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Clinical Trials |
Departments of Medicine [J. A. P., M. B. K., A. N., J. T., D. E. C., A. F. L., M. N. S.] and Pathology [W. E. G.], Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300; Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19046 [M. A. B.]; and Seattle Genetics, Inc., Bothell, Washington 98021 [J. M. L., A. P. S., C. B. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: A total of 46 patients with LeY-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m2, administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined.
Results: The maximum tolerated dose of SGN-10 was 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m2 dose revealed a t[1/2] of 2.5 ± 0.3 h and a Cmax of 389 ± 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of 
0.384 mg/m2. No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease.
Conclusions: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m2 with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunotoxins are targeted cytotoxic agents that incorporate an antibody-binding domain and a toxin joined by a chemical cross-linker, peptide, or disulfide bond (3, 4, 5, 6) . The potential therapeutic advantage of such agents is related to the specific targeting afforded by mAbs and the relative potency of the toxin moiety. Initially, immunotoxins were prepared by chemical conjugation of a purified antibody (native IgG or Fab fragment) to a separately prepared protein toxin. The resulting compounds were somewhat bulky and characterized by heterogeneity after chemical conjugation. Through advances in genetic engineering, it has been possible to create SCITs derived from fusion of an antibody variable region together with the active domain of a protein toxin.
SGN-10 (BR96 sFv-PE40) is a SCIT fusion protein composed of the VH and VL chains of the BR96 mAb fused to a binding defective form of PE referred to as PE40. There is a 15-amino-acid flexible linker between the VH and VL genes and a 7-amino-acid linker before the PE genes. The BR96 mAb specifically binds to a LeY-related carbohydrate antigen (7 , 8) . LeY is overexpressed as a surface membrane component of many carcinomas but is also expressed on GI epithelium and within the pancreas (9) . SGN-10 kills target cells by binding to LeY, followed by endosomal internalization and the inhibition of cytosolic protein synthesis (7) . After internalization, PE40 undergoes translocation from the endosomes to the cytosol and then inhibits protein synthesis by altering ADP-ribosylation of ribosomal elongation factor 2. In carcinoma cell lines, SGN-10-directed cytotoxicity is most often proportional to cell surface LeY expression.
Historically, the principal nontargeted toxicity of immunotoxins has been the VLS, consisting of edema, hypoalbuminemia, and weight gain (10 , 11) . Although the etiology of toxin-related VLS is poorly understood, there is experimental evidence that toxin activation of the arachidonic acid metabolism pathway may induce vascular leakage (12 , 13) . Preclinical studies in rat models demonstrated a dose-dependent VLS toxicity with SGN-10 (12) that was prevented by inhibition of arachidonic acid-mediated inflammation (13) . Additionally, structural motifs have been identified in toxins that directly target endothelial cells causing loss of vascular integrity (14 , 15) .
Preclinical murine studies using human breast and lung xenografts demonstrated that SGN-10 had significant antitumor activity, including complete regression of tumors (16 , 17) . Toxicology analysis of SGN-10 in murine models and in nonhuman primates demonstrated a potential therapeutic window between efficacious and toxic doses (18) . On the basis of favorable preclinical data, SGN-10 was developed for clinical testing in patients with LeY-positive advanced-stage carcinomas. This report describes the results of the first 46 patients treated with SGN-10 through seven dose levels. In this study, dose-limiting events were due to GI toxicity rather than to VLS.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients were required to meet the following eligibility criteria: (a) histologically confirmed, LeY-positive (see Footnote 4
) nonhematological tumors resistant to standard chemotherapy, or for which no effective therapy existed; (b) measurable or evaluable disease; (c) age >18 years; (d) an estimated median survival of at least 3 months; (f) Eastern Cooperative Oncology Group (ECOG) performance status of 
2; and (g) adequate hematopoietic function (hemoglobin >9.0 g/dl; total leukocyte count >3,000/µl; platelet count >100,000/µl), hepatic function [bilirubin <2.0 g/dl; transaminases or alkaline phosphatase levels (4 x upper limit of normal)], and renal function (serum creatinine <2.0 g/dl).
Major exclusion criteria included: (a) clinically significant extravascular fluid collections; (b) central nervous system metastasis; (c) pregnant or breast-feeding women; (d) major surgery, cytotoxic chemotherapy, or radiotherapy within the previous 4 weeks; (e) clinically significant cardiac disease; and (f) evidence of hepatitis or HIV infections.
Signed informed consent was obtained from each patient before enrollment into the trial. The protocol, informed consent, and informed consent procedures were reviewed and approved by Institutional Review Boards at the participating institutions.
Significant amendments to the original protocol included: (a) instituting medical management of GI toxicities and supplementation of the CTC scale to grade clinically significant GI toxic events; (b) addition of dexamethasone (12 mg p.o. the night before each dose of SGN-10) as VLS prophylaxis; and (c) addition of rofecoxib (12.5 mg every day for 14 days starting 4 days before the first dose of SGN-10) as additional VLS prophylaxis.
Criteria for Response and PD.
Patients were evaluable for response if they had received at least two courses of therapy (8 doses). Disappearance of all clinical evidence of tumor (including any measured serum tumor markers) determined by two observations not less than 4 weeks apart constituted a complete response. A 50% or greater decrease in the sum of the products of measured lesions determined by two observations not less than 4 weeks apart defined a partial response and a >25% and <50% decrease in the sum of the products defined a marginal response provided that there was no simultaneous increase in the size of any lesion, no appearance of new lesions and stability or regression of nonmeasurable lesions. A less than 25% decrease or no significant change for at least 4 weeks defined stable disease. This included a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Unequivocal increase of at least 25% from best response in the product of measured lesions or the appearance of new lesions constitutes PD.
LeY Antigen Detection.
Patient eligibility required immunohistochemical demonstration of LeY expression on each patient’s tumor sample (19, 20, 21)
. Briefly, paraffin blocks or precut 5-µm paraffin sections were obtained from the institution at which the patient originally received the diagnosis. Sections were cut and attached to SuperFrost/Plus slides (Fisher Scientific, Norcross, GA) by heating at 58°C for 1 h. Tissue sections were deparaffinized in xylene (three changes, 5 min each) and subsequently rehydrated in sequential ethanols for 5 min with one change each of absolute ethanol, 95% ethanol, and 70% ethanol. The sections were then transferred to a Tris buffer bath [0.05 M Tris base, 0.15 NaCl, and 0.0002% Triton X-100 (pH 7.6)]. Each section was treated with an aqueous solution of 3% H2O2 for 5 min to quench endogenous peroxidase activity. Slides were then incubated with 1% goat serum at room temperature for 20 min to reduce nonspecific immunostaining. After washing in Tris buffer, each section was incubated with the parental mAb BR96 (murine IgG3) at a concentration of 30 µg/ml for 1 h at room temperature. The negative control was normal goat serum (1%). A TAG-72-positive and -negative tumor section was included as a control as well.
The primary antibodies were detected using a multispecies detection system from Biogenex Laboratories, Inc. (San Ramon, CA). After incubation and washing, the sections were exposed to a biotinylated antimouse or antirabbit antibody for 20 min. After washing in the Tris buffer, peroxidase-labeled streptavidin was added for 20 min. A diaminobenzidine tetrachloride (DAB) supersensitive substrate kit (Biogenex, San Ramon, CA) was used to visualize the antibody-antigen complex. Each section was counterstained using hematoxylin and dehydrated using graded alcohols and three baths of xylene before attaching coverslips with Permount.
The immunostained slides were examined and classified with respect to the intensity of staining (0–4+) and the percentage of cells stained at any intensity. If the staining intensity was not greater than the negative controls, then a score of zero was assigned for a specimen.
Treatment Plan.
SGN-10 was administered as an i.v. push (2–5 min) on days 1, 4, 8, and 11, followed by a 14-day rest period. A multiple-dose schedule was selected based on optimization from preclinical models. A treatment course was 28 days long. Patients were to receive two courses of therapy and could continue for additional courses (up to a maximum of six) provided there was no evidence of disease progression or unacceptable toxicity.
Patients were initially treated in cohorts of three patients at escalating doses of SGN-10 from a starting dose of 0.024 mg/m2. If one of the first three patients demonstrated a DLT, three more patients were entered onto the cohort. If two of the six patients experienced a DLT, that dose was defined as the MTD. If more than two patients in the expanded cohort experienced a DLT, then MTD was exceeded. All of the patients who received SGN-10 were evaluated for toxicity according to the modified CTC scale. Retreatment was dependent on resolution of toxicities back to baseline within the next scheduled date of administration.
SGN-10 Manufacturing.
SGN-10 for injection was provided by Seattle Genetics, Inc. and was manufactured using a process derived from the one what was reported previously (7)
. SGN-10 was formulated as a solution containing 1 mg/ml protein and 0.05% weight per volume of polysorbate 80 (Tween 80) in 0.025 M sodium phosphate buffer and 0.05 M sodium chloride (at pH 7.5). Vials containing 2 ml were stored at -70°C and thawed and diluted just before administration.
Immune Response Analysis.
To measure the immunogenicity of SGN-10 and the specificity of the immune response, two different assays were used. A conventional ELISA assay was used to detect antibody to SGN-10 (HATA). Briefly, microtiter plates were coated with SGN-10 and incubated overnight at 4°C. Plates were washed and blocked with 1% BSA in phosphate buffer saline for 1–2 h at 37°C. Plates were rewashed and incubated with serial dilutions of patient sera for 2–4 h at 37°C. After washing, a secondary antibody cocktail composed of goat antihuman IgG/IgM/IgA was added and incubated for 1–2 h at 37°C. The substrate P-nitro phenyl phosphate in DEA buffer (Sigma Inc., St. Louis, MO) was added after additional washes and was incubated at 25°C for 25 min. Stop reagent (3 N NaOH) was added, and the plates were read at 405 nm. Results were reported as the highest dilution that gave an absorbance value greater than three SDs above background.
A radiometric, double-antigen assay (22) was used to compare the immune response against the BR96 mAb portion (v regions) versus intact SGN-10. Briefly, 6.4 mm polystyrene beads were coated with 2 µg/bead mBR96 mAb or SGN-10 in phosphate buffer solution by gentle agitation at 80 revolutions/min (rpm) overnight at room temperature. The beads were washed three times with phosphate buffer containing EDTA (PBS), blocked with PBS for 1 h at room temperature, and stored in PBS at 4°C. Patient sera or positive controls in PBS were added to a glass culture tube. After the addition of a single antibody-coated bead to the tubes, they were gently agitated at 140 rpm for 1 h at room temperature. Beads were washed by first adding and then gently aspirating with 4 ml of phosphate buffer solution. Radiolabeled 125I-labeled mBR96 mAb or 125I-labeled SGN-10 was added to respective tubes and gently agitated at 140 rpm for 1 h at room temperature. Beads were washed again as above. The beads were transferred to clean tubes, followed by 1 min of counting to determine the 125I-antibody-bound radiation. The assay result was calculated from the 125I-antibody bound radiation and the known specific activity of the antibody, with the result expressed as ng of mBR96 mAb or SGN-10 bound per ml of patient serum.
Statistical Methods.
Descriptive statistics were used in the analysis of all of the safety and laboratory observations. Any patient who received a single dose of SGN-10 was evaluable for toxicity. Patients were evaluated for response after two full courses of SGN-10. The overall incidence of AEs was tabulated as well as the proportion of patients exhibiting each AE and the number of patients experiencing severe AEs.
Pharmacokinetics.
Pharmacokinetic analyses were performed on eight patients treated with an SGN-10 dose of 0.641 mg/m2. Five ml of blood was obtained at the following time points: preinfusion and at 5, 15, 30, 60, 90, 120, 180, and 240 min after the completion of infusion on days 1 and 11. On days 4 and 8, samples were obtained at preinfusion and at 30 and 120 min posttreatment. Plasma was obtained by centrifugation.
Circulating SGN-10 levels were determined by a modified ELISA method (23)
. Briefly, microtiter plates were coated with anti-PE40 mAb EXA2–1H8 in DPBS and stored at 4°C for 16–48 h. Plates were manually flicked and blocked with 
pblocking buffer (1% BSA in PBS/0.1% NaN3)/3.0% BSA for 1–2 h. The plates were washed and incubated with serial dilutions of patient sera for 2 h. After washing, biotinylated anti-BR96 idiotypic mAb was added to the plates and incubated for 1 h at 37°C. The plates were washed again, diluted streptavidin/horseradish peroxidase conjugate was added, and incubated for 30 min. 3,3',5,5' tetramethylbenzidine chromogen/substrate buffer was added after additional washes and. after 10 min, was stopped with 1 m H3PO4. The plates were shaken for 30 s and absorbance was measured at 450 and 655 nm.
Pharmacokinetic parameters were analyzed by nonlinear least-squares regression to exponential equations. The regression was done using the nonlinear procedure of the Statistical Analysis System programs (24) . The estimates of the following parameters were calculated: maximum concentration (Cmax), half-life (t1/2), mean residence time (MRT), volume of clearance (Vc), area under the curve (AUC) and clearance (CL). The pharmacokinetic parameter estimates were calculated by subject for each course/study day combination. In addition, summary data including statistics of mean, SE, and SD were calculated for each pharmacokinetic variable for patients overall in each course/study day combination.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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summarizes patient accrual and dose-level assignments of the 10 patient cohorts. The principal toxicities and DLTs were GI-related and including diarrhea, nausea, and vomiting. The GI toxicities usually occurred within 12 h after an administered dose and lasted for 
24–36 h. Table 3
lists serious DLTs and other common toxicities that were observed.
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Fatigue emerged as a significant toxicity observed in patients treated with a SGN-10 dose of 0.384 mg/m2 or greater. Two of 20 patients treated at a dose level of 0.641 mg/m2 and 2 of 5 treated with a dose of 0.962 mg/m2 reported grade 3 level fatigue. The fatigue typically resolved within 7–10 days. Signs associated with VLS were primarily transient 10–30% decreases in serum albumin levels with little or no weight gain or edema. These findings occurred at dose levels of 0.384 mg/m2 and greater. There was no demonstrable dose effect. Because of the small number of patients, it was uncertain whether prophylaxis with dexamethasone and/or rofecoxib altered the degree of hypoalbuminemia. AEs were infrequent and mild during the second cycle of therapy, which reflected the intense HATA immune response and impaired the circulation of SGN-10.
Antibody Response to SGN-10.
The majority of patients (35 of 47) exhibited no evidence of prior PE exposure as demonstrated by relatively low anti-SGN-10 antibody titers (<1:1,000) with only two patients having pretherapy SGN-10 titers of 1:10,000. As expected, development of an immune response after treatment was rapid, such that, by day 15, 57% of patients had titers exceeding 1:10,000 and 31% of the patients had titers exceeding 1:100,000 (Table 4)
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rather than to the antibody component.
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. The plasma disappearance curve fit a one-compartment model (Fig. 1)
with a pharmacokinetic profile similar to other SCIT agents. The plasma half-life was 2.5 ± 0.4 h with a Cmax of 389 ± 112 µg/ml. The effect of elevated HATA titers was also examined. The Cmax on days 1, 4, 8, and 11 was expressed as a percentage of the day-1 Cmax. Thepercentage Cmax fell significantly by day 11 (Fig. 2)
, which reflected the HATA-induced poor plasma recovery of infused SGN-10 and/or its high clearance rate. This finding was persistent through the second cycle of therapy (data not shown) in the presence of elevated HATA titer.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The LMB-1 trial (11)
was noteworthy for demonstrating a modest antitumor effect in a solid tumor setting. Five of 38 patients treated were reported to have evidence of tumor regression. The DLT in that study was VLS, and immune responses to the murine antibody and PE were brisk. Using the same B3 antibody and toxin component, a SCIT was developed, LMB-7 [B3 (Fv)-PE38]. Similar to the experience with SGN-10, VLS was observed but was not dose limiting, although the doses reached were not as high as in the LMB-1 trial (26)
. The MTD of LMB-7 was reported to be 24 µg/kg administered on a schedule of every other day for three doses. A similar MTD (19 µg/kg) was found for SGN-10 using a schedule of two administrations/week for 2 weeks. Interestingly, the plasma half-life of LMB-7 was only 1 h, compared with 2.5 h for SGN-10. It is possible that more rapid clearance reflected decreased stability of LMB-7 in human sera (27)
, and clinical evaluation is pending. To overcome this lack of stability, a disulfide-stabilized construct was developed (28)
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Although it has been difficult to successfully treat solid tumors with immunotoxins, there have been exciting results with immunotoxins targeted against hematological malignancies. ONTAK, an interleukin 2-diphtheria toxin fusion protein, was shown to induce objective responses when given to patients suffering from cutaneous T-cell lymphoma (29) . Whereas ONTAK is not an antibody-toxin fusion protein, the agent has considerable similarity to SGN-10 in its single-chain configuration and in its mechanism of action, specifically ADP-ribosylation of elongation factor 2, which halts protein synthesis. Because of its antitumor activity at tolerated doses, ONTAK was approved for commercial use in early 2000 (30) . Potent antitumor efficacy has also been reported using a PE-based immunotoxin targeted to CD22. Treatment with RFB4 Fv-PE38 was found to induce objective antitumor activity in patients with hairy cell leukemia (5) .
There are multiple issues confronting development of immunotoxins as therapeutic agents for solid tumors. The most prominent of these include immunogenicity and VLS, although in our trial, GI toxicity precluded further dose-escalation. Strategies to reduce the human immune response to PE-based immunotoxins are needed to allow repetitive or extended schedules of immunotoxin therapy, which may be necessary in solid-tumor patients.
A rat model of VLS as evidenced by hydrothorax has been used to explore the vascular leak associated with PE (12) . Mutational analysis determined that both PE and PE40 induced alteration in ADP-ribosylation and proteolytic processing were necessary for induction of hydrothorax. Hydrothorax was dependent on direct binding to Ley. Interestingly, agents that inhibit inflammation through the lipoxyogenase/COX pathway, including dexamethasone and COX-2 inhibitors, ameliorated PE-induced hydrothorax in vivo (13) . In our trial, the administration of dexamethasone alone or in combination with the COX-2 inhibitor, rofecoxib, were well tolerated. However, because of the small numbers of patients treated, there was no definitive evidence that these agents altered the development of VLS.
The GI toxicities in this trial were principally nausea and diarrhea in contrast to hemorrhagic gastritis observed with BR96-doxorubicin. In that trial, the use of omeprazole decreased the observed injury (25) but did not ameliorate the nausea. Dexamethasone was used for VLS prophylaxis and as an antiemetic. There was no clear benefit, with its addition, for the degree of nausea or the alteration in serum albumins. The addition of rofecoxib along with dexamethasone similarly had little impact on the degree of toxicity observed in the three patients receiving both agents.
Given the short half-life and the rapid onset of anti-SGN-10 antibody response, an accelerated administration schedule that increases the cumulative number of doses/course is being explored. Additionally, efforts to blunt and/or delay the antibody response to SGN-10, using immunosuppressive agents, are ongoing. For example, agents such as CTLA4-IgG (31) , anti-CD154 (32) , and anti-CD20 mAbs such as rituximab (33) are being considered for incorporation in subsequent early-phase studies with SGN-10. It is hoped that these approaches will maximize the potential for clinical efficacy by increasing the duration and amount of drug exposure before host development of neutralizing antibodies.
In murine models, antitumor activity was observed in doses ranging from 0.15 mg/m2 to 2.25 mg/m2 with a higher percentage of durable responses achieved at doses closer to the upper end of this range. The MTD achieved in this trial (0.641 mg/m2) is within the range associated with preclinical activity. However, current preclinical models with human tumor xenografts are not always predictive of clinical activity. Tumor heterogeneity of antigen expression reduced the rates of internalization after antibody binding and altered the intracellular catabolism with inefficient cytoplasmic translocation; excessive binding to cross-reactive antigen expressed on normal host tissues could also contribute to a reduction in clinical efficacy. Therefore, further investigation will focus on minimizing the host-immune response while attempting to improve dose density and evaluating actual tumor targeting and molecular kinetics.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Seattle Genetics, Inc., Bothell, WA, and the National Cancer Institute Grant K23 RR16184 and conducted through the General Clinical Research Center. 
2 To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Comprehensive Cancer Center, 263 Wallace Tumor Institute, 1530 3rd Avenue South, Birmingham, Alabama 35294-3300. Phone: (205) 934-0916; Fax: (205) 934-1608; E-mail: James.Posey{at}ccc.uab.edu
3 The abbreviations used are: mAb, monoclonal antibody; SCIT, single-chain immunotoxin; VH, variable heavy; VL, variable light; PE, Pseudomonas exotoxin; LeY, LewisY; VLS, vascular leak syndrome; GI, gastrointestinal; MTD, maximum tolerated dose; CTC, Common Toxicity Criteria; DLT, dose-limiting toxicity; HATA, human antitoxin antibody; PD, progressive disease; AE, adverse event; COX, cyclooxygenase.
4 http://ctep.cancer.gov/reporting/ctc.html.
Received 4/ 3/02; revised 6/ 7/02; accepted 6/10/02.
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