PRODUCT MONOGRAPH

CEA-Scan®, Arcitumomab
Kit for the Preparation of Technetium 99mTc
Sterile, Non-pyrogenic,
Lyophilized Powder for Intravenous Use
Radiodiagnostic Agent, Tumor Imaging Agent

IMMUNOMEDICS, INC
300 American Road 
Morris Plains, New Jersey 07950
United States of America

Date of Initial Printing: November 21, 1995

Current Revision:
July 17, 1997

DESCRIPTION

CEA-Scan® is a radiodiagnostic agent consisting of a murine monoclonal antibody Fab’ fragment, Arcitumomab, formulated to be labeled with Technetium 99mTc.1 The active component, Arcitumomab, is a Fab fragment generated from IMMU-4, a murine IgG1 monoclonal antibody produced in murine ascitic fluid, supplied to Immunomedics, Inc. by Charles River Laboratories. IMMU-4 is purified from the ascitic fluid and is digested with pepsin to produce F(ab’)2 fragments and subsequently chemically reduced to produce the 50,000-dalton Arcitumomab. Each vial contains the non-radioactive materials necessary to prepare one patient dose. CEA-Scan® is a sterile, lyophilized formulation, containing 1.25 mg of Arcitumomab with stannous chloride, potassium sodium tartrate tetrahydrate, sodium acetate trihydrate, sodium chloride, acetic acid, glacial, hydrochloric acid, and sucrose.

The imaging agent, CEA-Scan® [99mTc] is formed by reconstitution of the contents of the CEA-Scan® vial with 30 mCi of [99mTc] sodium pertechnetate in 1 ml of Sodium Chloride for Injection, USP. The resulting solution is pH 5-7 and for intravenous use only. Following administration, the labeled antibody can be visualized by common nuclear medicine instrumentation.

Physical Characteristics of Technetium

Technetium 99mTc decays by isomeric transition with a physical half-life of 6.02 hours.² The principal photon that is useful for detection and imaging is listed in Table 1.

External Radiation

The specific gamma ray constant for Technetium 99mTc is 0.78 R/mCi-hr at 1 cm. The first half-value thickness of lead (Pb) for Technetium 99mTc is 0.017 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in the following table. For example, the use of 0.25 cm of Pb will decrease the external radiation exposure by a factor of about 1000.

To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 3.

* Calibration Time

ACTIONS AND CLINICAL PHARMACOLOGY

IMMU-4 is one of the most specific monoclonal antibodies reactive with carcinoembryonic antigen (CEA).^3,4,5 CEA is a tumor-associated antigen the expression of which is increased in a variety of carcinomas, particularly of the gastrointestinal tract, as well as in fetal gastrointestinal tissues and in certain inflammatory states (e.g., Crohn’s disease, inflammatory bowel disease, post-radiation therapy to the bowel) and in fetal gastrointestinal tissues. In those instances, CEA can be shed and detected in the serum.^6,7 Assays of serum levels of circulating CEA are performed to obtain prognostic information following potentially curative surgical resection and as an adjunct to monitoring for recurrent disease in patients who have undergone curative resection of colorectal cancer.⁸ Many cross-reactive, but genetically distinct, CEA variants have been described in the literature, including nonspecific cross-reactive antigen (NCA) and meconium antigen (MA). ⁵

IMMU-4 is specific for the classical 200,000-dalton CEA that is found predominantly on the cell membrane. The IMMU-4 antibody does not demonstrate cross-reactivity with NCA or with MA.5 CEA-Scan® (Arcitumomab) is the Fab’ fragment of IMMU-4. Technetium labeled product, CEA-Scan® [99mTc], forms complexes with circulating CEA and binds to CEA on the cell membrane. Less than 50% complexation was observed with plasma CEA levels up to 2000 ng/ml, and complexes were not detectable at serum CEA levels below 250 ng/mL.

Use of the IMMU-4 Fab -SH fragment minimizes induction of human anti-mouse antibody (HAMA). Of over 400 patients evaluated, less than 1% of the patients were sensitized, as demonstrated by lack of induction of HAMA reactive with mouse-IgG-fragment.9,10 (See ADVERSE REACTIONS section.) Additionally, the pharmacokinetics of the Fab’ fragment (as compared with intact immunoglobulin) minimizes liver metabolism and the Fab fragment clears rapidly from the blood.¹¹

Pharmacokinetic studies

Pharmacokinetic studies were performed after the intravenous administration of the product. Data were obtained on 32 patients from Phase 1/2 safety and efficacy trials from cancer patients administered 1 mg CEA-Scan® with 25 mCi [99mTc], from two different lots (Group 1 and 2, N=16 per group).9 At 1, 5 and 24 hours after infusion, the blood levels were 63%, 23%, and 7% of the injected dose (percent injected dose/liter blood), respectively. The initial half-life was approximately one hour; the terminal half-life was 13 ± 4 hours, with 28% of the radiolabel excreted in the urine over the first 24 hours after administration. Pharmacokinetic parameters calculated to determine plasma disposition and elimination of the product are presented in Table 4.

Clinical Experience

CEA-Scan® was evaluated for imaging efficacy and safety in four clinical trials, two of which were Phase 3, one in patients with known disease^10,12 and the other in patients with occult disease.^13,14

These imaging studies were conducted to evaluate the presence, location and extent of colorectal cancer, primarily in the liver and extrahepatic abdominal and pelvic regions. Patients eligible for these studies had no prior exposure to murine proteins or murine antibody products. The imaging protocol in both Phase 3 studies was the same. Whole-body planar images were to be obtained at 2-5 hours and 18-24 hours post-injection, with acquisition of 300K counts per view during the initial planar views and 200K counts per view for the late planar images. The protocols also required Single-Photon Emission Computed Tomography (SPECT) images of the head, thorax, abdomen and pelvis at 2-5 hours post-injection.

The two pivotal Phase 3 trials for CEA-Scan® were designed to answer several questions: When should CEA-Scan® be ordered, how are the scans to be interpreted, and how can the results be used in managing patients with colorectal cancer? The two Phase 3 studies were carried out in similar patient-groups who presented slightly different clinical problems. In both cases, it was anticipated that the study would be ordered as part of an oncology "extent-of-disease" work-up. The patient populations can best be described as follows:

Study A -
Known Disease Patients: Patients with a history of carcinoma of the colon or rectum who have known evidence of disease by standard diagnostic methods (SDM 95% of which were computer tomography) and are undergoing an evaluation for extent of disease in preparation for surgery or other therapy.

Study B -
Occult Disease Patients: Patients with a past history of carcinoma of the colon or rectum who have no evidence of disease by standard, non-invasive imaging techniques, but in whom recurrent or metastatic cancer is strongly suspected due to rising CEA, LDH, hepatic enzymes, clinical signs, etc. This group of patients would include those in whom standard imaging techniques yield equivocal results.

Performance Characteristics in Patients with Evidence of Disease Detected by Standard Modalities

An open-label, multi-center, single arm trial designed to evaluate the safety and efficacy of CEA-SCAN® [99mTc] was performed in patients with histologically confirmed colorectal cancer and evidence of primary and/or metastatic disease detected by physical examination, colonoscopy, and/or standard radiologic studies. A total of 222 patients received a 1-mg dose of the antibody labeled with 20-30 mCi of Technetium 99mTc. The primary analysis of imaging performance and potential clinical utility focused on the 122 patients in whom surgical/histopathological evaluation was performed. In patients with at least one site of recurrent or metastatic colorectal cancer identified by standard diagnostic modalities [SDM] (in 95% of patients, this was CT), CEA-Scan® showed an imaging sensitivity of 78% (90/115), a specificity of 86% (6/7), an accuracy of 79% (96/122), a positive predictive value of 99% (90/91), and a negative predictive value of 19% (6/31). When used in conjunction with SDM (identification of potentially malignant lesions by SDM and/or CEA-Scan®), the combination showed an imaging sensitivity of 97% (111/115), a specificity of 29% (2/7), an accuracy of 93% (113/122), a positive predictive value of 96% (111/116), and a negative predictive value of 33% (2/6).

While a formal study exclusively for patients with primary presentation of cancer of the colon or rectum has not been performed, 23 such patients were included in this study. The primary tumor was visualized in 18 of 23 patients by CEA-Scan®. In addition, 11 of these patients had metastatic disease identified at surgery. CEA-Scan® correctly identified at least one metastatic lesion in each of the 11 patients, including 10 patients who had liver metastases.

Performance Characteristics in Patients with Negative or Equivocal Evidence of Disease on Standard Diagnostic Studies

A single-arm, open-label, multi-center clinical trial designed to evaluate the safety and efficacy of CEA-Scan® (Arcitumomab) for detection of malignant lesions was performed in patients with a history of colorectal carcinoma and presumptive evidence of recurrence or metastasis, primarily due to an elevated and/or rising serum CEA level and negative or equivocal findings on standard radiologic evaluation (CT, MRI, ultrasound). The presence or absence of tumor in one or more sites was determined by histological confirmation from "second-look" surgery, biopsy or laparoscopy, in 88 patients.

Of these 88 patients, 63 had histologically-confirmed malignant lesions. Of these 63, 40 patients had malignant lesions identified on the CEA-Scan® (sensitivity 78%). In four of these 40 patients, reevaluation of the most recent CT scans revealed evidence of disease. Of the 25 patients in whom surgical exploration was negative, CEA-Scan® incorrectly identified a site of disease in 11 (specificity 56%). In this population, the predictive value of a positive CEA-Scan® was 78% (40/51) and the predictive value of a negative CEA-Scan® was 38% (14/37). These data are presented in Table 5.

*By definition SDM were negative or equivocal for entry; however on review, 4 patients had positive findings on CT scan

Imaging Performance by Region Based Upon Combined Results of the Phase 3 Studies

The data from the Phase 3 studies were combined to provide an integrated assessment of the imaging characteristics of CEA-Scan® in the abdomen, pelvis, and liver (Table 6).

In general, CEA-Scan® was more sensitive and less specific in the abdomen and pelvis than CT10; however, direct comparisons of the performance characteristics of SDM to CEA-Scan® are difficult to interpret, since the results of SDM were entry criteria for both Phase 3 protocols.

Complementarity Analyses Based Upon Combined Results of the Phase 3 Trials

Analysis of the complementary use of CEA-Scan® with SDMs showed that lesions identified in this population by both CT and CEA-Scan® were significantly more likely to be confirmed as cancer at surgery (positive predictive value (PPV) = 146/150, 97%) than the group of all lesions identified by CT scan (PPV = 200/233, 86%) or all lesions identified by CEA-Scan® (PPV = 240/292, 83%). When the scan results were discordant for the presence of a lesion and when both were negative in a region, the frequency with which tumor was found was lower (see Table 7).

* Negative lesions derived from number of potential sites of involvement per region explored
† Percentage of patients with histologically confirmed malignant lesions

In the detection of liver metastases, when added to CT scan evaluation, CEA-Scan®(Arcitumomab) indicated the presence of liver metastases in 18 additional patients of whom 10 actually had liver metastases. Thus, addition of CEA-Scan® increased sensitivity from 55/83 (66%) to 65/83 (78%), but decreased specificity from 113/126 (89%) to 105/126 (83%).

Resectability Analysis

After the studies were completed and analyzed, criteria were developed to assess the potential for curative resection (based on scans and/or surgical findings), and the data were reanalyzed to assess the role of CEA-Scan® in the pre-surgical evaluation of patients for possible curative resection of recurrent or metastatic disease. A patient or diagnostic scan was scored as resectable (R) if there were 4 lesions in the liver or only 1 region of abdominal or pelvic involvement, non-resectable (NR) if there were >4 liver lesions or 2 or more regions of involvement, and negative (N) if there was no evidence of disease. The patient assessment was based upon surgical exploration or procedures and pathologic findings.¹⁵

If lesions were considered present when identified by either CT or CEA-Scan®, CEA-Scan® in combination with CT correctly classified a greater percentage of patients with resectable disease (66% vs. 47%) and a greater percentage of patients with non-resectable disease (47% vs. 19%) compared with CT alone. However, adding CEA-Scan® to CT scan increased the frequency of incorrect identification of disease, among those patients with no disease at surgery, from 15% of patients to 32% of patients. Comparative data regarding the predictive values of CT and of CT plus CEA-Scan® for the absence of metastatic disease, the presence of resectability or of non-resectable disease are provided in Table 8. The predictive value of the combination of the two scans for the absence of malignant disease (i.e., both negative studies) was greater than for CT alone (67% vs. 38%), whereas the predictive value of findings of resectable or non-resectable disease on CT alone were similar to those of the combination.

*Denominators include some subjects with the "correct" resectability assessment based upon incorrect scan findings
†The percentage of scans for which the resectability status was correct, which is analogous to predictive value for resectability status
‡Lesions identified by either SDM and/or CEA-Scan® were considered positive

Based on the data obtained in the resectability analysis (Tables 8 & 10), the management paradigm (Table 9) was developed to evaluate the potential utility of CEA-Scan® as an adjunct to CT in the resectability analysis.. As noted in the paradigm, when CT and CEA-Scan® were discordant, the CEA-Scan®, by itself, was not to be relied upon.

†The management of any individual should be based on all the available information.

Among the 209 patients with surgical exploration and/or biopsy of lesions, 106 (51%) had CT and CEA-Scan® findings which were concordant, i.e., CT and CEA-Scan® identified the lesions in the same location with similar extent of involvement or both failed to identify any evidence of disease. When CEA-Scan® and CT were concordant, 29 of 31 (94%) patients without disease, 29 of 37 (78%) patients with resectable disease, and 17 of 38 (45%) of patients with non-resectable disease were correctly identified. The predictive value of concordant SDM and CEA-Scan® for absence of disease was 64% (29/45; 95% confidence interval = 50-78%), for the presence of resectable disease was 66% (29/44; 95% CI=52-80%), and for the presence of non-resectable disease was 100% (17/17; 95% CI= 80-100%) [see Table 10].

†CT and CEA-Scan® identified the lesions in the same location with similar extent of involvement or both failed to identify any evidence of disease.

DEVELOPMENTAL PHARMACOLOGY

Tumor Localization in Animals

IMMU-4 Fab'-SH Arcitumomab radiolabeled with 99mTc has been evaluated in athymic nude mice bearing xenografts of GW-39 human colonic adenocarcinoma.¹⁶ At six hours postinjection, the tumor/blood ratios were approximately one, but by 24 hours a ratio of 7.7 was attained.

Specificity of the localization has been demonstrated using a Fab'-SH fragment prepared from an anti-AFP (alpha-feto protein) control MAb (IMMU-31). The GW-39 human tumor xenograft does not express AFP and this IMMU-31 MAb has been used as a control for both imaging and therapy studies. The specific activity and immunoreactivity of the labeled anti-AFP control MAb were comparable to the specific activity and immunoreactivity of CEA-Scan® [99mTc] in the above studies.16 Compared with the specific targeting of CEA-Scan®, the tumor/normal tissue ratios after 24 hours were 0.5-1.0 when using the IMMU-31 control MAb.

Biodistribution

CEA-Scan® labeled with 99mTc at a concentration of 20 mCi/mg has also been evaluated in athymic nude mice bearing xenografts of GW-39 colonic adenocarcinoma; protein doses of I and 10 mg/mouse were evaluated. At one hour post-injection, the normal organs (liver, spleen, lungs, blood) all demonstrate tumor/normal tissue (T/N) ratios of 0.5-1.0. Four hours post-injection, T/N ratios of these organs have increased to 1.4-2.0, and 24 hours post-injection, T/N ratios are in the order of 3.0-10.0; liver T/N ratios are lower, ranging between 1.5-2.0. The percent injected dose/g in the tumor after 24 hours has ranged between 1 and 7% which is similar to results obtained with CEA-Scan® [99mTc].^16,17

Normal mice were injected with 1 and 10 ug of CEA-Scan® [99mTc] at a specific activity of 20 mCi/mg. As expected, the only organ demonstrating significant accretion of the injected radioactivity was the kidney. The data are in accord with the fact that Fab -SH is eliminated by the kidney. Within one hour post-injection the labeled drug was equilibrated in the blood, lymph and extracellular fluid. A significant amount of the total dose, 10-20%, was cleared by the kidney at this time point. By four hours post-injection, over 50% of the drug present at one hour post-injection is cleared by the kidney from the blood, and by 24 hours post-injection, over 95% of the drug was cleared from the blood.¹⁷

Animal Dosimetry of CEA-Scan® [99mTc]

Dosimetry calculations have been made using results obtained in the GW-39 tumor model biodistribution studies. The results obtained for biodistribution of the drug in normal mice were not significantly different than those obtained in the GW-39 tumor model.¹⁷

Metabolism experiments, in both normal mice and nude mice bearing the GW-39 human tumor xenograft, indicate that only the kidney will receive significant rad exposure. This is because Fab' is rapidly cleared from the blood and metabolized by the kidneys.¹⁸

Rad exposure was calculated for the kidney, liver and lung, using data from the metabolism studies of one experiment carried out in normal and tumor bearing mice. The organ dosimetry was obtained by assuming uniform distribution of 99mTc in spherically shaped organs. The S factors used for organs under 1 cm were determined by Dr. Michael Stabin of Oak Ridge Associated University. Rad exposure was calculated on the basis of a 7 mCi dose/mouse, equivalent to a 20 mCi dose given to a 60 kg patient. Using these parameters, the athymic mice bearing GW-39 received 4.1 5 rad to the kidneys and the normal mice received 1.43 rad to the kidneys. The exposure to liver and lung was less than 0.2 rad in both groups.¹⁷ The data presented above suggest that a 20 mCi dose of CEA-Scan® [99mTc] can be safely given to human subjects.

Metabolism

Elimination of CEA-Scan® [99mTc] in the mouse is primarily by the kidneys.^17,18 Although some of the fragment is excreted in an unaltered form in the urine, most of the fragment is absorbed by the proximal tubule, degraded and the degradation products slowly released in the urine.¹⁹

TOXICOLOGY

Single Dose Toxicity

Mouse

Groups of five male and five female ICR mice were given a single IV injection of CEA-Scan® [99Tc], 0.83 and 0.93 mg/kg, respectively. They were followed to autopsy after 14 days, complemented by histological examination of the principal organs.

No abnormalities were found after injection of 50-56 times the human dose.

Rat

In a similar study, groups of five male and five female Sprague-Dawley rats received 1. 1 6 and 1.33 mg/kg CEA-Scan® [99Tc], respectively, as a single IV injection.

Again, no harmful effects were seen after injection of 70-80 times the human dose.

Conclusions

CEA-Scan® [99Tc] was injected intravenously into mice and rats after allowing the radioactivity of the 99mTc to decay to 99Tc. The dosing solution contained all excipients employed in clinical practice.

No toxic effects were seen after these high doses.

Repeat Dose Toxicity

The subacute toxicity has been investigated in multidose tests designed to show whether there was any toxic risk.

Rat

Groups of ten male and ten female Sprague-Dawley rats were treated twice weekly by IV injection of CEA-Scan® [99Tc]. Each animal received an identical dose of 0.225 mg regardless of individual body weight. The dose (mg/kg) was derived from the average body weight/group. Five rats from each sex (randomly chosen) were sacrificed and autopsied on Day 15, after a total of four injections. The remaining animals (five males, five females) were autopsied on Day 29 after eight injections. Extensive hematological, chemical pathology and histological examinations were performed. No major effect was found. There were minor, unimportant fluctuations in the terminal (Day 28) lymphocyte and eosinophil counts. The total leukocyte count was low in control and treated animals.

Rabbit

In a similar study, groups of New Zealand White Rabbits (ten males and ten females), were treated twice weekly by IV injection of CEA-Scan® [99Tc]. Each animal received an identical dose of 2.25 mg regardless of individual body weight. The dose (mg/kg) was derived from the average body weight/group. Five rabbits from each sex were sacrificed and autopsied on Day 15 after a total of four injections. The remaining rabbits (five males, five females) were sacrificed and autopsied on Day 29 after eight injections. No major effect was found. The terminal (Day 28) lymphocyte count varied in females, but this is likely to have been due to biological fluctuation.

Conclusions

CEA-Scan® [99Tc] was repeatedly injected intravenously into rats and rabbits following a protocol representing a medium dose (four doses, each at 0.225 mg (rats) and 2.25mg (rabbits), 15 day study) and high dose (eight doses, each at 0.225 mg (rats) and 2.25 mg (rabbits), 29 day study) evaluation. The dosing solution used in this multidose study contained all excipients, identical in formulation to the clinical material.

No clinically significant treatment related abnormalities or toxicity in the rats and rabbits were found after repeated injections of each dose > 50 times the human dose.

Reproduction Toxicity

Animal reproduction studies have not been conducted with CEA-Scan®. Its chemical and biological nature do not suggest the propensity to cause reproductive toxicity. The frequency and circumstances of its clinical use, too, are further strong arguments against the need to perform animal experiments, and so is the absence of the relevant antigen (CEA) from suitable animals.

Mutagenic Potential

No test has been performed.

The predominant component of the preparation is a Fab-SH fragment of an antibody, which reacts with an epitope that is overexpressed on certain human cancer cells. This means that there is no relevant, specific test system available.

The chemical reducing agent and other pharmaceutical excipients are of an entirely conventional nature, and are already widely approved in IV preparations given to man for radioisotope imaging.

The 99mTc is widely accepted in clinical practice as a radioimaging agent for IV administration. This radionuclide emits only a pure gamma of relatively low energy.

Carcinogenicity/Oncogenic Potential

No study has been performed.

This is considered justifiable because of the nature of the preparation, the wide clinical acceptance of comparable protein-99mTc complexes and the nature of the intended clinical use of CEA-Scan® [99mTc]. The chemical composition of the active ingredient is a protein containing only amino acids present in human proteins including human IgG; only the amino acid sequences of the Fab'-SH vary from amino acid sequences of human IgG. After dilution into the blood pool, the concentration of CEA-Scan® is in the order of 200 ng/mL based on a blood pool volume of 5L. The concentration of human IgG is in the order of 10 mg/mL. Because the active ingredient is essentially chemically identical to the Fab' of human IgG and is present in minute amounts as compared to human IgG, there would appear to be no reason to test the active ingredient for oncogenic/carcinogenic potential. All other excipients are presently used in parenteral products, in concentrations that exceed those used in CEA-Scan®.

Local Toxicity

No formal study has been done. However, the single dose acute toxicity test in the rat resulted in necrosis of tail distal to the injection site in one treated male.⁹ Due to technical error in the injection technique, injection site crusts were observed in one treated male, one treated female, and two control females. The single dose acute toxicity test in the mouse and the 28-day repeated dose tests in the rat and rabbit did not reveal any local irritancy or other toxicity at the sites of administration.

From these findings and the many years of clinical experience of similar formulations, it is considered that there is no need to undertake a specific test of local toxicity. This is supported by the lack of evidence of any local adverse effects in the clinical studies.

Cross-Reactivity

In adult normal tissue, the CEA-epitope which reacts with the antibody in CEA-Scan® is only expressed in significant amounts in the apical glycocalyx (Fuzzy coat) of the gastrointestinal tract mucosa. This glycocalyx is a protective secretion which is excreted into the GI tract, and serves to protect the cells from bacteria, and to lubricate the tract. CEA secretion is polarized, with CEA present only on the apical surface of the normal epithelia cells which face the lumen of the tract. The tight-junctions between the epithelial cells prevents antibody injected into the blood from contacting the CEA on the apical surface of the cells.

Colon carcinomas arise from the normal epithelial cells, and the malignant cells invade the underlying tissues, thereby allowing antibody injected into the blood to access the CEA on the surface of the tumor cells. Furthermore, immunohistology studies have the apical face of the cells is lost, and CEA may be expressed on the total extracellular surface of the cells. This further favors the injected antibody localizing to the CEA in the cancer.

Although, in certain non-cancerous diseases very small amounts of CEA may gain access to the blood, the cells do not invade the underlaying tissue and the polarization of CEA to the apical face of the epithelial cells is maintained, therefore the CEA in the glycocalyx is not significantly targeted by parenterally administered antibody. Further, Fab' fragments do not bind to or activate complement, and so are most unlikely to trigger a dangerous acute cell lysis, even if bound to a surface epitope on a cell.

lmmunotoxicity

As CEA-Scan® is an Fab -SH antibody fragment of a murine monoclonal antibody, it was considered that specific tests for antibody formation in the rats and rabbits in the repeated dose tests would not give information relevant to man.

INDICATIONS AND CLINICAL USES

CEA-Scan® (Arcitumomab) is indicated, in conjunction with standard diagnostic evaluations (e.g., additional imaging evaluation), for detection of the presence, location and extent of recurrent and/or metastatic colorectal carcinoma involving the liver, extrahepatic abdomen and pelvis in patients with a histologically confirmed diagnosis of colorectal carcinoma. CEA-Scan® provides additional information in patients with no evidence of disease by standard diagnostic modalities (SDM) in whom recurrence or metastasis is suspected based upon elevated or rising serum CEA, and in patients with evidence of metastatic or recurrent disease on SDM. A retrospective analysis suggests that these data can be useful in the evaluation of patients in whom surgical intervention (biopsy, exploratory laparotomy and surgical resection) is under consideration.

CEA-Scan® is not indicated for the differential diagnosis of suspected colorectal carcinoma or as a screening tool for colorectal cancer. CEA-Scan® is not intended for readministration or for assessment of response to treatment.

CONTRAINDICATIONS

CEA-Scan® [99mTc] should not be administered to patients with known allergies or hypersensitivity to mouse proteins or any other ingredient of the preparation.

WARNINGS AND PRECAUTIONS FOR USE

The contents of this kit are intended for use in the preparation of 99mTc-labeled CEA-Scan® and are NOT to be directly administered to the patient.

The contents of the kit are not radioactive. However after the sodium pertechnetate [99mTc] is added, adequate shielding of the final preparation must be maintained to minimize radiation exposure to occupational workers and patients.

Radiopharmaceutical agents should be used only by those medical practitioners who are appropriately qualified in the use of radioactive prescribed substances in or on humans.

This radiopharmaceutical may be received, used and administered only by authorized persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses of local competent official organizations.

Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken, complying with the requirements of Good Manufacturing Practices (GMP) for pharmaceuticals.

The Technetium 99mTc labeling reaction involved in preparing the agent depends on maintaining the stannous ion in the reduced state. Any oxidant present in the sodium pertechnetate [99mTc] solution may thus adversely affect the quality of the radiopharmaceutical. Hence, sodium pertechnetate [99mTc] solutions containing oxidants should not be employed.

Technetium 99mTc labelled CEA-Scan® Arcitumomab Fab' fragments must be handled with care, and appropriate safety measures should be taken to minimize radiation exposure to the patients consistent with proper patient management, and to minimize radiation exposure to clinical personnel.

Immediately prior to use, contents of the vials are reconstituted with sodium pertechnetate 99mTc to prepare CEA-Scan® [99mTc]. The contents of the kit before preparation are not radioactive. However, after the sodium pertechnetate [99mTc] is added, adequate shielding of the final preparation must be maintained.

The preparation contains no bacteriostatic preservatives. Technetium 99mTc labeled Arcitumomab should be used or discarded within four hours after reconstitution. The solution should not be used if it is cloudy or contains particulate matter.

Imaging Interpretation

General

There are limited data to determine the imaging characteristics and efficacy of the CEA-Scan® (Arcitumomab) in detection of lesions outside of the abdominopelvic cavity.^7,8

Areas of potential false-positive readings, particularly with planar imaging, may be observed near the major blood pool organs (heart, major vessels, etc.) at very early imaging times, near the sites of antibody fragment metabolism (kidneys and urinary bladder), and in the intestines and gallbladder. Late imaging may also aid in the evaluation of suspected normal bowel activity.

With regard to imaging of tumor near the kidneys or urinary bladder, it is advisable to have the patient void urine prior to acquisition of imaging data to decrease bladder activity. Careful SPECT imaging near the kidneys and bladder has been helpful.

Porta Hepatis Region

Precise localization of lesions in the region of the porta hepatis has been difficult. Lesions within the porta hepatis region may be present within the liver or the portal nodes. At the time of surgical exploration, such lesions (which if nodal would preclude resection of hepatic metastases) should be explored first.

False-Positive Lesions

There were 52 false-positive lesions observed in 41 patients from a total of 209 surgically explored subjects in the two pivotal trials. Thirty-five of these lesions were in occult disease patients. Of the 52 false-positive lesions, 11 were observed in the liver, 17 in the extra-hepatic abdomen, and 24 in the pelvis. A pathological correlate to the lesions was infrequently documented; these included granulomas in the liver (1 instance), adhesions with or without suture granulomas (4 cases), surgical incision site (1 case). Descriptions of false-positive lesions within the abdomen were suggestive of colonic activity in several cases.

Hot, Rimmed, and Cold Lesions

Only hot or rimmed lesions should be considered as positive for tumor. Lesions that are rimmed or cold usually fill in as hot or rimmed, respectively, with time.^8,9 Often, large lesions, due to poor vascularization or central necrosis, will appear to be cold.

Pregnancy and Lactation

Women of Childbearing Potential

Animal reproduction and teratogenicity studies have not been conducted with Technetium 99mTc labeled Arcitumomab. It is also not known whether the Technetium 99mTc labeled Arcitumomab can cause fetal harm when administered to a pregnant women or can affect reproductive capacity. There have been no studies in pregnant women. Therefore, Technetium 99mTc labeled Arcitumomab should only be administered to women of childbearing capability if beta-HCG tests are negative. Ideally, examinations using radiopharmaceuticals, especially those elective in nature, in women of childbearing capability, should be performed during the first few days (approximately 10 days) following the onset of menses.

Lactation

Before administering a radioactive medicinal product to a mother who is breast feeding, consideration should be given as to whether the investigation could be reasonably delayed until the mother has ceased breast feeding and as to whether the most appropriate choice of radiopharmaceutical has been made, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breast feeding should be interrupted and the expressed feeds discarded. It is usual to advise that breast feeding can be restarted when the level in the milk will not result in a radiation dose to the child greater than 1 mSv. Due to the six-hour half-life of 99mTc, a dose of less than 1 mSv in mother's milk can be expected by 24 hours after the administration of CEA-Scan® [99mTc].

Carcinogenesis, Mutagenesis and Impairment of Fertility

No long term animal studies have been performed to evaluate the carcinogenic or mutagenic potential or whether CEA-Scan® affects fertility in males or females. As with other radiopharmaceuticals which distribute intracellularly, there may be increased risk of chromosome damage from Auger electrons if nuclear uptake occurs.

Pediatric Use

Safety and effectiveness in persons below the age of 21 have not been established.

Hypersensitivity

Patients who have been previously exposed to mouse proteins may develop hypersensitivity reactions following injection of this murine monoclonal product, due to the induction of a human anti-mouse antibody (HAMA) response. Rarely, patients may show the presence of an immunoglobulin (or immunoglobulin-like substance) that binds to the injected monoclonal antibody, even when there is no history of exposure to mouse antibody or mouse proteins.

Anaphylactic and other hypersensitivity reactions are possible whenever mouse protein materials are administered to patients. Full cardiopulmonary resuscitation facilities and trained personnel should be immediately available. Adrenaline (epinephrine), antihistamines and corticosteroids should be available for immediate use in the event of an adverse reaction.

Human Anti-mouse Antibody (HAMA)

HAMA to the Fab -SH fragment have been observed to develop after a single administration in < 1% of patients receiving CEA-Scan®. Pre-existing HAMA were also detected in some patients prior to receiving CEA-Scan®. Patients with pre-existing HAMA and those who have previously received murine-derived monoclonal antibody products have a greater chance of developing allergenic or hypersensitivity reactions and of showing diminished efficacy in tumor imaging. Similarly, patients who receive CEA-Scan® and develop a HAMA response may not be suitable candidates for future administration of murine MAbs-based immunodiagnostics or immunotherapeutics.

Renal or Hepatic Disease

Formal studies have not been performed in patients with renal or hepatic impairment. However, due to the low dose of protein administered and the short half-life of 99mTc, dosage adjustment is probably not necessary.

Interactions with Other Medicines and Other Forms of Interaction

The presence of HAMA in serum may interfere with two-site murine antibody-based immunoassays, such as assays for CEA and CA-125. If HAMA is known or suspected to be present, the clinical laboratory should be notified that interference may occur.

CEA-Scan® may interfere with serum assays for assessment of serum levels of CEA. Therefore, any determination of serum CEA should be made prior to injection with CEA-Scan®. Assays for serum CEA should not be performed within 7 days after injection of CEA-Scan®.

No data are available on possible drug interactions. Do not mix or administer CEA-Scan® with other products. Sufficient time should be allowed for clearance and radioactive decay before and after the use of this product and other products using radionuclides.

Effects on the Ability to Drive a Car or Use Machines

No known effect.

ADVERSE REACTIONS

In the over 500 patients studied with CEA-Scan® to date, the following minor self-limiting adverse events have been cited. Three patients each developed nausea, headache and rash, two developed fever and vomiting and one each developed the following minor self-limiting adverse effects: transient eosinophilia, diarrhea, epigastric and right upper quadrant pain, bursitis, urticaria, generalized itching, subdermal roughness, upset stomach, back pain, fatigue, sore throat, swollen glands, and chills. One report each of elevated liver function tests, elevated LDH, paresthesia, orthostatic hypotension and coagulopathy with thrombocytopenia have been received. All of which have been considered minor. There has been a single report of an apparent grand mal epileptic seizure in a severely hypertensive patient that was "possibly related" to CEA-Scan® infusion.

Over 400 patients who have received CEA-Scan® have been evaluated for HAMA by Immunomedics, Inc. using ELISA methodology.20 Fewer than 1% of the patients showed an elevation of HAMA levels to fragment after being injected with CEA-Scan®. If the physician suspects HAMA based on an adverse reaction or altered biodistribution pattern, and deems that a HAMA assay is clinically warranted, he/she should telephone Immunomedics, Inc., at 800 327-7211, between 8:30 a.m. and 5:00 p.m. Eastern Standard Time, for information on procedures to be followed for submission of patient serum for assessment of HAMA directed against mouse monoclonal antibody fragments.

OVERDOSE

Intravenous administration of intact IgG and F(ab')2 of IMMU-4 in therapeutic doses of up to 25 mg and the IMMU-4 Fab -SH fragment up to doses of 10 mg has not shown any serious adverse reactions. Fab -SH fragments have been demonstrated to be less immunogenic than intact IgG.

In the unlikely event of the administration of a radiation overdose with CEA-Scan®, the absorbed dose to the patient may be reduced by increased oral or intravenous intake of fluids to promote excretion of the radiolabel.

DOSAGE AND ADMINISTRATION

CEA-Scan® is reconstituted with sodium pertechnetate [99mTc] solution prior to use. (See section on Preparation of Technetium-Labeled CEA-Scan® [Arcitumomab].) The recommended adult dose is a single dose of 1 mg of Arcitumomab labeled with 20 to 30 mCi of 99mTc. Following dilution of the CEA-Scan® [99mTc] with 1 ml of Sodium Chloride Injection, USP, the dose is administered as a 2 ml intravenous injection. Alternately, the contents of the vial may be diluted to a total volume of 30 ml with isotonic Sodium Chloride Injection, USP. Intravenous infusion of CEA-Scan® [99mTc] diluted to 30 ml with Sodium Chloride Injection, USP, should be performed over a period of 5 to 20 minutes.

CEA-Scan® can be injected five minutes after reconstitution and should be used within 4 hours following reconstitution. Use of the product more than 4 hours after reconstitution may adversely affect imaging quality. The reconstituted preparation can be kept at room temperature prior to infusion.

Immediately prior to administration, the patient dose should be measured in a dose calibrator. Prior to patient administration, radiochemical purity must be 90% by Instant Thin Layer Chromatography (ITLC). The solution should be inspected visually; if there is particulate matter or discoloration, the preparation should be discarded and the manufacturer should be notified.

Immunoscintigraphy, using planar and Single-Photon Emission Computed Tomography (SPECT) techniques, should be performed at 2-5 hours after injection; selected additional views may be obtained up to 24 hours (as indicated by earlier imaging).

INSTRUCTIONS FOR PREPARATION

Read complete directions thoroughly before starting the preparation procedure. All procedures should be conducted using aseptic technique and standard precautions for handling radionuclides.

The contents of the vial before preparation are not radioactive. However, after sodium pertechnetate [99mTc] is added, adequate shielding of the preparation must be maintained. Appropriate safety measures should be used to minimize radiation exposure to clinical

personnel and patients consistent with proper patient management.

The product has been formulated to function only when the required amount of sodium pertechnetate [99mTc] is added to the complete content of each vial. Any change in the ratio of the ingredients, adulteration of the vial’s content, including extreme temperature changes for storage after opening the vial, or reduction of the administered dose, will likely result in an ineffective product.

Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. If any particulate matter or discoloration is observed, the vial should be discarded.

Preparation of Technetium-Labeled CEA-Scan® (Arcitumomab)

1. Required Materials, Not Supplied

a. Technetium 99mTc, oxidant-free
b. 2, 1-ml shielded, sterile syringes
c. Alcohol (or germicidal) swabs
d. Lead shield for 2-ml vial
e. Sodium Chloride for Injection, USP
f. 10- l pipette
g. Silica gel impregnated glass fiber strips, 1 x 9 cm
h. Acetone
i. Chromatography jar
j. Gamma counter
k. Dose calibrator
l. Counting tubes
m. Sterile 1- and 2-ml disposable syringes

2. The container for Arcitumomab does not contain preservatives. It is important that the user adhere to strict aseptic procedures during the preparation, withdrawal and administration of the CEA-Scan® product.

3. Obtain 25 to 30 mCi sodium pertechnetate [99mTc] in Sodium Chloride Injection, USP, at a concentration of 30 mCi/ml. With in-house generators: in a 2-ml vial, dilute 25-30 mCi of sodium pertechnetate [99mTc] to a final concentration of 30 mCi/ml with Sodium Chloride Injection, USP. Draw up 1 ml of sodium pertechnetate into a 1-ml shielded syringe (with a permanently affixed needle).

4. Inject 25-30 mCi of sodium pertechnetate [99mTc] in 1 ml into a shielded vial of Arcitumomab to resuspend the contents.

5. Swirl and shake the vial for approximately 30 seconds making sure all sodium pertechnetate [99mTc] is in contact with the antibody. Allow the labeling reaction to proceed for at least five minutes. Add 1 ml of Sodium Chloride Injection, USP, in order to facilitate easy removal. Remove the entire contents of the vial. Assay the product in a suitable dose calibrator.

6. After radiolabeling the antibody, dilute a 10- l sample with 1.5 ml saline. Determine the radiochemical purity by Instant Thin Layer Chromatography on silica gel impregnated glass fiber strips, 1 × 9 cm, using acetone as the solvent, to ensure that levels of free Technetium meet the specifications of less than 10%. When the solvent front is within 1 cm of the top of the strip, remove it, cut it in half and place each half into a glass tube. Count each tube in a gamma scintillation counter, dose calibrator or radiochromatogram analyzer. Calculate the percent free Technetium as follows:

	Activity in top half of strip
% Free Technetium =		x 100
	Total Activity

7. Based on the activity measured in the activity calibrator, withdraw a sufficient amount of the product to provide the desired activity (20-30 mCi of 99mTc). CEA-Scan® [99mTc] can be used after five minutes and should be used within four hours after preparation. CEA-Scan® [99mTc] can be stored at room temperature after radiolabeling.

8. Prior to administration, the solution should be inspected visually for particulate matter and discoloration. If either appear, the vial should be discarded and the manufacturer notified.

Image Acquisition

Planar imaging of the pelvis and abdomen, at four to eight hours post-injection with at least 500K counts per view, should be made. Image acquisition in analogue and/or digital word-mode with a 128 × 128 matrix is recommended.

SPECT of the pelvis and abdomen at four to eight hours post-injection should also be acquired. SPECT acquisition parameters recommended are: 60 projections in a 360  step-and-shoot technique, 30 seconds per view in a 64 × 64 matrix. Data processing by filtered back-projection and reconstruction in three planes (transaxial, coronal and sagittal) is recommended. Where it is desired to evaluate possible non-specific activity, later imaging may be advisable.

If late imaging is performed (up to 24 hours post-injection), intestinal and gall bladder activity may interfere with true tumor imaging. Therefore, such late images should be

compared to those made at earlier times (four to eight hours) and interpreted conservatively. Non-specific gut activity should shift with time, in contrast to a tumor lesion. Occasionally, bowel and gallbladder activity also may be visualized on the early images.

Due to excretion of the labeled fragment in the urine, the patient should urinate prior to imaging of the pelvis in order to decrease bladder activity.

RADIATION DOSIMETRY

Radiation dosimetry for individual organs is provided below. The values were calculated according to Medical Internal Radiation Dosimetry (MIRD). Data represent the mean of ten patients, with the exception of kidney (nine patients), ovary (eight patients) and testes (two patients).

Effective dose equivalent 13.1 Sv/MBq (48.5 Rem/mCi)
Effective dose 9.1 Sv/MBq (33.7 Rem/mCi)

HOW SUPPLIED

Package containing one (1) vial, with a single-use dose of 1.25 mg lyophilized Arcitumomab. The product should not be used beyond the expiration date printed on the label.

STORAGE

Store at 2 -8 C. Do not freeze.

Following reconstitution and radiolabeling, the material can be held at room temperature and must be used within four hours following reconstitution.

EXPIRATION

The expiration date for this kit stored at 2 -8 C, is 36 months from the day of manufacture.

References

^1. Hansen HJ, Jones AL, Sharkey RM, Grebenau R, Blazejewski N, Kunz A, Buckley MJ, Newman ES, Ostella F, and Goldenberg DM. Preclinical evaluation of an 'instant' 99mTc-labeling kit for antibody imaging. Cancer Res. 1990;50:794-7980.
^2. Kocher DC. Radioactive decay data tables. DOE/TIC-11026. 1981;108.
^3. Hansen H, Goldenberg DM, et al. Characterization of second generation monoclonal antibodies against carcinoembryonic antigen. Cancer. 1993;71:3478-3485.
^4. Sharkey, RM, Goldenberg, DM, et al. Murine monoclonal antibodies against carcinoembryonic antigen: Immunological, pharmacokinetic and targeting properties in humans. Cancer Res. 1990;50:2823-2831.
^5. Primus FJ, Newell KD, Blue A, and Goldenberg DM. Immunological heterogeneity of carcinoembryonic antigen: Antigenic determinants on carcinoembryonic antigen distinguished by monoclonal antibodies. Cancer Res. 1983;43:686-692.
^6. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122:467-481.
^7. Hansen HJ, Snyder JJ, Miller E, Vandevoorde JP, Miller ON, Hines LR, Burns JJ. Carcinoembryonic antigen (CEA) assay: A laboratory adjunct in the diagnosis and management of cancer. Human Path. 1974;5:139-147.
^8. National Institutes of Health Consensus Statement. Carcinoembryonic antigen: its role as a marker in the management of cancer. Brit Med J. 1981;282:373-375.
^9. Data on file at Immunomedics, Inc.
^10. Moffat FL, Pinsky CM, Hammershaimb L, Petrelli NJ, Patt YZ, Whaley FS, Goldenberg DM, the Immunomedics Study Group. Clinical utility of external immunoscintigraphy with the IMMU-4 99mTc-Fab antibody fragment (CEA-Scan™) in patients undergoing surgery for carcinoma of the colon and rectum: results of a pivotal Phase-III trial. J Clin Oncol. 1996;14:s.
^11. Behr T, Becker W, Hanappel E, Goldenberg DM, Wolf F. Targeting of liver metastases of colorectal cancer with IgG, F(ab )2, and Fab anti-carcinoembryonic antigen antibodies labeled with 99mTc: the role of metabolism and kinetics. Cancer Res. 1995;55:5777s-5785s.
^12. Moffat FL, Vargas-Cuba RD, Serafini AN, et al. Radioimmunodetection of colorectal carcinoma using technetium-99m-labeled Fab' fragments of the IMMU-4 anti-carcinoembryonic antigen monoclonal antibody. Cancer. 1994;73:836-845.
^13. Pinsky CM, Goldenberg DM, Wlodkowski TJ, Sasso NL, Mojsiak JZ, Hansen HJ. Detection of occult metastases of colorectal cancer by the use of anti-CEA Fab' fragments labeled with Tc-99m. Nucl Med. 1991;32:1052.
^14. Patt YZ, Podoloff SC, Kasi L, et al. Technetium 99m-Labeled IMMU-4, a monoclonal antibody against carcinoembryonic antigen, for imaging of occult recurrent colorectal cancer in patients with rising serum carcinoembryonic antigen levels.  J Clin Oncol. 1994;12:489-495.
^15. Hughes K, Pinsky C, Petrelli N, Patt YZ, Hammershaimb, LD, Goldenberg DM. Use of radioimmunodetection with CEA-Scan™ in planning for resection of recurrent colorectal cancer. Proc Amer Soc Clin Oncol. 1995;14:544,[abstr].
^16. Primus JP, MacDonald R, Goldenberg DM, et al. Localization of GW-39 human tumors in hamsters by affinity-purified antibody to carcinoembryonic antigen. Cancer Res. 1977;37:1544-1547.
^17. Hansen HJ, Jones AL, Sharkey RM, et al. Preclinical evaluation of an 'instant' 99mTc-labeling kit for antibody imaging. Cancer Res. 1990;50:794s-798s.
^18. Brown BA, Comeau RD, Jones PL, et al. Pharmacokinetics of the monoclonal antibody B72.3 and its fragments labeled with either 125I or 111In. Cancer Res. 1987;47:1149-1154.
^19. Maack T, Johnson V, Kau ST, et al. Renal filtration, transport, and metabolism for low-molecular-weight proteins: a review. Kidney Intl. 1979;16:251-270.
^20. Hansen, HJ, Sharkey, RM, Sullivan, CL, Goldenberg, DM. HAMA interference with murine monoclonal antibody-based immunoassays. J Clin. Immunoassay. 1993;16:294-299.

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