Treatment of Hormone-refractory Prostate Cancer with 90Y-CYT-356 Monoclonal Antibody1

Abstract

A Phase I dose-escalation study using #{176}Y-CYT-356 monoclonal antibody was performed in 12 patients with hormone-refractory prostate carcinoma. Biodistribution studies using “In-CYT-356 were performed 1 week before #{176}Y-CYT-356 administration. Of the 12 patients, 58% had at least one site of disease imaged after administration of’ “InCYT-356. The dose of #{176}Y ranged from 1.83-12 mCi/m2. Both ‘DIn and #{176}Y-CYT-356 were tolerated well, without significant nonhematological toxicity. Myelosuppression was the dose-limiting toxicity and occurred at dose levels of 4.5-12 mCi/m2. Of the patients receiving 9 mCi/m2, 55% had grade 1 or 2 leukopenia and/or thrombocytopenia. Two of three patients treated with 12 mCi/m2 experienced grade 3 thrombocytopenia and leukopema. One patient treated with 12 mCi/rn2 had grade 4 neutropenia. The maximum tolerated dose of #{176}Y-CYT-356 was 9 mCi/m2. Only one patient developed a human anti-mouse antibody 4 weeks after treatment. No patient attained a complete or partial response based on prostate-specific antigen and/or radiological criteria. Three patients had transient subjective improvement in the symptomatology of their disease. In addition, patients treated with 12 mCi/rn2 of ‘ #{176}Y-CYT-356 had a slightly longer freedom from disease progression than patients treated with doses of #{176}Y.CYT.356 9 mCi/m2. INTRODUCTION Prostate cancer is the most common noncutaneous malignancy in men and the second leading cause of cancer death in Received 1 1/20/95; revised 4/23/96: accepted 5/6/96. I Supported in part by General Clinical Research Center, Public Health Service Grant No. MO1-RR0007O, and a grant from Cytogen Corporalion. S. K. had an American Cancer Society Career Development Award. 2 To whom requests for reprints should be addressed. at Stanford University Medical Center. Department of Radiation Oncology (A-093). 300 Pasteur Drive, Stanford, CA 94305-5105. Phone: (415) 723-5832: Fax: (415) 725-8231. men in the U.S ( I ). The estimated number of new cases of prostate cancer diagnosed in 1995 was 244,000, with 40,400 deaths expected (1). The use of the PSA3 test for screening has resulted in an increase in the detection rate of early stage prostate cancer (2, 3). Nevertheless, approximately 50% of patients present with nonlocalized disease (4). Initial therapy for metastatic prostate cancer typically involves some form of androgen blockade or ablation (5-7). Although the majority of patients attain significant subjective responses. fewer patients have objective clinical responses with a reduction in tumor volume after hormone therapy (8-10). Unfortunately. the duration of response to hormone therapy is temporary. and most patients develop progressive disease after 12-19 months ( I I). Hormone-refractory patients are incurable with standard therapy, and palliative therapies, including local/wide-field external beam radiation therapy, bone-seeking radionuclides, chemotherapy, or biological response modifiers, vary in terms of efficacy and response rate (8, 12, 13). Responses to these therapies are often transient, with progressively shorter periods of FFP of disease. Because this disease typically afflicts the elderly. these second-line therapies are frequently toxic and have a relatively low long-term therapeutic potential (14, 15). Therefore, new therapies are needed for this disease that may have a larger therapeutic index than the currently available treatment modalities. One such promising new therapy is RIT using systemically administered radiolabeled MAB. RIT is a promising new therapy for the treatment of hematopoietic malignancies and solid tumors (16-20), but to date, the only consistently promising results have been observed in patients with hematological and lymphoid malignancies. A variety of MABs have been developed that react with prostate cancerassociated antigens (8, 21-23). CYT-356 is an IgG, murine antibody specific for the 7E1 l-C5.3 antigen expressed on prostate epithelial cells (24). Higher levels of CYT-356 MAB bind to prostate adenocarcinoma than to benign prostatic hypertrophied tissue or normal prostate tissue (24). Importantly. the expression of the 7E1 l-C5.3 antigen is hormone independent and is expressed by both hormone-refractory and nonrefractory tumors (25). Few studies to date have used radiolabeled MAB for therapeutic purposes in patients with prostate cancer (8, 26-29). Clinical studies using radiolabeled MAB for diagnostic purposes have demonstrated that it is possible to detect sites of metastatic prostate carcinoma, which were undetectable by conventional radiographic studies (8, 25, 30, 3 1). A Phase I/Il study using ‘ ‘ ‘In-labeled CYT-356 MAB for the imaging of 3 The abbreviations used are: PSA, prostate-specific antigen; RIT, radioimmunotherapy: MAB, monoclonal antibody; FFP, freedom from progression: HAMA. human anti-mouse antibody: PAP, prostatic acid phosphatase: UA, urinalysis: HPLC. high pressure liquid chromatography: G-CSF. granulocyte-colony stimulating factor: WBC. white blood cell; CBC, complete blood cell count. Research. on October 23, 2017. © 1996 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 1290 RIT of Prostate Cancer Table 1 #{176}Y-CYT-356 p atient characteristics” MAB Patient Dose reactivity Current Sites of % BM no. Age (mCi) (%)h Prior therapy hormone Rx disease irradiated 1 58 6.76 60 Orchiectomy, flutamide, somatostatin, Emcyt, Velban, Adriamycin, 5FU. XRT Bone Paraspinal LN’ 37 2 66 3.66 60 Rad prost, XRT, orchiectomy, flutamide Eulexin Bone PA LN 4 3 80 3.40 90 XRT, Lupron/flutamide Lupron/flutamide Bone 48.5 4 52 7.82 75 Lupron/flutamide, XRT, Honvan Lupron & hydrocort Nizarol Bone Pelvic LN 35 5 50 9.46 20 Lupron/flutamide. XRT, gallium nitrate, hydroxyurea Lupron/flutamide Bone Para/pretracheal LN Pleural base 25 6 74 9.16 95 Orchiectomy, XRT Bone 39 7 73 21.6 90 Rad prost, Lupron/flutamide, aminoglutamide Lupron Bone 8 52 16.7 90 XRT, orchiectomy, flutamide Bone Pelvic/PA LN Mediastl It. hilar LN 37 9 69 15.2 100 XRT/’921r Lupron Bone Prostate 52 implant/hyperthermia, flutamide/Lupron, Emcyt 10 68 28.9 85 XRT, Lupronlflutamide Lupron Bone 67.5 1 1 66 24.8 >20 Rad prost, XRT Lupron Bone 4 12 77 24.1 50 Orchiectomy, Lupron/flutamide, Megace, XRT Lupron Bone Retroperitoneal LN 58 C, Rad prost, radical prostatectomy; XRT, radiation therapy; Emcyt, estramustine phosphate sodium; PA. para-aortic; LN, lymph node; hydrocort, hydrocortisone; Honvan, estrogen-like drug; Rx, treatment; BM, bone marrow; 5FU, 5-fluorouracil. b MAB reactivity = % of tumor cells stained with the 7El l-C5.3 antibody on immunohistologic analysis of biopsy material. C Paraspinal mass versus adenopathy on MRI. metastatic prostate carcinoma demonstrated that this immunoconjugate had favorable immunohistochemical characteristics and was safe, was not very immunogenic, and was localized in known sites of disease (25, 32). We report the novel use of #{176}Y-labeled CYT-356 MAB for the treatment of hormonerefractory prostate carcinoma. #{176}Y was chosen for preparation of the radioimmunoconjugate because it is a pure 3 emitter with an average energy of 0.937 MeV (maximal energy 2.28 MeV) and a half-life of 64 h (33). Other #{176}Y-labeled MABs have been used to treat non-Hodgkin’s lymphoma (34), Hodgkin’s disease (35, 36), T-cell leukemia (37), breast cancer (38, 39), and ovarian cancer (40) with encouraging results and have also been used to treat other solid tumors including colorectal cancer (41), and malignant gliomas (42). In the Phase I study described here, #{176}Y-CYT-356 was used to treat patients with hormone-refractory metastatic prostate cancer. The dose of #{176}Y-CYF-356 was escalated by 3 mCi/m2 in groups of three patients to determine the maximum tolerated dose of 9#{176}Y-CYT-356 in this patient population. In addition, the biodistribution and immunogenicity of 90Y-CYT356 MAB were studied. PATIENTS AND METHODS Patients. This study was approved by the Food and Drug Administration (IND# BB-4l38) and the Stanford University Internal Review Board. Twelve patients with hormone-refractory metastatic prostate cancer were treated with #{176}Y-CYT-356. They ranged from 50-80 years old, with a mean age of 65 years. All patients had failed at least one hormonal regimen, as evidenced by a rising PSA level. Of the 12 patients, 1 1 had previously received a minimum of one course of external beam radiation therapy before study entry. The characteristics of these patients, including prior therapies, are summarized in Table 1. Before study entry, patients had to meet the following eligibility criteria: (a) metastatic prostate cancer refractory to hormonal therapy (defined as >50% increase above the lowest PSA value after initiation of hormonal therapy measured on three consecutive evaluations); (b) immunohistological tests documenting 20% tumor reactivity with 7E1 l-C5.3 antibody; (c) physiological age 75 years; (d) Karnofsky performance status 60% with a life expectancy of >6 months; (e) WBC count 4,000 cells/mm3, platelet count 100,000 cells/mm3, and hemoglobin count l0g/dL; (1) serum creatinine 2.0 mg/dL, serum glutamyl amino transferase 2 X the upper limit of the laboratory normal range, and bilirubin S 1 .5 mg/dL; (g) negative serum antibody test for HIV; (h) HAMA level <.4 p.g/ml; (i) no chemotherapy or radiation therapy within 4 weeks of treatment; (I) no evidence of clinical spinal cord compression or known brain metastasis; (k) no serious illnesses that would preclude study completion or impede the determination of causality of any adverse effects experienced during the study; (1) serum immune complexes <25% on preinfusion analysis; (m) no participation in other clinical trials within 4 weeks before I I ‘In-CYT-356 infusion; and (n) signed informed consent. In addition to the 12 patients treated on this study, 4 other patients met these eligibility criteria and were entered in the study. They Research. on October 23, 2017. © 1996 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 1291 did not receive a therapeutic dose of 90Y-CYT-356 MAB because of the inability to image known sites of disease in two patients before amendment of the protocol so that this was no longer required, >25% serum immune complexation in preinfusion serum from one patient, and unacceptable biodistribution in one patient with the estimated liver dose (246 cGy/mCi) from 90Y-CYT-356 MAB exceeding 10 times the estimated wholebody dose. Study Design. Within 2-4 weeks of study entry, patients underwent a thorough physical examination, electrocardiogram, chest X-ray, bone scan, and laboratory studies (including CBC, comprehensive chemistry panel, UA, and assays for creatinine phosphokinase, PSA, PAP, and HAMA). Additional radiographic imaging studies were used to obtain tumor measurements, when possible. HAMA assays were performed before both ‘ ‘ ‘In and 9#{176}Y-CYT-356 administration and 2, 4, 8, and 24 weeks posttreatment or at the time of study withdrawal. Immunoscintigraphy was performed using 0.5 mg of CYT-356 labeled with 5 mCi of ‘ ‘ ‘In. The ‘ ‘ ‘In-MAB was injected as a slow iv. push. In vivo biodistribution studies for dosimetric estimates were conducted in each patient as follows. Immediately after ‘ ‘ ‘In-CYT-356 administration, patients were imaged in the anterior and posterior projections in a whole-body area mode. Imaging was repeated 14-18, 24, 48, and 72 h after injection. Single-photon emission computed tomography of the pelvis and/or other regions of interest with known sites of disease were performed 30 mm and 72 h after ‘ ‘ ‘In-CYT-356 administration in selected patients. Whole-body average (effective) retention times were estimated using an existing algorithm based on single exponential analysis (with five points). In addition, for recognizable organs or tumor lesions, appropriate regions of interest were drawn, and retention times were similarly computed. The total dose was expressed in camera cpm using the first (immediate postinjection) whole-body counts. A region of interest was drawn around the head, trunk, and limbs; around recognizable organs (e.g. , heart, liver, spleen, and lumbar spine); and some tumors. Using an algorithm described previously (43), the regions were used to compute organ volumes, and concentrations (fraction of total dose/g) were calculated. Cumulative concentrations were then computed using a single exponential fit and a decay correction for ‘ ‘ ‘ In, and estimated anticipated doses from 9#{176}Y-CYT-356 were calculated using the equilibrium dose constant for 90Y. MAB biodistnibutions were considered to be acceptable if in any organ or tissue (excluding the spleen or tumor) the estimated cumulative dose from Yttrium was < 10 x the whole-body dose, or if the estimated cumulative dose for the liver was < I 500 cGy. Patients with acceptable biodistributions were then treated with 90Y-CYT-356 antibody within 1 week of ‘ ‘ ‘In-MAB administration. Vital signs were measured before and at 15, 30, 45, 60, 90, and 120 mm after ‘ ‘ ‘In or 90Y-CYT-356 administration. Patients were hospitalized overnight after MAB infusions and were discharged after their radioactivity level measured <5 mR/h at I m (the highest level of radioactivity observed was 8 mR/h at 1 m in one patient 1 h after 9#{176}Y-CYT-356 MAB infusion). Before discharge, a physical examination, an electrocardiogram, a UA, a CBC, serum chemistry, and assays of creatinine phosphokinase and HAMA were obtained. Initially, patients received approximately 2-3.5 mCi/m2. After safety was documented at each dose level, the dose level was increased by increments of approximately 3 mCi/m2. Only after two of the three patients treated at a given dose level had their blood counts return to either a grade 1 toxicity or to normal was the next patient treated at the next dose level. Dose escalation was stopped when two patients in a given dose level experienced grade 3-level toxicity. The maximum tolerated dose was defined as the next lower dose level. After treatment, weekly CBCs were performed for 8 weeks or until blood counts were either within 10% of the pretreatment level or within the normal range. PSA and PAP levels were obtained 2, 4, 6, 8, 12, and 24 weeks posttreatment, and chemistry studies and UA were obtained 2 and 4 weeks after treatment. Patients returned for follow-up physical examinations, bone scans, and radiological studies at monthly intervals. Follow-up was discontinued at the time of disease progression, providing there were no blood count or chemistry abnormalities. For patients with measurable lesions, the following criteria established response. A complete response was defined as the complete disappearance of all measurable disease by physical examination or radiological studies and return of the PSA to the normal range. A partial response was a reduction of 50% from baseline in the sum of the products of the longest perpendicular diameters of all indicator lesions and no new lesions. In addition, if the baseline PSA was elevated, a decline of 80% on three successive determinations was required for a partial response. Stable disease was defined as a response that did not meet the criteria for a partial response with no evidence of progressive disease for at least 3 months. Progressive disease was defined as two to three consecutive increases in PSA (measured at biweekly intervals) to >50% above the pretreatment baseline, an increase of >25% in the sum of the products of the longest perpendicular diameters of measurable lesions, or the development of new sites of disease. For patients with elevated PSA levels and bone as the only site of metastasis, the following response criteria were used. A complete response was the normalization of PSA for three consecutive evaluations performed at 2-week intervals. A partial response was defined as a decrease in PSA by 80% for three consecutive determinations performed at 2-week intervals. Stable disease was defined as a <25% change in PSA over a 3-month period, and progressive disease was defined as two to three successive increases in PSA of 50% from baseline when measured biweekly. The duration of response was evaluated at 4-week intervals from the time of documented response to the time of progressive disease as defined above. Serum Immune Complex Assay. Preand postinfusion patient serum samples were initially assayed by Cytogen Corporation for complexation with the CYT-356 antibody by HPLC. In the second patient studied, the biodistribution of ,, was unacceptable, and the level of complexation postinfusion surprisingly was 74. 1 %, at a time when the patient did not have a detectable HAMA response. This patient was not treated, and thereafter the protocol was revised to require complexation of ‘ ‘ ‘In-CYT-356 in pretreatment serum to be <25% for patients to be eligible for participation in the study. When immune complexation was determined on preinfusion samples at Cytogen Corporation, serum samples were spiked with I ‘In-CYT-356 to yield a final concentration of 167 ng/ml, which was equivalent to a 0.5-mg dose distributed in 3000 ml of plasma. After six patients were treated, the remaining preinfuResearch. on October 23, 2017. © 1996 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 1292 RIT of Prostate Cancer sion complexation assays were performed at Stanford University. Because of differences in equipment between the two laboratories used for the complexation assay, serum samples at Stanford University were spiked with ‘ ‘ ‘In-CYT-356 to yield a final concentration of 15 i.g/ml in order for the level of radioactivity in the samples to be within the detection range of the HPLC radiodetector (in comparison, when a therapy dose is infused and distributed in 3000 ml of plasma, the antibody concentration is approximately 3.3 p.g/ml). Briefly, 20-30 j.Ci of ‘ ‘ ‘In-labeled CYT-356 (2.5 p g) were allowed to complex for 20 mm with a I : 1 dilution of patient serum diluted with Dulbecco’s PBS at room temperature. Positive and negative control sera were similarly diluted and were incubated with ‘ ‘ ‘ In-CYT356. One p.Ci of these mixtures was then loaded individually on a TSK-3000 7.8 mm X 30-cm gel-filtration HPLC column (Phenomenex, Torrance, CA) and was separated with Dulbecco’s PBS solvent at a flow rate of 0.8 ml/min. The column retention time was calculated using a Model I 70 radiodetector (Beckman Instruments, Palo Alto, CA) and a Model 3390A integrator (Hewlett-Packard, Palo Alto, CA). The percent of ‘ I ‘In-CYT-356 that complexed with serum was calculated from the curve of eluted radioactivity as a function of column retention time. Radiolabeled Antibody. The MAB used for both imaging and therapy was 7El l-C5.3, a murine IgG, MAB. This antibody reacts with membrane-rich fractions of human prostatic carcinoma LNCaP cells, but not with PSA or PAP. It was supplied by Cytogen Corporation as an immunoconjugate (CYT-356) linked to glycyl-tyrosyl-(N,E-diethylenetriaminepentaacetic acid)-lysine produced under IND# BB-4138. All MAB preparations were tested for general safety, sterility, pyrogenicity, polynucleotides, mycoplasma, and adventitious viral contamination. For imaging doses, 0.5 mg of CYT-356 was conjugated to ‘ ‘ ‘In [in 0.04 N HC1 as cation 10 mCi/ml (Amersham Medi-Physics, Arlington Heights, IL)]. For therapy doses, 10 mg of CYT-356 were conjugated to 90Y [in 0.04 N HCI as cation 20 mCi/ml (Amersham Medi-Physics, Arlington Heights, IL) or in 0.05 N HC1 as cation 50 mCi/ml (Nordion International, Inc., Katana, Canada). Briefly, the radioisotope was buffered with 2.0 M sodium acetate. The buffered radioisotope was then added to the immunoconjugate and was allowed to react at room temperature for 30 mm. Radioincorporation of the radiolabeled MAB was determined by instant thin layer chromatography using a MAB quality control kit for radiolabeled monoclonal antibodies (Bionuclear Consulting, Inc., Naperville, IL). Briefly, 1 p.1 of the radiolabeled MAB was spotted on the instant thin layer chromatography strip in duplicate and then was placed in solvent (0.9% NaCl) for development until the solvent reached the top of the strip. The strips were cut in half, and each half was counted using a Packard auto-gamma counter with detection windows set at 100-500 keV for ‘ ‘ ‘In and 15-500 keV for 90Y. The percentage of incorporation was determined as follows: % incorporation The labeling efficiency of all preparations was above 95%, with a mean (± SD) labeling efficiency of 96.9 ± I . I % for ‘ ‘ ‘InCYT-356 and 97.3 ± I .4% for #{176}#{176}Y-CYT-356 MAB. The immunoreactivity of 9#{176}Y-CYT-356 labeled to specific activities of 5 and 30 mCi/mg was 66 and 76%, respectively, relative to the reference standard and was consistently above the release specification of 55%,4 The radiolabeled antibody was administered as a bolus injection within 4 h of manufacturing and quality control testing. HAMA Assay. HAMA levels were determined using an ELISA. The 96-well microtiter plates (Dynatech Laboratories, Inc., Chantille, VA) were coated with CYT-356 MAB. The coat antigen solution [50 iL; 5 p.g/ml in carbonate buffer (pH 9.6)1 was dispensed in each well, and the plates were incubated overnight at 4#{176}C. Plates were washed five times with 0.05% Triton X-100 in PBS before use. Nonspecific protein binding was blocked by incubating plates with 3% BSA in PBS for 30 mm at 37#{176}C. Plates were washed five times, and 50 p.L of patients’ serum samples were plated in serial dilutions in 3% BSA. The serum of a HAMA-positive patient (Cytogen Corporation) was used as a positive control. Plates were incubated at 37#{176}Cfor 1 h and were washed five times. Fifty p.L of horseradish peroxidase-conjugated goat anti-human X and K chain antibodies (1 : 1 in volume; Sigma, St. Louis, MO) at a dilution of 1 : 1000 were added to each well. After 1 h of incubation at 37#{176}C, plates were washed, and 50 p.L of enzyme substrate solution of ABTS [2,2’-azinobis(3-ethylbenzthiazolinesulfonic acid); Sigma] were added to the plates. Plates were incubated at 37#{176}C for 20 mm in the dark and were read in an automatic ELISA kinetic microplate reader (Molecular Devices, Palo Alto, CA) at a wavelength of 405 nm. A HAMA level of <0.4 pg/ml was required for study entry. This level was chosen because of prior experience with the antibody B72.3 in which HAMA levels of <0.4 p.g/ml were very unlikely to alter the biodistribution of a 10 mg dose of antibody.5 RESULTS Biodistribution and Dosimetry. Biodistribution studies were performed in all patients after the injection of ‘ ‘ ‘ In-CYT356 MAB. Whole-body images were obtained immediately after injection of the radiolabeled antibody and thereafter at approximately 14-17, 24, 48, and 72 h postinjection. Table 2 summarizes the results of the biodistribution studies in terms of the number of known sites of disease that were imaged. At least one site of disease was imaged in 7 of 12 patients treated, but only a small proportion of all known sites of disease were imaged. No lesions were detected by single-photon emission computed tomography that were not detected by planar imaging. Pharmacokinetic data and dose estimates based upon ‘ ‘ ‘ Inlabeled imaging studies for anticipated doses from 9#{176}Y-labeled antibody (cGy/mCi) are shown in Table 3. All dose estimates are for the conditions used for administration of the therapeutic dose of 90Y-anti-CYT-356 antibody. Mean doses ± SD are shown for the whole body, cardiac blood pool, liver, spleen, and cpm of bottom of strip cpm of bottom of strip + cpm of top of strip X 1 4 P. Kaladas, Cytogen Corporation. personal communication. 5 R. Maguire, Cytogen Corporation. personal communication. Research. on October 23, 2017. © 1996 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 1293 Table 2 Sites imaged No. Patient no. Lesions imaged Known sites of disease” I I BS-multiple: paraspinal mass/lymph node 2 1 BS-multiple: para-aortic adenopathy 3 1 BS-multiple 4 1 BS-9 lesions: bulky local disease perirectal nodes 5 0 ES-multiple: paratracheal adenopathy 6 2 BS-5 lesions 7 1 BS-8 lesions 8 0 135-3 lesions; para-aortic and supradiaphragmatic adenopathy 9 0 BS-l lesion 10 1 BS-multiple 11 0 BS-0 12 BS-multiple “ BS. bone scan; multiple, lO lesions. tumor. SDs are relatively large because of considerable interpatient variability in antibody biodistribution. The estimated mean tumor dose was 16.2 ± 2 1 .9 cGy/mCi, which was based on estimated tumor doses from only five patients because the relatively poor imaging of known sites of disease precluded calculation of estimated tumor doses in the majority of patients studied. In a comparison of paired data sets from four patients, the mean plasma half-life of the ‘ ‘ ‘In-CYT-356 MAB was 84.5 h (79.6 h for six patients) and 48.0 h for the #{176}Y-CYT-356 MAB (P < 0.05): however, the estimates of plasma cGy/mCi and plasma % doseli for ‘ ‘ ‘In-CYT-356 did not differ significantly (P > 0.05) from 9#{176}Y-CYT-356. The average urinary excretions of ‘ ‘ ‘In and 90Y-labeled antibody were 8.5% and 1 1 .7%, respectively, 71 h after antibody administration and were not significantly different. Toxicity. The antibody infusions were tolerated well, and there were no significant acute adverse events. A summary of nonhematological toxicity observed is shown in Table 4. After ‘ ‘ ‘In-CYT-356 infusion, two patients had transient edema, and two patients had elevated systolic blood pressure. These events were probably unrelated to the ‘ ‘ ‘In-CYT-356 infusion. However, the fever experienced by one patient approximately 3 h after infusion was most likely related to ‘ ‘ ‘In-CYT-356 administration. After 9t yCyT356 infusion, five patients experienced mild fatigue, and four patients had liver function test abnormalities (elevation of alkaline phosphatase in three patients and serum glutamyl amino transferase in two patients). These findings were not clinically significant and did not require treatment. One of 12 patients developed a positive HAMA titer 1 month after administration of 9#{176}Y-CYT-356 MAB. Hematological toxicity was dose-related and occurred in eight patients. The observed hematological toxicity is summarized in Table 5 in terms of type, grade, and frequency. WBC and platelet nadir counts as well as the time of onset and duration of blood count nadirs are shown in Table 6 as a function of dose level. Most patients experienced grade 1 or 2 leukopenia and/or thrombocytopenia at doses between 4.5-9 mCi/m2 lasting I -5 weeks before returning to the normal range. Two patients treated with I 2 mCi/m2 experienced grade 3 thrombocytopenia 5 weeks after #{176}Y-CYT-356 administration. Platelet count recovery to the normal range occurred within 3-6 weeks. These two patients also experienced grade 3 leukopenia 7 weeks after 9#{176}Y-CYT-356 treatment. One patient (#10) had a grade 2 absolute neutrophil count toxicity with recovery of counts to the normal range within 3 weeks. This particular patient had previously received extensive palliative radiation therapy for multiple bone metastasis. Another patient (#1 1) experienced a grade 4 absolute neutrophil count toxicity at week 7, requiring G-CSF support over a 2.5-week period. The duration of neutropenia for this patient was 12+ weeks. This patient only had one prior course of external beam radiation therapy to the pelvis. Six patients with grade 1 anemia pretreatment did not progress to grade 2 toxicity after 90Y-CYT-356 therapy. Three patients with grade 1 anemia pretreatment progressed to grade 2 at week 5, 6, and 9, respectively. Two of these patients (#2 and #12) required transfusion with recovery of blood counts to at least pretreatment levels. The other patient (#10) recovered to his pretreatment grade 1 level toxicity without intervention 1 week later. None of the other patients required transfusions. One patient with grade 2 anemia pretreatment did not progress to grade 3 after treatment with 9#{176}Y-CYT-356. Clinical Responses. The clinical responses after a single treatment with 9#{176}Y-CYT-356 MAB are summarized in Table 7. Ten of 12 patients were evaluable for response. Of the evaluable patients, none achieved a complete or partial response based on either PSA levels or tumor measurements. One patient (#3) had a 12% decrease in the PSA level at 1 month posttreatment. Unfortunately, this patient was not evaluable thereafter because he died of causes unrelated to his malignancy and treatment. The other nonevaluable patient (#1) received radiation therapy for symptomatic disease 1 week after #{176}Y-CYT-356 therapy. Four patients had progression of disease on the basis of an increase of 50% in two consecutive PSA values. Two patients had progression of disease due to radiological findings alone. Four patients had both a rise in PSA and radiological findings consistent with disease progression. The median time to progression was I and 2 months for patients receiving 9 mCi/m2 and 12 mCi/m2, respectively. By linear regression analysis. the FFP = -0.69 + 4.25 x mCi/m2, with the slope significantly different (P < 0.05) from zero and a correlation coefficient of 0.79. Five patients required alternative therapy within 6 weeks of 9#{176}YCYT-356 administration. These patients received external beam radiation therapy, chemotherapy, or systemic Strontium-89 for symptomatic progressive disease. Two patients (#1 and #2) noted subjective decreased bone pain 4 weeks after treatment. In one case, the region of symptomatic improvement correlated with a radiological response in the same site. The patient experiencing the longest duration of FFP (3 months) received 12 mCi/rn2 and noted an overall improvement in well-being, but no significant change in pain.

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@inproceedings{Deb2005TreatmentOH, title={Treatment of Hormone-refractory Prostate Cancer with 90Y-CYT-356 Monoclonal Antibody1}, author={Nimisha Deb and Michael L. Goris and Kirk Trisler and Sherry Fowler and Jeannette Saal and Shoucheng Ning and Mark Becker and Carol M. Marquez and Susan J. Knox}, year={2005} }