chromium release. Minimum and maximum release were determined via the incubation of labeled target cells in culture media alone or media supplemented with 1% NP40 detergent, respectively. Percentage of lysis was determined by the formula below.
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Results are presented as mean specific lysis of triplicate wells (difference between percentage of lysis of Herceptin-coated targets and percentage of lysis of control IgG-treated targets).
Differences in the number of NK cells and percentage of specific lysis over time were tested using a Wilcoxon matched-pairs signed rank test and between responders and nonresponders using a Kruskal-Wallis one-way ANOVA (16) .
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The percentage of patients found to overexpress HER2 would be expected to be greater than the percentage in the population at large, particularly for breast cancer, because many tumors were known to have HER2 overexpression by local assay before samples were submitted for central screening. The majority of patients entering the treatment phase of the trial had tumors strongly (3+) overexpressing HER2 (Table 2)
. Four patients treated had tumors that stained 2+ or 3+ using DAKO reagents but stained 0 or 1+ by the central 4D5 assay; one patient never had tumor sent for central assay. Thirty of the patients treated on the study also had their tumors assayed by FISH (for 3 patients, FISH was technically unsuccessful, and for 11 patients, there were no additional slides available). Results are shown in Table 3
. All specimens that stained 3+ using the central 4D5 assay showed gene amplification. One tumor that was scored 0 on the centrally performed 4D5 assay but 3+ on a local assay using DAKO reagents did show gene amplification by FISH. Other characteristics of patients treated on the study are shown in Table 4
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. There was no evidence of increasing toxicity related to increasing trastuzumab dose. However, at the starting IL-2 doses (a low dose of 1.25 million IU/m2 and an intermediate dose of IL-2 of 15 million IU/m2), 12 of 18 patients (67%) were either removed from study therapy for IL-2-related toxicities or required dose reductions of the low- and/or intermediate-dose IL-2. Gastrointestinal, constitutional, and hematological toxicities predominated. IL-2 doses were therefore reduced to a low dose of 1.0 million IU/m2 and an intermediate dose of 12 million IU/m2. Eight of the subsequent 27 patients (30%) required dose reductions or were removed from study therapy because of IL-2-related toxicities. Constitutional toxicity such as fatigue and malaise became markedly less common; 6 of the final 26 patients noted grade 2 or higher fatigue or malaise. Tables 6
, 7
, and 8
show selected grade 2 and higher toxicities in the cohorts of patients receiving the initial and reduced doses of IL-2. Institutions were instructed to code toxicity as related to either intermediate-dose IL-2 or low-dose IL-2 (not both) or to trastuzumab alone or trastuzumab in combination with IL-2. In practice, it was difficult to separate out the attribution of many IL-2-related toxicities.
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Intermediate-dose IL-2 frequently resulted in nausea, vomiting, and fevers (see Table 7
). Injection site reactions with intermediate-dose IL-2 also occurred frequently and were managed with local measures and by dividing the dose into two separate injections. There were five pulmonary toxicities of grade 3 or higher noted on this study, and three of these were attributed primarily to intermediate-dose IL2. One patient at the 2 mg/kg trastuzumab dose level with breast cancer metastatic to the lungs tolerated her first dose of trastuzumab but became progressively more hypoxic starting hours after her first intermediate dose of IL-2 and was admitted to the hospital. She gradually improved and was rechallenged in cycle 2 with a 25% reduction in the dose of intermediate-dose IL-2. She again became hypoxic and was removed from study therapy. The second patient was on the 8 mg/kg trastuzumab dose level and had lung cancer. She also tolerated her first dose of antibody, but after the first injection of intermediate-dose IL-2, she gradually became severely dyspneic and was admitted to the hospital the following day. She recovered over several days, but she was not rechallenged. A third woman with breast cancer and extensive lung metastases developed dyspnea and an acute respiratory distress syndrome-like syndrome after her second trastuzumab dose in association with an infection related to her indwelling catheter. The other two pulmonary reactions were temporally related to the initial trastuzumab infusion and are described below. Of the seven grade 2 or higher pulmonary toxicities that were felt to be treatment related, six occurred among the 21 patients known to have lung involvement by tumor (P = 0.042, Fisher’s exact test).
Trastuzumab or the combination of trastuzumab with IL-2 was felt to be primarily responsible for one episode of severe pulmonary toxicity. A patient with breast cancer and mediastinal node involvement developed severe neck pain progressing down to her chest about 4 h after her first 4 mg/kg trastuzumab infusion. The following day, a chest X-ray showed development of subsegmental atelectasis, and a computed tomography scan showed an increase in the size of her adenopathy, which was compressing her airway. She was treated with antibiotics and steroids and fully recovered. She was removed from protocol therapy and treated uneventfully with single-agent trastuzumab. There were also several trastuzumab first-dose infusion-related reactions with pulmonary components. These could be dramatic, but they were not treated with dose reductions. For example, one woman with breast cancer metastatic to liver, bronchus, and pleura developed flushing, tachycardia, and a decrease in oxygen saturation 7 min into her first trastuzumab infusion. She recovered, was rechallenged the next day, and continued on protocol for 18 cycles.
There was no cardiac toxicity reported on this study, and no patient died of toxicity.
Responses.
Four major responses were noted, two CRs (lasting 4 months and 33 months) and two PRs. All responses were in breast cancer patients treated at trastuzumab doses of 4 mg/kg every other week (Table 9)
. Of the 18 breast cancer patients treated at doses of 4 mg/kg, 4D5 immunostaining results were as follows: fourteen 3+; two 2+; one 1+; and one 0. One patient with evaluable inflammatory skin disease had tumor regression short of a CR and was coded as SD. Six breast cancer patients treated at dose levels of 4 mg/kg had SD, and four were NE because they were removed from study early for toxicity. Four had PD. One of those with PD had prior trastuzumab therapy, and one stained 0 on the central 4D5 immunoassay. Of the three breast cancer patients entered who had prior trastuzumab therapy, one had PD, and two were NE for response. Overall, at a dose of 4 mg/kg, breast cancer patients had a 22% (4 of 18) response rate.
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The results for the 10 patients analyzed for NK cell surface antigens revealed a consistent and significant (P = 0.02) increase in percentage of CD56+ NK cells over the course of low-dose IL-2 therapy from baseline (mean = 16.9%) to cycle 3 day 1 (mean = 36.0%; Fig. 2A
). The CD56bright/CD16- subset of NK cells, which normally comprises approximately 1% of PBMCs, increased in response to therapy (see Fig. 2B
for one example). This subset comprised 25.7% (standard deviation, 18%) of NK cells posttherapy and decreased in only one patient. In addition, the CD56+/CD16+ population, capable of recognizing antibody-coated targets, increased from baseline (mean = 14.9%) to cycle 3 day 1 (mean = 28.7%; P = 0.008). However, when clinical response of individual patients was evaluated in relation to NK cell expansion, there was no significant difference in the absolute magnitude of NK cell expansion between responders and nonresponders.
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. Specific lysis of targets by effector cells without IL-2 activation was, on average, 15% in this assay, regardless of cycle. However, PBMCs obtained during cycle 3 of therapy (two patients with PBMCs from cycle 4 included) mediated an average of 45% and 54% (days 1 and 4 of the cycle, respectively) specific lysis of trastuzumab-coated targets when stimulated in vitro with IL-2, as compared with 42% specific lysis for cells obtained pretherapy. When ADCC results of individual patients were analyzed with respect to objective clinical response, it was determined that changes in ADCC during the course of therapy by patient PBMCs did not correlate with clinical response. Fig. 3B
shows the individual patterns of ADCC activity of patient PBMCs in response to IL-2 therapy by clinical outcome.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The toxicities on this regimen were manageable after dose reduction of the IL-2 component. It is not certain why we observed more toxicity with the initial doses of IL-2 than reported in the Phase I trial (12) . In particular, Meropol et al. (12) reported no hematological toxicity, whereas there were five instances of grade 3–4 platelet or neutrophil toxicity among our 18 patients treated at the same doses. However, it is likely that our patients were more heavily pretreated with agents that damage the bone marrow. Fourteen of the 19 patients in the initial report had colorectal cancer, which, at the time, was treated primarily with 5-fluorouracil-based therapy. Twenty-nine of our patients had three or more prior chemotherapy regimens, and 14 had high-dose chemotherapy with autologous marrow or stem cell rescue. The pulmonary toxicities were concerning, and patients with extensive pulmonary disease should only receive this regimen with extreme caution. We also noted a number of first infusion-related reactions. It is not possible to determine whether these are more common or more severe than those seen with single-agent trastuzumab; conceivably, the low-dose IL-2 may have primed the immune system and worsened the initial infusion-related reactions. One possible adjustment to the schedule would be to give a dose of trastuzumab before any IL-2, and this adjustment has been incorporated in an ongoing trial of this regimen in patients who have previously received trastuzumab.4 Another possibility for abrogating the toxicity of the regimen would be to give the low-dose IL-2 without the intermediate-dose pulses. Although the intermediate-dose pulses are theoretically important to augment effector cell cytotoxicity, the peak IL-2 levels observed by Meropol et al. (12) were only in the 150–200 pM range. Our lower-dose regimen may not have achieved even these levels. Nanomolar concentrations of IL-2 are required to saturate intermediate-affinity receptors, although lower concentrations might engage a significant number (7) . The contribution of the intermediate-dose pulses is therefore uncertain.
An increase in the percentage of NK cells was demonstrated in this study, but it was far less dramatic than the mean 800% increase observed by Meropol et al. (12)
. This may partially reflect a more heavily pretreated group of patients. We have reported previously that low-dose IL-2 can expand a class of CD56+ effector cells that retain the ability to lyse antibody-coated target cells (18)
. In this trial, there was no significant increase in ADCC activity in the assay used, possibly because the expansion of the NK cell compartment was smaller than that observed in previous trials (although there is a nonsignificant trend toward more lysis after the intermediate-dose IL-2 administration). Moreover, there is no correlation between clinical response and the lytic capacity of patient PBMCs as measured in our assay. This may be a limitation of the assay. It might also imply that other effector mechanisms, such as cytokine secretion, may be involved in the elimination of tumor cells. Indeed, we have demonstrated previously that immobilized IgG and IL-2 synergistically stimulate the production of IFN- by NK cells in vitro (18)
. Thus, cytokine secretion by IL-2-expanded NK cells should be examined in future clinical trials of trastuzumab with IL-2. Another cause for the lack of correlation between clinical response and ADCC is that this trial was not designed to evaluate response. Very few breast cancer patients treated at higher doses had frank progression, yielding low power for any correlation within breast cancer patients alone. Moreover, if only the higher doses of trastuzumab produce sufficient antigen saturation for adequate enhancement of immunological activity, then patients treated at the lower trastuzumab doses might not be expected to respond regardless of any increase in ADCC.
All major responses were observed in breast cancer patients at the higher doses of trastuzumab. The level of activity in breast cancer patients at doses of 4 mg/kg (22%) might be compared with the response rate to single-agent trastuzumab. In a large Phase II study of single-agent trastuzumab in breast cancer patients with one or two prior chemotherapy regimens for metastatic disease, the response rate among those patients staining 3+ by either 4D5 or CB11 was 18% (2)
. None of the patients in that trial had prior trastuzumab, all had measurable disease, and toxicity did not require early withdrawal of therapy. In conclusion, it is impossible to meaningfully compare response rates from this trial with those in the literature. However, activity is at least maintained. We believe further development of this approach is warranted, particularly if some of the IL-2-related toxicities can be mitigated by schedule or dosage adjustments.
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ACKNOWLEDGMENTS |
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participated in this study. |
FOOTNOTES |
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1 Research for Cancer and Leukemia Group B 9661 was supported in part by grants from the National Cancer Institute (CA31946 and CA 44691) to the Cancer and Leukemia Group B (Richard L. Schilsky, M. D., Chairman). 
2 To whom requests for reprints should be addressed, at University of Chicago Medical Center, Section of Hematology/Oncology, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637. Phone: (773) 702-6712; Fax: (773) 702-0963; E-mail: gfleming{at}medicine.bsd.uchicago.edu
3 The abbreviations used are: mAb, monoclonal antibody; PBMC, peripheral blood mononuclear cell; IL, interleukin; ADCC, antibody-dependent cellular cytotoxicity; NK, natural killer; FISH, fluorescence in situ hybridization; ULN, upper limits of institutional normal values; LVEF, left ventricular ejection fraction; NCI, National Cancer Institute; CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; NE, not evaluable; USP, United States Pharmacopoeia; DSW, dextrose 5% water.
4 C. Shapiro, personal communication.
Received 3/25/02; revised 7/29/02; accepted 8/ 8/02.
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