Purpose: In previous studies, humanized A33 (huA33) demonstrated modest antitumor activity in chemotherapy-resistant colorectal cancer patients. In addition, unexpected major tumor responses were observed in patients treated with a specific chemotherapy regimen [carmustine, vincristine, fluorouracil, and streptozocin (BOF-Strep)] administered after huA33 protocols. We designed the present Phase I, open label, cohort, dose-escalation study of huA33 and a fixed dose of BOF-Strep to (a) determine the maximum tolerated dose of huA33 immunotherapy administered with chemotherapy, (b) determine whether chemotherapy modifies huA33 immunogenicity, and (c) develop preliminary information regarding antitumor activity.

Experimental Design: Stage IV fluorouracil/leucovorin and irinotecan-refractory colorectal cancer patients (n = 16) received escalating weekly doses of huA33 (5–40 mg/m2) with BOF-Strep chemotherapy.

Results: Four patients requiring radiotherapy or surgery were removed early. Of 12 evaluable patients, grade 3 and 4 neutropenia (n = 2) and grade 3 thrombocytopenia (n = 1) were observed. Seven of 12 (58.3%) patients developed anti-huA33 activity. Three patients had radiographic partial responses for 7.5, 5.5, and 14 months with greater than 85% decline in serum carcinoembryonic antigen levels. One mixed response (4.5 months with a serum carcinoembryonic antigen decline of 38%) was also observed.

Conclusions: huA33 can be safely combined with BOF-Strep chemotherapy. The present report provides compelling evidence supporting our previous observations of major antitumor activity with the combination of huA33 and BOF-Strep chemotherapy. huA33 is still immunogenic when administered with chemotherapy. Future studies to evaluate the immunogenicity of new huA33 antibodies and identify which drugs in the BOF-Strep regimen are critical for enhanced antitumor efficacy are planned.

mAb3 A33 recognizes a cell surface differentiation antigen (Mr 43,000) of the lower gastrointestinal mucosa, whose expression is maintained in 95% of primary and metastatic colon cancers (1, 2, 3). The A33 antigen is unusual among the tumor targets we surveyed because it is expressed homogenously and at high levels in colorectal cancers (1). Preclinical mouse models demonstrated the capability of radiolabeled mAb A33 to rapidly and homogeneously target transplanted human colon cancers and to induce tumor regressions (4, 5, 6, 7, 8). For these reasons, mAb A33 was evaluated in a clinical radioimmunolocalization study with special attention to its normal tissue reactivity (9). Biopsy-based Phase I 131I-mAb A33 studies quantitatively demonstrated high levels of A33 antibody targeting to colorectal cancer tissue, and autoradiograms confirmed specific homogenous targeting to tumor cells (9). Normal bowel uptake was also evident, but antibody bound to colonic mucosa was cleared more rapidly compared with tumor sites (9, 10, 11). Due to this differential concentration and retention in colorectal cancer compared with normal tissues, single-dose Phase I studies with radiolabeled mouse A33 antibody were carried out (10, 11). Minor antitumor effects were noted due to the tumor targeting of radioisotope carried by mouse A33 antibody (10, 11). A review of the outcomes of the radiolabeled A33 study patients revealed that 8 of 22 patients completing the trial were subsequently treated with chemotherapy consisting of BOF-Strep (11). Of these eight patients treated with BOF-Strep, three had objective responses, and two had stable disease, whereas no major responses were identified in the group receiving other systemic chemotherapy (11). Because of our experience with BOF-Strep in patients with advanced disease resistant to multiple chemotherapeutic agents, these responses were considered unexpected. We hypothesized that the tumor irradiation by radiolabeled mAb A33, although not a sufficient radiation dose to induce major objective responses, was nevertheless sufficient to increase the tumor sensitivity to chemotherapy with BOF-Strep. This interaction between radiation effects and chemotherapy was supported by data from mouse models demonstrating synergistic antitumor effects between fluorouracil and 131I-mAb A33 radioimmunotherapy (12). In this model, complete responses were obtained with a fluorouracil-resistant human colon cancer tumor even when the 131I-mAb A33 dose was reduced by 80% (12). These results are also consistent with the established role of localized radiotherapy and chemotherapy in treatment of primary rectal cancer.

Due to the immunogenicity of the mouse mAb A33, an IgG1 humanized version (huA33) was developed and shown to be equivalent in specificity assays, whereas avidity was modestly reduced (13, 14). huA33 was also found to direct antibody-dependent cell-mediated lysis of antigen-positive tumor lines. In a Phase I study of huA33, three cohorts of patients treated at 10 mg/m2 (five patients), 25 mg/m2 (three patients), and 50 mg/m2 (three patients) were evaluated (15). No DLT was reached. huA33 was found to be immunogenic in a subset of patients, and toxicities were, in general, related to development of antibodies to the huA33 antibody (HAHA+) in 8 of 11 (73%) patients (16). huA33 was found to have antitumor activity because one of the three patients not developing HAHA achieved a radiographic partial response (serum CEA declined from 80 to 3 ng/ml) remaining on treatment for 48 months (15, 16). A Phase II study was initiated to develop efficacy data using the lowest dose of huA33 studied in the Phase I trial. However, despite the low dose of huA33 (10 mg/m2/week), the incidence of HAHA+ patients (71%) remained high. Due to the high rate of HAHA activity and the early removal of patients from this study, assessment of the activity of this agent was not possible. Post-huA33 treatment outcomes were examined in patients from these two studies. Of 14 patients who had received BOF-Strep chemotherapy after a huA33 protocol, 4 showed major durable radiographic responses. This finding suggested that the huA33-directed immune attack of tumor cells and their subsequent exposure to chemotherapy resulted in enhanced cell lysis. Which drug in the BOF-Strep combination was responsible for the augmented antitumor activity is not known.

These observation cases provide compelling preliminary evidence that huA33 can be used in combination with chemotherapy either as a radiolabeled construct to radiosensitize tumors or as an IgG1 construct to mediate chemotherapy-augmented immune lysis of tumor cells. The first reports that combinations of chemotherapy and antibody-directed immune effector functions enhance tumor cell lysis date back to 1975 (17, 18). It has been demonstrated that chemotherapeutic agents can specifically inhibit molecular cellular processes critical to tumor cell defense mechanisms against immune-mediated killing (18, 19). Inhibition of tumor cell antioxidant defenses has been noted in one case to be a key aspect of enhanced antibody-dependent immune-mediated killing, especially with carmustine (19, 20). Other antibody and chemotherapy combinations have shown significant enhancement of efficacy and have become standard therapies, although other molecular mechanisms may also be involved (21, 22, 23).

The current study was designed to evaluate toxicities associated with combining huA33 immunotherapy and BOF-Strep chemotherapy and to determine whether this chemotherapy significantly reduces the immunogenicity of huA33. Although not a primary end point of this study, tumor response data were also captured because all patients were required to have radiographic measurable disease.

Production and Purification of huA33 Antibody.

huA33 antibody is a fully humanized IgG1 mAb derived from murine A33 antibody by complementarity determining region grafting (13). The antibody was expressed in NSO cells, and culture supernatant was produced in bioreactors by Celltech Limited (Berkshire, United Kingdom) and concentrated (13). huA33 was purified from NSO cell supernatant at the New York Branch of the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center. Details of the purification process have been reported previously (16).

Patient Selection and Eligibility.

Histology slides from all patients in this study were reviewed in the Department of Pathology of Memorial Sloan-Kettering Cancer Center, and diagnosis was confirmed to be colorectal carcinoma in all cases. Eligibility criteria included: age of at least 18 years; histological confirmation of a diagnosis of colorectal cancer; and immunohistochemical score of A33 antigen expression of >50% of the cells in the lesion (includes 95% of colorectal cancer cases) and metastatic stage IV nonresectable lesions measurable by X-rays, CT scans, or magnetic resonance imaging. Patients were required to have disease resistant to conventional chemotherapy (including prior treatment with a fluorouracil-based therapy) and to have completed chemotherapy, radiotherapy, or immunotherapy at least 4 weeks before starting the protocol. Patients were required to have a Karnofsky performance status of at least 80 and to have a projected survival of at least 14 weeks. Serum bilirubin had to be less than 1.1 mg/dl, and less than 50% of the liver could be replaced by tumor, as estimated from CT scans or magnetic resonance imagings. Other criteria include WBC > 3,500/mm3 , platelet count > 100,000/mm3 , prothrombin time < 1.3× control, serum creatinine < 1.4 mg/dl, and a negative pregnancy test. The patient had to be sufficiently reliable to use contraception and to sign informed consent according to institutional and federal guidelines for participation in this study. Exclusion criteria included: no prior exposure to antibody therapy or BOF-Strep therapy; no clinically significant cardiac disease (New York Heart Association Class III/IV); no infection; no evidence of CNS tumor involvement and no illnesses requiring the use of steroids or other anti-inflammatory reagents was allowed.

Study Design.

The study was a Phase I, open label, cohort, dose-escalation study of huA33 antibody administered with a fixed dose regimen of BOF-Strep chemotherapy. Blood samples were collected every week to monitor HAHA activity. Thus, the observed toxicities could be correlated to the presence or absence of HAHA throughout the treatment course. All patients were treated in the outpatient facility, and all infusion-related toxicities had to be resolved before discharge. Patients who could not be treated as outpatients were removed from the study.

Measurement of Anti-huA33 Antibody Response.

Antibody responses to huA33 induced after treatment were analyzed by surface plasmon resonance technology using a BIACORE 2000 instrument (BIACORE, Inc., Piscataway, NJ) as described previously (16). HAHA was scored as transient, low positive titers (type I response); high positive with increasing titers (type II response); or negative (16).

Treatment Schedule.

Patients were started on week 1 with huA33 and received weekly doses for 14 weeks (Fig. 1). The antibody was diluted in 100–150 ml of physiological saline containing 5% human serum albumin and infused through a line containing normal saline at a rate of approximately 1 mg/min. Antibody was administered weekly (weeks 1–14) with cohorts of patients entered at the following dose levels: 5; 10; 25; and 40 mg/m2/week. Starting on week 5, patients received chemotherapy as follows: carmustine (30 mg/m2) daily for 5 days during week 5; fluorouracil (300 mg/m2) daily for 5 days during weeks 5 and 10; vincristine (1 mg total dose) on weeks 5 and 10, and streptozocin (500 mg/m2) weekly for weeks 5–14.

Toxicity.

Toxicity was graded in accordance with the Common Toxicity Scale developed by the National Cancer Institute in 1998. Standard criteria for DLT were used, and the maximum tolerated dose was defined as the dose level immediately below the dose level inducing DLT in two patients (of three to six patients tested). The protocol schedule was designed to capture toxicities due to treatment with huA33 alone (weeks 1–4) and huA33 combined with chemotherapy (weeks 5–14). Complete toxicity data for weeks 1–8 were required to be evaluable for toxicity related to antibody and antibody combined with chemotherapy. Hematological toxicity due to the chemotherapy was expected during weeks 7 and 8. Patients would need to be examined and evaluated through week 8 to be fully evaluable.

Response.

Tumors were evaluated for response by radiographs at week 14 and every 10 weeks thereafter. Responses not maintained to week 14 were not assessed as response. Response parameters were as follows: (a) complete response, disappearance of all measurable disease at week 14 or thereafter, lasting for at least 4 weeks; (b) partial response, >50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions at week 14 or thereafter, lasting for at least 4 weeks; (c) mixed response, >50% decrease in the sum of the perpendicular products of some measurable lesions and without development of new lesions or increase in size of any measurable lesion at week 14; (d) stable disease, <50% decrease and <25% increase in the size of any measurable lesion and without the development of new lesions at week 14; (e) progression, >25% increase in any measurable lesion at week 14. Determination of responses and progression was based on measurements provided by the Department of Radiology, Memorial Sloan-Kettering Cancer Center (New York, NY).

Patient Characteristics.

Patient characteristics are shown in Table 1. All patients had advanced colorectal cancer with lung lesions, and nine patients also had liver metastases. Peritoneal, bowel, or abdominal wall disease was present in six cases. Patients were treated at one of four escalating dose levels of huA33 administered in combination with a fixed dose of BOF-Strep chemotherapy, with three fully evaluable patients at each dose level. The protocol schedule was designed to capture toxicities due to treatment with huA33 alone (weeks 1–4) and huA33 combined with chemotherapy (weeks 5–14). Of the 16 patients registered for this study, 4 patients (patients 4, 8, 12, and 16) were removed from the study early for either radiotherapy (central nervous system disease) or surgery (bowel obstruction) and thus were not evaluable for toxicity (Table 1). Three of these four patients never received the chemotherapy doses. Patient 12 was subsequently restarted on the protocol under a single use exemption after completing a course of radiotherapy. Patients developing HAHA (n = 7) and those who had antibody treatments terminated early due to HAHA (n = 2) were evaluable because HAHA is considered to be a treatment-related toxicity. One of these patients also chose to discontinue her chemotherapy (patient 7) and was considered evaluable because she received the full week 5 of chemotherapy, and her hematological parameters were obtained each week, to week 8.

Prior Therapies and Chemoresistance.

Table 1 outlines the prior treatments for each patient. All patients had tumors resistant to a fluorouracil-based therapy, and four patients (patients 2, 4, 5, and 14) received fluorouracil in more than one therapy. Seven patients (patients 1, 5, 6, 7, 9, 13, and 16) had received floxuridine as intrahepatic treatment, and three patients (patients 5, 6, and 16) had residual measurable hepatic metastases. All patients had tumors resistant to irinotecan, and six patients (patients 7, 9, 11, 13, 14, and 15) had tumors resistant to fluorouracil, irinotecan, and oxaliplatin.

Toxicity.

Whereas bowel toxicity was expected in some cases to be a significant effect of the BOF-Strep chemotherapy alone, a focus of this trial was to determine whether huA33 increased the bowel toxicity of chemotherapy (because huA33 binds to colon mucosa) and to define a huA33 maximum tolerated dose if bowel toxicity was dose-limiting. The realization of this study objective was hampered in part by the development of HAHA (Table 2), which may mask treatment-related toxicities by blocking antibody binding to antigen-positive normal tissue, such as colonic mucosa. Thus, one limitation of the data collected was that bowel toxicity might be underestimated due to HAHA induction in 7 of these 12 evaluable patients. However, the five patients who developed a type I HAHA reaction all had resolution of their HAHA activity by week 8. Because type I HAHA activity is generally not associated with systemic toxicity and frequently resolves, these patients were continued on huA33 treatments (16). No significant bowel toxicity was noted in these five patients in the time period after their HAHA activity resolved and while they were receiving chemotherapy and huA33 treatments.

Patients had weekly tests of stool for occult blood as an indicator of bowel toxicity. No cases of bowel bleeding attributable to the antibody and/or chemotherapy were found. Diarrhea (grade 1 and 2) was observed in relation to the 2 weeks of fluorouracil treatments (weeks 5 and 10; Table 2). No grade 3 or 4 episodes of diarrhea were noted. No patients required parenteral support for dehydration. Some patients were on antidiarrhea medication at the start of the protocol due to persistent intermittent bouts of diarrhea as a chronic toxicity from prior treatments. Nausea and vomiting were well controlled with antiemetic therapy, with the majority of episodes occurring on days 6 and 7 of weeks 5 and 10.

Another goal was to define bone marrow toxicities, primarily related to the chemotherapy. Because the patient population was now more heavily pretreated than previous BOF-Strep study patients, redefining these toxicities was essential for future studies. Three cases of grade 3 or 4 hematological toxicities were observed, one grade 3 thrombocytopenia at the second dose level, one grade 3 neutropenia at the third dose level, and one case of grade 4 neutropenia at the fourth dose level (Table 2).

HAHA+ activity was detected in 7 of 12 patients (58.3%; Table 2). Two patients (patients 7 and 13) with high and increasing levels of HAHA+ activity (type II response) had antibody treatments discontinued (16). One of these patients (patient 7) chose to discontinue her chemotherapy also. This patient developed fever, chills, rash, and pruritus with her infusions. Five patients (patients 1, 3, 5, 14, and 15) had transient low levels of HAHA+ activity (type I response; Ref. 16). We did not discontinue treatment in these cases because we had noted that HAHA+ type I responses frequently revert to HAHA− (tolerance) in a subset of these cases, and generally there is no significant toxicity associated with this type I HAHA response (16). These five patients all became tolerant to huA33 by week 8. Patient 5 is an example of a case of low-level HAHA+ reverting to HAHA− (Fig. 2.). Of note in this case is that although the patient’s CEA levels rose during the time interval while he was HAHA+, it fell rapidly once the HAHA had reverted to negative (Fig. 2). This patient went on to achieve a partial response.

Efficacy.

Although efficacy was not a primary end point of this study, eligibility criteria required that patients have radiographic measurable disease to capture these data. Eleven of the 12 evaluable patients had follow-up radiological evaluation for response at the end of the treatment cycle, and the 1 patient treated as a single use exemption was also evaluated. Patients were not evaluated for response by radiographs before week 14, even if decreased serum CEAs were noted. Thus, only radiological responses durable to week 14 were documented and assessed. Three of the 12 patients (patients 5, 9, and 13) achieved partial responses (25%), 1 patient (# 11) had a mixed response (9%), and 1 patient (# 2) had stabilization of disease (9%; Table 3). Serial serum CEA levels for the three patients with major objective responses are shown in Fig. 2. Of note is that serum CEA levels were declining in response to huA33 treatments in two of the three patients (patients 9 and 13) during the first 4 weeks of treatment, before starting the chemotherapy part of the protocol. With regard to patient 5 (Fig. 2), the relation of HAHA activity to the serial changes in serum CEA levels shows that for the first 5 weeks of treatment, patient 5 had a HAHA+ response that would have blocked huA33 antitumor effects. This patient’s serum CEA levels declined only after his HAHA activity disappeared and he became tolerant to huA33. In general, initial declines in CEA were observed only in the absence of HAHA+ activity (patients 2, 9, 11, and 13) or after this activity resolved (patient 5). Fig. 3 shows serial CT scans of patient 13. This patient had tumors resistant to fluorouracil, irinotecan, and oxaliplatin and had a partial response to huA33 + BOF-Strep for 14 months, with normalization of serum CEA levels from 280.0 to 0.9 ng/ml. This patient also developed HAHA at week 8 and had her huA33 treatments discontinued. Patient 5 achieved a partial response of his liver metastases on the huA33 + BOF-Strep regimen after progressing on intrahepatic floxuridine. The patient treated as a single use exemption had stabilization of her disease (6 months). Of note is that the two patients with grade 3 or 4 bone marrow suppression achieved partial responses, and the third patient with grade 3 neutropenia had a mixed response. These data suggest that chemotherapy dose-increase modification may be appropriate in some patients, and the relationship of chemotherapy dose to response will need to be investigated.

The present study indicates that huA33 immunotherapy can be safely combined with BOF-Strep chemotherapy without apparent new toxicities and without increased bowel toxicity. However, the high incidence of HAHA (58%) may have prevented the manifestation of toxicities due to huA33-neutralizing antibodies in the HAHA reaction. The chemotherapy had only a small effect, if any, on the huA33-induced HAHA incidence, which has been in the range of 71–73% in prior studies (15, 16). A HAHA rate of 58% would make higher level studies difficult to interpret due to a significant loss of patients from treatment protocols. New human A33 antibodies have been developed to overcome huA33 immunogenicity problems and are being prepared for the clinic. Although response was not a major end point of this Phase I study, we are very encouraged that major responses were observed in these patients with large tumor burdens and with fluorouracil- and irinotecan-resistant tumors. In one case, a patient previously failing fluorouracil, leucovorin, irinotecan, and oxaliplatin achieved a partial response lasting 14 months. The responses were at antibody doses (10, 25, and 40 mg/m2) that were well tolerated. The transient bone marrow suppression observed as a result of the chemotherapy was manageable and did not require hospitalization. The induction of tumor regression was not seen once HAHA levels became detectable, suggesting that responses were dependent on the specific tumor targeting of antibody and that nonspecific effects of immune complexes of huA33 and HAHA did not play a role in antitumor effects. We expect that tumor response rates and duration would increase in the absence of huA33-neutralizing antibodies (HAHA) with a new nonimmunogenic form of this antibody.

The present study was based on clinical observations and an outcomes analysis of a group of patients participating in prior huA33 protocols and subsequently receiving chemotherapy. The observation that significant antitumor responses could be obtained in a group of patients with large tumor burdens and chemoresistant disease led to the present study. An analysis of the responses obtained in this study (n = 3) and those from the prior observation cases (n = 4) reveals that in five of seven cases, serum CEA declines were evident before the initiation of the chemotherapy. These data suggest that patient tumors showing sensitivity to huA33 therapy are more likely to respond to the addition of chemotherapy. Once a nonimmunogenic huA33 construct has been evaluated in a Phase I study, questions regarding the establishment of response rates for the antibody, the chemotherapy, and the combination treatment can be addressed in a series of well-controlled clinical trials. Because BOF-Strep is not commonly used as salvage treatment, there is little current information regarding response rates in patients with multidrug-resistant disease. Between 1980 and 1988, six Phase II studies were carried out to define the objective response rate of the regimen of methyl-CCNU, Oncovin, fluorouracil, and streptozotocin (MOF-Strep) in previously untreated colorectal cancer patients with advanced disease (24, 25, 26, 27, 28, 29). Methyl-CCNU eventually became unavailable, and carmustine was substituted for methyl-CCNU at the same dose and schedule (BOF-Strep). Major response rates varied from 10% to 35%, with an overall response rate of 26% for the 281 patients treated in these studies. However, the larger pivotal studies of previously untreated patients tended to have lower response rates, in the range of 10–16%, similar to fluorouracil as a single agent (26, 27). Based on these studies, the response rate in previously treated, chemoresistant patients who had failed a fluorouracil-based treatment or fluorouracil plus irinotecan is expected to be very small. As other regimens with greater activity became established, BOF-Strep took the place of last-line salvage treatment by some oncologists. Our experience with BOF-Strep in patients with chemoresistant disease is that major responses are infrequent, and palliation by achieving stabilization of disease is the primary goal.

The addition of immunocytotoxic antibody therapies to established active chemotherapy drugs/regimens is the focus of many ongoing studies and has become a standard in clinical practice (21, 22, 23). In most cases, antibody therapy has been added to active established drug regimens (21, 22, 23). Whether the results obtained here represent reversal of drug resistance, as has been reported by others (30), or modulation of immune effector functions by specific chemotherapy (17, 18, 19) remains to be determined.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

Supported in part by Grants CA-33049 and CA-08748 from the National Cancer Institute, NIH (Bethesda, MD).

3

The abbreviations used are: mAb, monoclonal antibody; BOF-Strep, carmustine, vincristine, fluorouracil and streptozocin; huA33, humanized A33; HAHA, human antihuman antibody; CEA, carcinoembryonic antigen; DLT, dose-limiting toxicity; CT, computed tomography; CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

Fig. 1.

Treatment schedule of 14-week cycle is shown. Treatment starts with weekly huA33 doses, and chemotherapy begins on week 5. Arrows indicate daily doses × 5 of carmustine or fluorouracil during the weeks 5 and 10. Subsequent cycles started with week 5.

Fig. 1.

Treatment schedule of 14-week cycle is shown. Treatment starts with weekly huA33 doses, and chemotherapy begins on week 5. Arrows indicate daily doses × 5 of carmustine or fluorouracil during the weeks 5 and 10. Subsequent cycles started with week 5.

Close modal
Fig. 2.

Serial serum CEA levels and HAHA levels plotted over time for the three patients with radiographic major objective responses. Patterns of HAHA activity are shown, measured by BIACORE in relative response units (RU). Patient 13 develops high levels of HAHA, and huA33 treatments are discontinued. Patient 5 has an early spike in HAHA titer but becomes tolerant to continued huA33 treatments. Patient 9 is negative. Patient 5 serial serum CEA measurements and HAHA curve indicate a temporal relationship between resolution of HAHA (after week 5) and decline in CEA levels.

Fig. 2.

Serial serum CEA levels and HAHA levels plotted over time for the three patients with radiographic major objective responses. Patterns of HAHA activity are shown, measured by BIACORE in relative response units (RU). Patient 13 develops high levels of HAHA, and huA33 treatments are discontinued. Patient 5 has an early spike in HAHA titer but becomes tolerant to continued huA33 treatments. Patient 9 is negative. Patient 5 serial serum CEA measurements and HAHA curve indicate a temporal relationship between resolution of HAHA (after week 5) and decline in CEA levels.

Close modal
Fig. 3.

Comparative pre- and posttreatment CT scan images demonstrating a partial response of metastatic pulmonary lesions in patient 13.

Fig. 3.

Comparative pre- and posttreatment CT scan images demonstrating a partial response of metastatic pulmonary lesions in patient 13.

Close modal
Table 1

Patient characteristics and huA33 dose level

Patient no.SexAge (yrs)PrimaryHuA33 dose (mg/m2/week)KPSaSites of diseaseCEA (ng/ml)LDH (units/liter)Prior therapies
67 Sigmoid 80 Lu, LN 350.5 276 F, FD, I 
52 Rectal 90 Lu, LN 1952.5 301 F, I, R 
63 Rectal 90 Lu, Li, O 381.7 162 F, I, R 
69 Sigmoid 80 Lu, O 7.7 161 F, I, R 
60 Rectal 10 90 Lu, Li, O 7845 161 F, FD, I 
66 Right 10 90 Lu, Li, O 21.5 191 F, FD, I, R 
36 Sigmoid 10 90 Lu, Li, O 1500.5 168 F, FD, I, Ox 
58 Sigmoid 10 90 Lu, O 594.5 264 F, I 
85 Rectal 25 80 Lu, Li, O 170.7 210 F, FD, I, Ox, R 
10 51 Right 25 90 Lu, O 5.8 154 F, I 
11 50 Sigmoid 25 90 Lu, Li, O 27.9 167 F, I, Ox, R 
12 62 Sigmoid 25 90 Lu, O 65.9 163 F, I 
13 54 Left 40 90 Lu 273 350 F, FD, I, Ox 
14 48 Rectal 40 90 Lu, Li, O 130807 789 F, I, Ox, R 
15 80 Sigmoid 40 90 Lu, Li, O 3767.9 764 F, I, Ox, R 
16 39 Sigmoid 40 80 Lu, Li, O 60.1 178 F, FD, I 
Patient no.SexAge (yrs)PrimaryHuA33 dose (mg/m2/week)KPSaSites of diseaseCEA (ng/ml)LDH (units/liter)Prior therapies
67 Sigmoid 80 Lu, LN 350.5 276 F, FD, I 
52 Rectal 90 Lu, LN 1952.5 301 F, I, R 
63 Rectal 90 Lu, Li, O 381.7 162 F, I, R 
69 Sigmoid 80 Lu, O 7.7 161 F, I, R 
60 Rectal 10 90 Lu, Li, O 7845 161 F, FD, I 
66 Right 10 90 Lu, Li, O 21.5 191 F, FD, I, R 
36 Sigmoid 10 90 Lu, Li, O 1500.5 168 F, FD, I, Ox 
58 Sigmoid 10 90 Lu, O 594.5 264 F, I 
85 Rectal 25 80 Lu, Li, O 170.7 210 F, FD, I, Ox, R 
10 51 Right 25 90 Lu, O 5.8 154 F, I 
11 50 Sigmoid 25 90 Lu, Li, O 27.9 167 F, I, Ox, R 
12 62 Sigmoid 25 90 Lu, O 65.9 163 F, I 
13 54 Left 40 90 Lu 273 350 F, FD, I, Ox 
14 48 Rectal 40 90 Lu, Li, O 130807 789 F, I, Ox, R 
15 80 Sigmoid 40 90 Lu, Li, O 3767.9 764 F, I, Ox, R 
16 39 Sigmoid 40 80 Lu, Li, O 60.1 178 F, FD, I 
a

KPS, Karnofsky performance status; LDH, lactate dehydrogenase; Lu, lung; Li, liver; O, other sites; F, fluorouracil; FD, FdUrd; I, irinotecan; Ox, oxaliplatin; R, radiotherapy; LN, lymph node.

Table 2

Toxicities and HAHA response

Toxicities scored by grade (0–4).

PatientHAHARashFeverChillsNauseaEmesisDiarrheaANCaPlatelets
  
Neg       
  
ND         
   
Neg      
IIb 
ND         
Neg    
10 Neg    
11 Neg     
12 Neg   
13 IIb    
14      
15     
16 ND         
PatientHAHARashFeverChillsNauseaEmesisDiarrheaANCaPlatelets
  
Neg       
  
ND         
   
Neg      
IIb 
ND         
Neg    
10 Neg    
11 Neg     
12 Neg   
13 IIb    
14      
15     
16 ND         
a

ANC, absolute neutrophil count; I, type I HAHA response; II, type II HAHA response; Neg, negative; ND, not done (patient removed from study early).

b

huA33 discontinued due to HAHA (patient 12 was treated off-study after course of radiotherapy interrupted protocol).

Table 3

Efficacy

ResponseNo. of patients (n = 16)Duration (mo)
Complete  
Partial 5.5, 8.0, 14.0 
Mixed 5.0 
Stable 6.0 
Progression  
Not evaluable  
ResponseNo. of patients (n = 16)Duration (mo)
Complete  
Partial 5.5, 8.0, 14.0 
Mixed 5.0 
Stable 6.0 
Progression  
Not evaluable  
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