ADI/(717] ()m'n/ (('('T) ISM). 307—313. [995
`
`\(I 1995 Lippincott—Ravcn Publishers. Philadelphia
`
`Phase I Study of Monoclonal Antibody-Ricin A
`Chain Immunoconjugate Xomazyme-79l in
`Patients with Metastatic Colon Cancer
`
`P. M. LoRusso. D.O., P. L. Lomen, M.D., B. G. Redman. D.O..
`E. Poplin, M.D.. J. J. Bander. MD, and M. Valdivieso. M.D.
`
`The immunoconjugate XMMCO-791/RTA consists of ricin
`A chain bound to a murine monoclonal antibody MoAb
`791T. This monoclonal antibody (MoAb) binds to a glyco-
`protein of 72 kD. which is expressed on human colorectal
`carcinoma. ovarian carcinoma. and osteogenic sarcoma.
`XMMCO-791/RTA was tested in a Phase I trial with pro-
`posed dose escalation steps of 0.02. 0.04. 0.15. and 0.2 mg/
`kg per day. Twelve patients with metastatic colorectal car-
`cinoma were treated at 0.02. 0.03. and 0.04 mg/kg per day
`dose levels administered over 1 hour on days 1—5. Study—
`related toxicities were hypotension (6 patients): greater than
`10% weight gain (6 patients): peripheral edema (9 patients);
`fever (4 patients); confusion (3 patients); diarrhea (3 patients):
`proteinuria. as identified by dipstick (3 patients). greater than
`0.6 mg/dl decrease in serum albumin (I 1 patients): greater
`than 25% decrease in oncotic pressure (10 patients). and a
`decrease in ionized calcium (8 patients). Six patients received
`a second course of treatment. HAMA levels developed in 9
`patients and titers increased with number of courses admin-
`istered. Decreased overall toxicity. in comparison to the first
`course. was noted. but one patient had an allergic-type re-
`sponse (hypotension. crushing chest pain. diaphoresis) after
`the test dose of the second course (HAMA level > 10.000
`lgG). Life-threatening toxicity in the form of fluid shift. re-
`sulting in noncardiac pulmonary edema and third-spacing
`occurred after course 1
`in 1 of 3 patients at the 0.04 mg/kg
`per day level. No further dose escalation was attempted and
`no antitumor activity was seen.
`Key Words: Xomazyme 79l—Monoclonal antibody—Im-
`munoconjugate—Colorectal carcinoma.
`
`
`
`From the Divisions of Hematology/Oncology and Critical Care
`Medicine. Department oflnternal Medicine. Wayne State University
`School of Medicine. Harper Hospital. Detroit. Michigan. and Xoma
`Corporation. Berkeley. California. USA.
`This work was supported in part by Xoma Corporation and NIH/
`NCl PO-l #CA46560.
`Address correspondence and reprint requests to Dr. Patricia Mucci
`LoRusso. Harper Hospital. Division of Hematology and Oncology.
`PO. Box 02143. Detroit. MI 48201. USA.
`
`The technology permitting the development of con-
`tinuous cultures of fused cells secreting antibody of
`predefined specificity was described by Kohler and col-
`leagues in 1975 (1). Since that time. hybridoma tech-
`nology has provided monoclonal antibodies for a va-
`
`riety of purposes. including the diagnosis and therapy
`of malignancy in humans.
`The concept of drug targeting through the use of
`monoclonal antibodies (MoAb) directed against hu-
`man tumor-associated antigens is actively being inves-
`tigated against a wide variety of human malignancies
`(2—5). In theory. coupling of a cytotoxic agent to a
`monoclonal antibody (MoAb) will allow specific deliv-
`ery of the agent to the cancer cell with decreased toxicity
`to the normal cell lacking the antigen. One such moiety
`is the monoclonal antibody 791T/36 (MoAb 791T/36)
`coupled to ricin toxin A chain (Xomazyme—79l. Xoma
`Corporation. Berkeley. California).
`MoAb 791T/36 recognizes the gp72-kD antigen that
`is expressed on the tumor cells derived from ovarian.
`colorectal. and osteogenic sarcoma tissues (6—10). In
`diagnostic imaging studies. this MoAb bound to over
`80% of colorectal and ovarian tumor cells (7—9). The
`ricin toxin A chain (RTA) is a ribosomal-inactivating
`protein. which exerts its cytotoxic action by enzymat—
`ically modifying the 288 ribosomal subunit. thereby
`inhibiting protein synthesis (1 1). RTA does not bind
`to cells. is not internalized efficiently. and is function-
`ally inactive as a tumoricidal agent. However. by cou—
`pling RTA to MoAb 79 lT/36. RTA has the potential
`of being targeted to the tumor cells with resultant in-
`ternalization and cytotoxicity (l2). Preclinical studies
`confirmed cytotoxic activity against human colorectal
`carcinoma of the conjugate RTA/MoAb791T/36
`(Xomazyme-79l) (13). and a Phase I trial in patients
`with metastatic colorectal carcinoma was conducted
`
`307
`
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`308
`
`I’.
`
`.ll. LURL'SSO li'l'
`
`.11..
`
`using immunoconjugate in which the ricin compound
`consisted of RTA“, and RTA}. (2).
`The immunoconjugate used in this study contained
`only the less glycosylated isoenzyme of ricin toxic A
`chain. RTA)“. This immunoconjugate was developed
`in an effort to improve the pharmacokinetic properties
`ofthe compound. primarily to prolong serum residence
`time to improve tumor penetration.
`
`MATERIALS AND M ET} [ODS
`
`lmmunoconjugate
`The immunoconjugate Xomazyme-791 was pre-
`pared by coupling ricin A chain (RTA) to a monoclonal
`antibody XMMCO-791 that recognizes a 72-kD gly-
`coprotein present on the surface of human sarcoma
`and ovarian and colorectal
`tumors. XMMCO-791
`
`MoAb is ofthe lgG2b immunoglobulin subclass with
`kappa light chains. It was produced in the ascites of
`specific pathogen-free BALB/c mice and purified using
`standard procedures (data on file. Xoma Corporation).
`RTA (2 isoenzymcs—RTAM, and RTA“) is a polypep-
`tide derivcd from castor beans that is known to inhibit
`ribosomal function. When coupled to a monoclonal
`antibody that binds to a cell surface antigen. it is in-
`ternalized into the cell with resulting cell death.
`It
`is
`estimated that one molecule is sufficient to cause cell
`death.
`
`Several preclinical studies of XOMAZYME-79l in
`mice xenografts showed an inhibition of growth oftu-
`mor cell lines (C170. HT29) with increase in survival
`time ofanimals. lt was also found that the immuno—
`
`conjugate consisting of XMMCO-79l antibody and
`isozyme RTA“, immunoconjugate in the tumor was
`threefold more XMMCO 791-RTAN immunoconju-
`gate. The ratio is similar to the ratio ofserum residence
`times. thus increased residence time likely contributed
`to the increase in the amount of immunoconjugate
`delivered to the tumor (reference on file. Xoma Cor-
`poration).
`Xomazyme—791 was supplied as a solution contain-
`ing 1 mg/ml ofthe Xoma/.yme-7‘)l immunoconjugate.
`The molecular weight of RTA is 30 and the molecular
`weight of the antibody is approximately 150. Thus.
`about 17% ofthe total molecular weight is contributed
`by RTArm. The product was diluted 1:25 with normal
`saline before administration and filtered through a 0.22-
`pm low-protein binding filter (Millex-(w). The final di-
`lution was administered from a Travenol intravenous
`
`pack.
`
`Patient Profile and Methods
`
`Adult patients with metastatic colorectal adenocar-
`cinoma were eligible for this study. Pretreatment re-
`
`.l/N.l(‘/HI()H11'/l( ('li. lu/
`
`IN, MI 4. NW
`
`quirements included a Karnofsky performance status
`of 270%. a total bilirubin < 2.0 mg/dl. a serum al—
`bumin of 23.0 g/dl. normal prothrombin and partial
`thromboplastin time. serum creatinine < 1.5 mg/dl.
`granulocytes > 1.500/mm3. normal brain computed
`tomogram. presence of measurable disease. and no sig-
`nificant cardiac or pulmonary disease. N0 chemother—
`apy and/or radiation therapy could have been admin-
`istered within 4 weeks of Xomazyme-79l administra-
`tion. All patients were required to give informed
`consent prior to initiation oftreatment.
`Xomazyme-79l was administered as a 1-hour in-
`travenous infusion daily for 5 consecutive days with a
`16-day rest period (one 21-day cycle). On day 1 ofcach
`cycle. patients received an 80-pg IV bolus test dose. If
`no acute toxicities were noted with the test dose. the
`
`remaining portion of the calculated day 1 dose of
`XMMCO-79l/RTAm was infused. Based on animal
`studies. a starting dose of 0.02 mg/kg per day immu—
`noconjugate for 5 days. with subsequent dose escala-
`tions to 0.04. 0.08. 0.15. and 0.2 mg/kg per day im-
`munoconjugate were proposed. Three patients were to
`be enrolled at each escalating step until a maximum
`tolerated dose was reached. A total of 6 patients were
`scheduled for treatment at the maximum tolerated dose
`
`level. No intragroup. intrapatient. or intercyclc dose
`escalation was permitted. To maximize potential pa-
`tient benefits from tumor response. a two—cycle regimen
`was devised. A second cycle was initiated (toxicity per-
`mitting) on day 2| ofcycle one. Daily weight. physical
`examinations. and laboratory evaluations were done.
`including complete blood count with dilferential.
`serum chemistry profile. direct and ionized calcium.
`urinalysis. and arterial oncotic pressures. Days 1 and
`5 evaluation included protein electrophoresis to help
`identify components of protein loss during therapy.
`urinary electrolytes. and plasma hemoglobin to detect
`intravascular hemolysis. Serum samples for human
`anti-mouse antibody levels (HAMA) were drawn on
`days 0. 6. 15. and 21. Carcinoembryonic antigen (CEA)
`samples were drawn on days 1. 21. and 42. A baseline
`chest radiograph and electrocardiogram were done
`pretreatment.
`The starting dose of Xomazyme-791 was 0.02 mg/
`kg per day. The second scheduled dose level was 0.04
`mg/kg per day. After encountering unacceptable tox-
`icity at the 0.04-mg/kg per day dose level. an inter-
`mediate dose of 0.03 mg/kg per day was selected as a
`potential maximum tolerated dose.
`Standard tumor response criteria were used. Dis-
`appearance of all known lesions with development of
`no new lesions for a minimum of4 weeks wasjudged
`a complete response. Partial response was defined as a
`reduction of at least 50% ofthe sum ofthe perpendic-
`
`IMMUNOGEN 2301, pg. 2
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`

`XOAIAZY/IIIf-791 1N .MIin'ISTxITICV COLON CANCER
`
`309
`
`ular diameters of all indicator lesions lasting 4 weeks
`minimum without appearance of new lesions or pro-
`gression of disease at other sites. Progression was de-
`fined as a 250% increase ofthe sum of the perpendic-
`ular diameters ofall measurable lesions or the appear-
`ance of new lesions. Stable disease was defined as a
`
`decrease in tumor size from 0 to 50% or a steady state
`not qualifying for increasing disease ol‘at least 8 weeks
`duration. To be evaluable for response. patients must
`have received one complete course oftreatment defined
`as a 2I—day cycle. Serum levels ot‘CEA were monitored
`but not used in the definition of response.
`
`RESULTS
`
`Twelve patients with advanced. measurable. histo-
`logically proven metastatic colorectal adenocarcinoma
`were treated with Xomazyme-79l. Ages ranged from
`46 to 69 (median: 60). Median Karnot‘sky performance
`status was 80% (range: 70—100%). Previously. 11 pa-
`tients were treated with 5-fluorouracil. Four patients
`had previously received radiation therapy in an adju-
`vant setting. No patient received prior immunotherapy.
`All patients had elevated serum carcinomembryonic
`antigen levels(range: 5.2—1978: median: 57 IU: normal:
`()—2.5 for nonsmokers. 55.0 for smokers). All 12 pa-
`tients were evaluable for response and toxicity.
`In this study. 9 patients (75%) had liver metastasis.
`5 patients (42%) had pelvic and retroperitoneal lymph
`node involvement. 6 patients (50%) had lung involve-
`ment. 4 patients (33%) had lung and liver involvement.
`and 4 patients (33%) had abdominal and pelvic disease
`(excluding lymph nodes).
`Study-related toxicities were observed at all dose
`levels and appeared to be dose-dependent (Table I ). A
`decrease in blood pressure was gradual in onset. usually
`beginning on days 3 to 4. At 0.02 mg/kg per day max-
`imum decrease in systolic blood pressure was 20—29
`mmHg. occurring in I patient during the first course
`
`and 2 patients during the second course. Neither fluid
`challenge nor pressors were administered. At 0.04 mg/
`kg per day (the second step in dose escalation). 3 of 3
`patients experienced a minimum of 20 mmHg decrease
`in systolic blood pressure. while 2 of 3 patients re-
`sponded to intravenous fluids. The third patient de-
`veloped profound. sustained. symptomatic hypoten-
`sion requiring therapy with multiple pressor agents.
`albumin. and fluids. At 0.03 mg/kg per day. hypoten-
`sion was noted in 3 of6 patients. Fluid supplementa-
`tion was given to these patients. Fluid administration
`was begun when systolic blood pressure consistently
`decreased more than 20 mmHg below the baseline
`reading. No patient. however. developed clinical
`symptoms related to their hypotension. Fluid admin-
`istration was maintained until near normalization of
`
`systolic pressure. often requiring an additional day of
`hospitalization.
`Dose-dependent changes were noted in serum al—
`bumin and total serum protein (Table 1). All patients
`had >3.0 mg/dl pretreatment serum albumin levels.
`At the 0.02-mg/kg per day dose. there was no significant
`decrease in serum albumin or protein. In the first cycle
`oI'0.03 mg/kg per day. grade I to grade III hypoalbu-
`minemia was noted in 4 of6 patients. and 6 of6 pa-
`tients had a decrease of total serum protein. At the
`dose of 0.04 mg/kg per day. grades ll-IV decrease of
`serum albumin and grades 1-1“ decrease oftotal protein
`was noted in 3 of 3 patients. In patients who received
`a second course of therapy (0.02 and 0.03 mg/kg per
`day dose). there was neither hypoalbuminemia nor hy-
`poproteinemia observed. Protein electrophoresis was
`done on patients treated at the 0.03 mg/kg/day dose
`level and did not demonstrate any specific subset con-
`tributing to the protein depletion. Dipstick of urine for
`protein ranged from 0 to 2+.
`Coinciding with the hypoalbuminemia was an ob-
`served weight gain. Again. this was seen predominately
`with the first course oftherapy (Table I). At a dose of
`
`TABLE 1. Toxic/ties: number of patients (grade)
`
`Dose (mg/
`Peripheral
`kg/day)‘
`N"
`IBPC
`(Albumin
`(Protein
`(Weight
`edema
`Diarrhea Neuromood
`Drug fever
`Total
`Ionized
`
`
`ICaIcuum
`
`0.02 (cycle 1)
`(cycle 2)
`0.03 (cycle 1)
`
`3
`3
`6
`
`(I)
`1
`2 (I)
`3 (2—I; 14V)
`
`o
`O
`4 (3—1;
`
`t—Ill)
`
`o
`O
`6 (4—1; 2,")
`
`0
`O
`2 (ll)
`
`0
`0
`4 (I)
`
`3(1~|I; 2—Ill)
`3 (24; 1—")
`O
`0
`6(1—II: 2—III;
`5 (2—1; 1—”;
`3—IV)
`1—III; 1—IV)
`0
`2
`6 (1—1; 5—”)
`4 (I)
`2 (II)
`3 (2—I;
`t—ll)
`1 (14)
`0
`0
`1 (l)
`3
`(cycle 2)
`III)
`II.
`III. IV)
`0.04
`Not
`Not
`3(2—I|;1—|V)
`2(1A||;1—I||)
`1
`(III)
`3 (IV)
`3 (II.
`III, IV)
`3 (I,
`3 (II.
`3 (II. III. IV)
`3
`
`drawn drawn
`‘ Based on dose of immunotoxm
`° Number of patients treated.
`‘ Blood pressure decrement.
`
`0
`0
`6 (1—1; 5~I|)
`
`1
`O
`4
`
`0
`O
`4
`
`.Im .I ( 'lm ()Hm/ (('('l). lu/
`
`IN. \u 4.
`
`[VI/.5
`
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`

`310
`
`P. M. LURUSSO 127.111..
`
`0.02 mg/kg per day. grades I to II weight gain was seen
`in all three patients during the first cycle. At 0.03 mg/
`kg per day. grade IV toxicity was noted in the first
`cycle. At the 0.04 mg/kg per day dose level. grades 11
`to IV weight gain was noted. In those patients receiving
`a second cycle ot'therapy. weight gain was less marked.
`again seemingly corresponding to serum albumin
`levels.
`
`Significant peripheral edema was also noted and ap-
`peared to be dose-dependent (Table 1). Furosemide
`administration did not minimize the weight gain and.
`in fact. led to additional decrease of blood pressure.
`Gentle administration ofdiureties in conjunction with
`albumin was ofminimal benefit. Other dose-dependent
`toxicities included diarrhea. mood changes and fever
`(Table I).
`All patients had normal levels ofionized calcium at
`the onset oftreatment. In those patients in whom ion-
`ized calcium levels decreased to borderline or below
`
`normal levels (Table l). a decrease in systolic and di-
`astolic blood pressure was also noted. The rest of the
`serum electrolytes remained stable and urinary elec-
`trolytes were noncontributory.
`In several patients treated at the 0.03 mg/kg per day
`dose. serial arterial oncotic pressures were determined
`to identify a possible correlation between serum al—
`bumin levels and blood pressure alterations. Where
`measurements were available. we found a consistent
`
`downward trend in arterial oncotic pressure. A decrease
`in blood pressure paralleled a decrease in arterial on-
`cotic pressure.
`Blood urea nitrogen and creatinine were monitored
`closely and were unremarkable. except for one patient
`who developed severe hypotension at the 0.04 mg/kg
`per day dose level. This patient developed a clinical
`picture consistent with prerenal azotemia.
`Human anti-murine antibody (HAMA) titers were
`available in all 12 patients pre- and posttherapy for
`
`course I. and in 3 of6 patients for course 2 (Table 2).
`In 3 of 12 patients. the pretreatment HAMA levels
`were slightly increased (Patients 8. IO. and 12). In Pa-
`tient 8. it was not until the second course of therapy
`that a significant increase in HAMA level was noted.
`with an lgG HAMA rising to 2.000. lgM HAMA in
`this patient remained at baseline levels. HAMA levels
`measured after treatment in Patient 10 showed an in-
`
`crease of lgM-800 and lgG—I800. This patient was
`treated at the 0.04-mg/kg per day dose and demon-
`strated the least overall clinical toxicities of three pa-
`tients treated at that level. In the third patient with
`high pretreatment HAMA levels (Patient 12). the titers
`did not increase after course I. This patient had an
`intermediate level ofclinical toxicities encountered by
`patients at the 0.04—mg/kg per day dose level. Overall.
`after course 1. HAMA levels rose in 8 of 12 patients
`tested. Three patients in whom HAMA were measured
`after course 2. demonstrated incremental increases in
`HAMA levels.
`
`Patient 6 had a HAMA level of> 10.000 after com-
`
`pletion of course 1. Upon administration of the test
`dose for cycle 2. the patient had an acute episode of
`crushing chest pain. diaphoresis. hypotension. and
`tachycardia. Symptoms abated approximately 10 min-
`utes after onset. Protocol therapy was discontinued in
`this patient.
`No tumor response was observed. The dose-limiting
`toxicity appeared to be related to fluid shifts.
`
`DISCUSSION
`
`This Phase I study of Xomazyme-791 immunocon—
`jugate in patients with metastatic colorectal cancer has
`evaluated clinical toxicities in patients treated at 0.02.
`0.03. and 0.04 mg/kg per day for 5 days. with a repeat
`course at 21 days. Several study-related toxicities oc-
`curred in a dose—dependent fashion. As assessed by
`
`TABLE 2. HAMA levels
`
`Pretherapy
`Dose —
`
`Patient
`(mg/kg/day)
`1 gM
`1 96
`1 9M
`1 96
`
`Postcourse 1
`
`Postcourse 2
`
`1 9M
`
`1 9G
`
`0
`
`3.800
`
`2.200
`0
`<t/10
`<1/1O
`0.02
`1
`710
`0
`<1/10
`<1/10
`0.02
`2
`0
`0
`0
`O
`0.02
`3
`500
`10
`0
`0
`0.03
`4
`100
`100
`O
`0
`0.03
`5
`>10.000
`130
`0
`O
`0.03
`6
`0
`0
`O
`0
`0.03
`7
`15
`0
`20
`10
`0.03
`8
`100
`100
`O
`0
`0.03
`9
`1,800
`800
`0
`130
`0.04
`10
`500
`0
`0
`0
`0.04
`1 1
`40
`0
`100
`0
`0.04
`12
`
`
`200
`
`10
`
`>10.000
`
`2.000
`
`.lm./('/In (hurt/((17). lu/ IS. .\n 4, I‘l‘lf
`
`IMMUNOGEN 2301, pg. 4
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`

`XOMAZYxlIIi-Nl IN .‘llli'lI-lS'Ylvl'l'IC' COLON ('.-1/\"('liR
`
`3/]
`
`computed tomography scans of measurable disease. no
`signs of objective clinical response were seen in the 12
`patients treated.
`
`Fluid shifts resulting in noncardiac pulmonary
`edema and third—spacing was the principal dose-lim-
`iting treatment related toxicity. This toxicity may have
`a pathogenetic component of increased vascular per-
`meability. The fluid shift and fluid retention most likely
`contributed to the hypotension and increased weight
`observed in several patients. It appears the pathophys-
`iology offluid shifting was similar to what is seen in a
`“capillary leak syndrome." The end result of"capillary
`leak syndrome“ is third spacing oflluid and. if severe
`enough. progressive decline in systemic vascular resis-
`tance. followed by a decrease in mean arterial pressure.
`despite increases in cardiac output (changes similar to
`those seen in septic shock). Calcium supplementation
`therapy (calcium chloride) resulted in an increase of
`blood pressure with increasing levels of ionized cal-
`cium. We have also observed a similar phenomenon
`in association with high-dose lL-2 therapy ( 15). It is of
`interest to note that DeNardo and coworkers found a
`
`beneficial effect of increased vascular permeability in
`their preclinical models (Reference on file: XOMA
`Corporation). In their analysis. such an increase was
`credited with improved delivery of tumoricidal agent
`to the tumor.
`
`Some clinical toxicity might be related to cross-reac-
`tivity of the XMMCO-79l antibody with normal hu-
`man tissue. During pre-Phase I trials. XMMCO-79l
`showed a low level of reactivity with human tissues. lt
`bound weakly and nonspecifically to human red blood
`cells and to macrophages. There was weak binding to
`granulocytes and to a proportion of phytohemagglu-
`tinin-stimulated lymphoblasts. which have been shown
`to express the gp72 antigen. There was no binding to
`progenitor cells or to normal lymphocytes. lmmuno-
`peroxidase staining demonstrated that XMMCO-791
`bound to predominately noncellular stromal elements.
`The vascular endothelium of some capillaries and ve-
`nules in varying tissues were weakly positive. but most
`of the venules were negative. XMMCO-791 showed
`positive reactivity with about 10% of the alveolar ep-
`ithelium and macrophages in lung tissue in 2 of4 au-
`topsy specimens. There was very faint reactivity with
`less than 10% ofthe glomeruli in 1 of4 kidneys tested.
`Other tissue that showed some reactivity were epithe-
`lium of the lumen of skin ducts and glandular epithe-
`lium of colon. In the fetal tissue that was tested. there
`was some reactivity in the alveolar and bronchial ep-
`ithelium of the lung and tubule epithelium ofthe kid-
`ney (Reference on file: XOMA Corporation). Antigen
`shedding by cells binding immunoconjugate was not
`detected (Personal communication. Dr. Vera Byers).
`
`In several patients who completed a second course
`oftherapy. the degree of study-related toxicity was not
`as pronounced as in course 1. Weight loss. hypoalbu-
`minemia. hypocalcemia. and hypotension were all at—
`tenuated (Table l). The reasons for this observation
`are unclear. although we can postulate that HAMA
`response causes a more rapid clearance through for-
`mation ofantibody/immunoconjugate complexes de-
`creasing the likelihood of immunoconjugate-induced
`clinical toxicities (16).
`
`An earlier Phase 1 dose escalation study was carried
`out
`in which 17 patients with metastatic colorectal
`cancer were treated with doses ofimmunotoxin Xom-
`
`azyme-79l ranging from 0.02 to 0.2 mg/kg per day in
`a 1-hour intravenous infusion for a 5-day course (2).
`In this study. the ricin A immunotoxin contained two
`isoenzymes (molecular weight: 30 and 33: RTA“, and
`RTA“). There was no documented response. although
`there was some suggestion of tumor regression (drop
`in CEA levels. decreased size of lesions on CT scans.
`chest radiograph. and physical examination) in 5 of
`the 17 patients treated (2). Side effects in the previous
`study included a composite of signs and symptoms
`thought to be generic to RTA immunotoxin. including
`decreased serum albumin. weight gain with secondary
`peripheral edema. elevated temperatures. asymptom-
`atic proteinuria. mild fatigue. and reversible mental
`status changes (2). There was no life-threatening tox-
`icity noted.
`
`Pharmacokinetics done in a preclinical (mice) study
`have determined the half-life alpha phase ofthe RTA“.
`immunoconjugate to be 0.7 hours and the beta phase
`half-life to be 20.4 hours. In the previously published
`Phase 1 study oonmazyme-79 1. attempts were made
`to measure serum concentrations of79 l/RTA (2). The
`assay available was not sensitive enough to detect serum
`levels. Since the study reported here used one-tenth of
`the dose used in the first Phase I trial. no attempt was
`made to measure serum levels. Hence no definitive
`
`correlation between serum levels in the responding an-
`imals versus nonresponding patients can be made.
`It is of interest to note that 3 of the 12 patients had
`elevated pretreatment lgG or lgM HAMA levels. There
`was no obvious reason for this phenomenon. Several
`patients developed elevation of HAMA titers postin-
`fusion. but levels did not correlate with the type or
`severity of adverse effects observed during the study.
`In this Phase I study using Xomazyme-791 immu-
`noconjugate in patients with metastatic colorectal car-
`
`cinoma. it was found that at a dose of0.03 mg/kg per
`day X 5 days. the compound has clinically acceptable
`side ellects. Even though we saw no objective tumor
`response. Phase ll studies should be considered to de-
`
`line therapeutic utility of this immunoconjugate in
`
`lm./ ( '///I (min/((17).
`
`l'n/
`
`IN. \u 4.
`
`I‘M."
`
`IMMUNOGEN 2301, pg. 5
`Phigenix v. Immunogen
`|PR2014—00676
`
`IMMUNOGEN 2301, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
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`

`312
`
`1’. M. LoRUSSO ET AL.
`
`mu
`mo
`
`lticyele regimens. either as a primary therapy or.
`re likely. as an adjuvant therapy after tumor de-
`bulking procedures.
`(it
`
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`IMMUNOGEN 2301, pg. 6
`Phigenix v. Immunogen
`|PR2014—00676
`
`IMMUNOGEN 2301, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`