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Originally published as JCO Early Release 10.1200/JCO.2005.05.160 on April 18 2005 © 2005 American Society of Clinical Oncology. Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate CancerFrom the Department of Urology, Division of Hematology and Medical Oncology; Department of Medicine, Division of Nuclear Medicine; Department of Radiology, Weill Medical College of Cornell University, New York, NY Address reprint requests to Neil H. Bander, MD, Weill Medical College of Cornell University, 525 E 68th St, E-300, New York, NY 10021; e-mail: nhbander{at}med.cornell.edu
PURPOSE: To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of 177Lutetium-labeled anti–prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) in patients with androgen-independent prostate cancer (PC). PATIENTS AND METHODS: Thirty-five patients with progressing androgen-independent PC received 177Lu-J591. All patients underwent 177Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments.
RESULTS: Thirty-five patients received 177Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m2, and the 70-mCi/m2 dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m2 was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing CONCLUSION: The MTD of 177Lu-J591 is 70 mCi/m2. Multiple doses of 30 mCi/m2 are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.
Prostate-specific membrane antigen (PSMA) is the most well established, prostate cancer (PC) –restricted, cell-surface antigen identified to date.1 PSMA is a 100-kD type II transmembrane glycoprotein that is expressed by all prostate cancers.2 The density of PSMA expression progressively increases in higher-grade cancers, metastatic disease, and hormone-refractory PC.3-6 The 19–amino acid cytoplasmic domain of this nonsecreted protein contains a novel MXXXL internalization motif,7,8 resulting in its internalization and endosomal recycling. These characteristics make PSMA an ideal target for monoclonal antibody (mAb) therapy. J591 is an anti-PSMA mAb that binds with 1-nM affinity to the extracellular domain of PSMA.9,10 Murine J591 antibody was deimmunized using a novel method involving specific deletion of human B- and T-cell recognized epitopes.11 In vitro and animal studies of radiolabeled J591 demonstrated the superiority of radiometals Yttrium-90 (90Y) and Lutetium-177 (177Lu), presumably due to their longer intracellular half-life (t1/2), as compared with the rapid dehalogenation and washout of 131I-J591.10,12-13 90Y and 177Lu have very different physical properties. As compared with 177Lu, 90Y has a shorter t1/2 (2.7 v 6.7 days), a higher energy (max, 2.3 v 0.5 MeV), and a longer range (max, 12.0 v 2.2 mm). Modeling of radioimmunotherapy (RIT) reveals that the optimal tumor size for treatment using the higher energy beta of 90Y is 28 to 42 mm, while that for the lower energy beta of 177Lu is 1.2 to 3.0 mm.14 In the case of tumors smaller than the optimum, energy is deposited beyond the boundaries of the tumor; in larger tumors, the periphery is not adequately dosed. As a pure beta emitter, 90Y cannot be used for imaging and requires the use of 111Indium as a surrogate label for scintigraphy and dosimetry calculations. In contrast, 177Lu emits 15% of its energy as a gamma emission in addition to the beta emissions, and can be imaged directly using a gamma camera. These properties of 177Lu confer several theoretical benefits over 90Y for RIT: (1) the longer t1/2 of 177Lu may provide for emission of radiation over a longer time period while the radiometal is sequestered in the tumor cell; (2) the shorter range of 177Lu may result in less bystander toxicity, particularly in the bone marrow, the most common site of PC metastases, as well as the most radiosensitive normal tissue compartment; and (3) the shorter range may be beneficial by delivering a greater proportion of its energy within micrometastatic sites rather than around the tumor.14 Despite the potential benefits, there is very little clinical experience with 177Lu.15-17 We elected to evaluate both 90Y- and 177Lu-J591 in two independent phase I clinical trials. We recently reported the results of a phase I trial of 90Y-J591.11 We now report the results of the phase I dose-escalation trial of 177Lu-J591 in patients with progressing androgen-independent PC.
Patient Eligibility and Screening Eligible patients had a prior histologic diagnosis of PC with a rising prostate-specific antigen (PSA) level and/or tumor progression on radiologic studies including bone scan, computed tomography (CT), and/or magnetic resonance imaging (MRI), despite androgen deprivation therapy and castrate testosterone levels. Patients were required to have three sequential rising PSA values over a period of  2 weeks and a PSA 1.0 ng/mL at study entry. Eligible patients had a Karnofsky performance status 60% and life expectancy more than 6 months at the time of entry. Luteinizing hormone-releasing hormone agonist was either maintained for the duration of treatment and follow-up, or terminated 10 weeks (for 28-day depot) or 24 weeks (for 3-month depot) before entry. Nonsteroidal antiandrogen therapy was either maintained for the duration of treatment and follow-up, or terminated 6 weeks before entry. Patients were not permitted to receive aspirin or nonsteroidal anti-inflammatory agents within 2 weeks of entry; corticosteroids, adrenal hormone inhibitors or the herbal supplement PC-SPES within 4 weeks of entry; and systemic chemotherapy or radiation therapy within 6 weeks of entry. Patients with a history of prior radiation therapy encompassing more than 25% of the skeleton or prior treatment with 89Strontium or 153Samarium were ineligible for the trial. Patients were required to have adequate bone marrow function with an absolute neutrophil count (ANC) 2.0 x 109/L and a platelet count 150 x 109/L. Patients were required to have a unilateral or bilateral posterior iliac crest bone marrow biopsy demonstrating  10% or 25%, respectively, of the intratrabecular marrow space involved by PC. Additional exclusion criteria included serum creatinine greater than 2.0 mg/dL, serum AST 2.0x the upper limit of normal (ULN), serum total bilirubin 1.5x the ULN, serum calcium 12.5 mg/dL, and an abnormal coagulation profile (prothrombin time and partial thromboplastin time) unless on anticoagulant therapy. Anticoagulant therapy was to be stopped if the platelet count fell to less than 50 x 109/L. Patients were excluded from the study for CNS metastases, history of seizure and/or stroke, HIV infection, active serious infection, active ischemic heart disease or heart failure (New York Heart Association Classification III-IV), and other serious illnesses involving the cardiac, respiratory, CNS, renal, hepatic, or hematologic organ systems that might preclude completion of the study or interfere with determination of causality of any adverse effects experienced. All patients provided written institutional review board (IRB) –approved informed consent. Pretreatment evaluation included a history, physical examination, routine laboratory studies including PSA, prostatic acid phosphatase, testosterone, and an ECG. Radiologic studies included a chest x-ray; CT or MRI of the abdomen, pelvis, and brain; as well as a bone scan. Patients were required to have a bone marrow biopsy within 6 weeks of study entry.
Treatment Plan and Toxicity Evaluation Pharmacokinetics and biodistribution studies. Venous blood samples (4 mL) were obtained at 10 minutes; 1, 2, 4, and 24 hours; and days 2, 3, 4, and 7. The percent injected dose was determined by measuring an aliquot of blood along with a known 177Lu standard. To assess the biodistribution of mAb J591, total body images were obtained within 1 hour postinfusion (day 0) and again at four additional time points in the subsequent 2 weeks (days 2, 4 to 5, 6 to 7, and 12 to 14). The gamma camera images were obtained using a dual-head gamma camera with a medium energy collimator (ADAC, Milpitas, CA; General Electric Medical Systems Inc, Milwaukee, WI). The percent injected dose in major organs (heart, liver, spleen, kidneys, bone marrow, GI tract, and bladder) was estimated by drawing regions of interest and determining the relative counts in each organ and compared with a standard. SPECT studies of the abdomen, pelvis, and/or areas of suspected metastatic lesions were performed on day 2 or 3 in selected patients. Using the values obtained from sequential biodistribution studies and plasma PK, radiation dosimetry of 177Lu-J591 was estimated by substituting the physical characteristics of 177Lu.18
Evaluation of targeting.
With rare exception, lesions outside the prostate were not assessed by biopsy. To evaluate/compare targeting on antibody scan, bone lesions were defined as metastatic versus benign on the basis of clinical interpretation by a nuclear medicine physician with occasional corroboration by CT and/or MRI. Soft tissue masses
177Lu-J591 dose-escalation design.
Based on limited prior clinical experience with 177Lu-labeled antibodies consisting of a single trial15 where the MTD of intravenously administered CC49-DOTA-177Lu was 15 mCi/m2, the US Food and Drug Administration initially approved only two dose levels of 10 and 15 mCi/m2 to be followed by a data safety review before further dose escalation. Following the data review, the US Food and Drug Administration and IRB approved an amendment to (1) increase the dose increment between dose levels from 5 mCi/m2 to 15 mCi/m2 with dose increment reductions at the onset of grade 3 and/or 4 toxicity, and (2) to allow for repeat dosing if the patient had recovered from any earlier hematologic toxicity and continued to meet study entry criteria. The following dose levels were ultimately evaluated: 10, 15, 30, 45, 60, 70, and 75 mCi/m2. The 177Lu dose was escalated in cohorts of three to six patients. Dose escalation was held until at least three patients at each dose level had been followed for
DLT was defined as the following: hematologic toxicity consisting of grade 4 thrombocytopenia (platelet < 10 x 109/L) and/or grade 4 neutropenia (ANC < 0.5 x 109) lasting more than 5 days; and other toxicity consisting of any grade Patients were followed for a minimum of 12 weeks after 177Lu-J591 administration. Routine clinical and laboratory assessments (including biochemical profile, PSA, prostatic acid phosphatase, and testosterone) were performed at defined intervals. CBC and platelet counts were initially monitored one to two times per week, and then every 4 weeks until blood count stabilization. If the ANC was less than 1.0 x 109/L, and/or platelets less than 50 x 109/L, blood counts were monitored every other day. Chest x-ray, CT or MRI of the abdomen and pelvis, and a bone scan were performed 12 weeks post-treatment. Human anti-J591 antibody response was monitored at weeks 1, 2, 4, 8, and 12. Grading bone scans. As part of the data analysis, we compared bone marrow involvement and myelotoxicity. Bone scans were graded 0 (no involvement), 1 (one to five lesions), two (six to 10 lesions), three (11 to 20 lesions), four (> 20 lesions), and five (superscan).
Re-Treatment Re-treatment consisted of patients receiving the same 177Lu-J591 dose as their initial cycle unless dose modification was required based on the hematological toxicity of the preceding treatment cycle. Dose modification was as follows: 25% dose reduction for platelet count nadir 50 to 75 x 109/L (grade 2); no re-treatment for a platelet count nadir less than 50 x 109/L (grade 3 or 4); 25% dose reduction for ANC count nadir 1,000 to 1,499/L (grade 2) and 50% dose reduction for ANC 500 to 999/L (grade 3). Patient 4, who was initially treated at 15 mCi/m2 with grade 0 platelet and ANC toxicity, was permitted to receive re-treatment at 30 mCi/m2. After completing the 75 mCi/m2 dose level and defining the single dose MTD, additional patients were entered to define the tolerability and toxicity of repeated dose therapy. Patients were followed for a minimum of 12 weeks after their last dose of 177Lu-J591, and those patients with stable or responding disease were followed until progression.
Human Anti-J591 Antibody Response
Response Criteria
Thirty-five patients with androgen-independent PC whose pertinent demographic characteristics are presented in Table 1 were enrolled on the study between March 2001 and August 2003. The 177Lu-J591 dose levels, number of patients treated at each dose level and number of re-treated patients are listed in Table 2.
Pharmacokinetics, Biodistribution, and Dosimetry Based on plasma-time activity data and fit to a monoexponential curve, the plasma t1/2 for 177Lu-J591 was 39 ± 13 hours. The volume of distribution was estimated to be 4,156 ± 858 mL with a clearance rate of 88 ± 47 mL/h. The biexponential curve fit of plasma-time activity data showed that more than 80% of labeled antibody clears from circulation with a t1/2 (ß component) of 44 ± 16 hours. Early images document most of the activity in the circulation with the liver as the only organ sequestering a significant amount of 177Lu activity. By day 7, the whole body activity was almost 70% of the injected dose; the liver activity was 24% ± 7% of the injected dose. The radiation dosimetry of 177Lu -J591 is summarized in Table 3. The critical organ with highest radiation dose is liver (7.8 ± 2.2 cGy/mCi), followed by spleen and kidneys. The radiation dose to bone marrow based on blood radioactivity is 1.2 ± 0.4 cGy/mCi of 177Lu administered.
J591. Targeting Among the 35 patients receiving 177Lu-J591, 30 (86%) had metastatic disease detected on screening imaging studies. Specifically, 21 (60%) patients had bone-only metastases, six (17%) had soft tissue–only metastases, and three (9%) had both bone and soft tissue disease. In all of these 30 patients, all known sites of metastatic disease were successfully imaged by 177Lu-J591 scintigraphy. One patient with bone metastases had many more lesions visible on antibody scan than on bone scan (Fig 1). Another patient with a negative bone scan had a positive antibody scan that was confirmed positive by MRI.17 The bone scan of both patients later converted to positive in sites presaged by their antibody scans.
In addition to the series of imaging sessions after the first J591 dose for PK and dosimetry studies, patients receiving multiple doses were imaged 1 week after dose 2 and, where applicable, dose 3. In all of these cases, consistent tumor targeting was seen on serial images (Fig 2). No change in 177Lu-J591 clearance rate nor increased reticuloendothelial system uptake was noted after any dose.
Hematologic Toxicity Hematologic toxicity was dose related and is summarized in Table 4. Of the three patients at the 75-mCi/m2 dose level, one experienced dose-limiting (grade 4) thrombocytopenia, while the remaining two patients experienced grade 3 thrombocytopenia. All three of these patients experienced grade 4 neutropenia, one of which was dose-limiting neutropenia of 6 days' duration. As two of three patients at this dose level experienced DLT, no additional patients were entered at this dose. At the prior dose level of 70mCi/m2, six patients were entered. Two patients had transient grade 4 neutropenia not meeting the definition of DLT; one of these patients had grade 4 thrombocytopenia. As there was only one DLT in these six patients, the 70-mCi/m2 dose level was determined to be the MTD.
Post-treatment platelet counts followed a consistent pattern regardless of how many doses the patient received. Platelet declines generally begin at 2.5 to 3 weeks post-treatment, with platelet nadirs occurring at 4 to 5 weeks post-treatment thereafter, followed by a recovery phase. A composite graph of the mean normalized platelet counts at each dose level (Fig 3) reveals that each successively higher dose level was associated with a lower platelet nadir and longer time to recovery. Interestingly, when comparing dose levels, the decline phase of the platelet curves follows a more consistent, less variable time course whereas the recovery phase is more variable. As seen in Figure 3, the mean platelet counts returned to 80% to 95% of their pretreatment values.
Neutrophil (ANC) toxicity (Table 4) was significantly more variable and demonstrated less consistent post-treatment patterns than platelet counts. As the dose level increased, the ANC nadir was reached earlier. For example, at doses less than 60 mCi/m2, the ANC nadir occurred at approximately day 49; at 60 mCi/m2: day 42 to 49; at 70 mCi/m2: day 42; and at 75 mCi/m2, the ANC nadir occurred at day 39.
Of 19 patients receiving a single dose, 16 (84%) recovered platelet counts to
All 35 patients in the trial had ANC recovery to
Nonhematologic Toxicity
Re-Treatment Re-treatment was prescribed at the same dose as initially administered unless prior hematologic toxicity mandated a dose reduction (see Patients and Methods). A US Food and Drug Administration and IRB-approved exception was permitted for the first patient to be re-treated (patient 4). This patient was among the first six treated, and he had received a dose of 15 mCi/m2. This patient had grade 0 platelet and ANC toxicity after his first dose, accompanied by a 50% PSA decline lasting 5 months. Due to the time for data collection, submission, review, and trial amendment, his second dose was administered 238 days after his first dose. At that time, a dose of 30 mCi/m2 had been shown to be safe, and he was granted a protocol exception to receive re-treatment at a dose of 30 mCi/m2. At the time the single-dose MTD was defined as 70 mCi/m2, 10 patients had received more than one dose: five patients had received two or three doses at 30 mCi/m2, three patients had received two doses at 45 mCi/m2, and two patients had received two doses at 60 mCi/m2. At 45 mCi/m2, two of the three patients developed prolonged grade 3 thrombocytopenia, each requiring three platelet transfusions between days 35 to 48 and 38 to 56, respectively, after the second dose (Table 6). The one remaining patient receiving two doses at 45 mCi/m2 had grade 0 hematologic toxicity. At 60 mCi/m2, two patients received two doses: one experienced grade 4 platelet toxicity and required 13 platelet transfusions between days 40 to 105 after the second dose. This patient also experienced grade 4 neutropenia lasting 22 days, including a 16-day course of granulocyte-colony-stimulating factor. Before entry in this trial, he had failed radiation therapy, primary and secondary hormonal therapy, chemotherapy with carboplatin, paclitaxel and estramustine, an experimental telomerase vaccine plus granulocyte macrophage colony-stimulating factor (GM-CSF), and a protocol of interleukin-2 plus GM-CSF. Thirteen months after receiving his first dose of 177Lu-J591, he received XRT to the brain and spine for progression of disease. Subsequent to this last course of radiation, he became platelet transfusion-dependent and a bone marrow biopsy indicated a hypocellular marrow mostly replaced by cancer cells. This patient expired 20 months after his first dose of 177Lu-J591 as a result of widespread PC. A week before his death, he was noted to have an elevated blast count, and flow cytometric analysis was consistent with a diagnosis of acute myelogenous leukemia. The only other patient treated with two doses of 60 mCi/m2 experienced grade 0 to 1 platelet and ANC toxicity.
In contrast to the significant hematologic toxicity seen with more then one dose of 45 mCi/m2, multiple doses of 30 mCi/m2 were well tolerated. With IRB permission, seven more patients were added to further evaluate the safety of up to four doses of 30 mCi/m2. A total of 11 patients received two or more doses of 30 mCi/m2: one patient received three doses consisting of 15 mCi/m2 followed by two doses at 30 mCi/m2; six patients received two doses; and four patients received three doses. The median time between doses 1 and 2 was 64 days (range, 42 to 238 days) and between doses 2 and 3 was 53 days (range, 50 to 55 days). The four patients who received three doses totaling 90 mCi/m2 did so over a period of 98 to 126 days.
Hematologic toxicity of all re-treated patients is presented in Table 6. Among the 10 patients receiving two doses of 30 mCi/m2 (excluding patient 4), seven were eligible for a third dose. The three ineligible patients were disqualified by platelet nadirs less than 50 x 109/L (two cases) and ANC recovery to less than 2 x 109/L (in a patient carrying a pretreatment diagnosis of benign neutropenia). Of the seven eligible patients, four received the third dose, while three were not further treated due to disease progression. Of four patients receiving three doses at 30 mCi/m2, three were eligible to receive a fourth dose, while one began a different therapy due to disease progression, before being able to fully assess toxicity from the third dose. Although three patients were eligible for a fourth dose, none received further treatment due to tumor progression. Platelet count recovery of these 11 patients (including patient four) was as follows: two patients recovered to No dose-limiting nonhematologic toxicity was seen in the re-treated patients. Three of the 10 patients experiencing grade 1 AST and/or ALT elevations were among those patients receiving multiple doses. However, in none of these cases was there evidence of a cumulative or dose-related association. One patient receiving three doses of 30 mCi/m2 had a single episode of grade 1 AST 9 weeks after dose 1 and 6 weeks after dose 3 but no toxicity after dose 2. The second patient, at 45 mCi/m2, had grade 1 AST elevation at 8 and 12 weeks after dose 1, and at 5 weeks after dose 2. The third patient, at 60 mCi/m2, had grade 1 AST and ALT elevations after each of two doses. Imaging was performed in all patients after each dose, and in every case, tumor targeting remained consistent. No evidence of more rapid clearance was seen, nor were there any allergic reactions, consistent with the lack of human anti-J591 antibody response detected in any of the patients.
Formation of Human Anti-J591 Antibodies
Antitumor Activity
RIT has proven very successful in the treatment of NHL, with both 131I- and 90Y-labeled antibodies inducing high and durable response rates. The reasons for the success relate to the high radiosensitivity of lymphoid cells and their ready accessibility in bone marrow and lymph nodes to circulating antibody. Yet it remains an unanswered question whether RIT can be effectively applied to treat solid tumors. Current efforts in several types of solid tumors will help answer this question. In this regard, PC represents a particularly favorable setting in which to test the relevance of this approach in solid tumors. PC is a relatively radio-sensitive malignancy with a propensity to form small foci in the bone marrow and lymph nodes. These small foci allow ready accessibility of circulating mAb to its target antigen, in contrast to many other solid tumors that may be more radioresistant and where tumor masses are often bulky and poorly perfused. Furthermore, PSMA is an ideal cell-surface antigen given its expression by all PC, its high degree of specificity, its high level of expression (± 106 sites per cell),10 its internalization leading to the irreversible sequestration of radiometals within the targeted tumor cells,10 and the absence of a competing reservoir of antigen in the plasma. Given the favorable setting, PC and the PSMA antigenic system offer a model for the investigation and development of RIT as well as a litmus test of RIT in solid tumors. If RIT cannot succeed in PC, it will likely be very difficult to succeed in other solid tumors. We have previously published our experience with 111In/90Y-labeled J591, which demonstrated excellent tumor targeting in PC patients without prior selection for PSMA expression.11,19 In that trial, 90Y-J591 was well-tolerated, with observed biologic activity consisting of concordant biochemical (PSA) and measurable tumor responses. The concordance of PSA and measurable responses implies that PSA may provide a reasonable assessment of biologic activity in early-phase RIT trials. In this trial, using the same preparation of J591-DOTA and a similar patient population, we set out to study a second radiometal, 177Lu, with physical characteristics different from 90Y. 177Lu has the advantage over 90Y of allowing direct imaging. In addition, the longer t1/2, lower energy, and shorter range of the beta emission of 177Lu provide theoretical advantages in PC, in which the metastases tend more often to be small volume sites measured in µm to mm in bone marrow rather than bulky multicentimeter sites in lymph nodes or viscera. As in our previous trials, patients in this trial were not prescreened or selected for PSMA expression. Nevertheless, as previously observed with the J591 antibody, targeting in this trial was excellent, further confirming immunopathological studies indicating that all prostate cancers are PSMA-positive2 and are therefore, potential candidates for the J591-targeted monoclonal antibody. In this trial, all known lesions clinically defined on bone scan and CT or MRI were detectable on planar J591 images. In at least three cases, bone lesions were apparent on the J591 scan before becoming evident on conventional bone scan. Sequential imaging in patients who received multiple doses continued to consistently localize to tumor sites with no change in pharmacokinetics or biodistribution, consistent with laboratory assays that demonstrated a lack of J591 immunogenicity and human anti-J591 antibody development. DLT in this trial, as in RIT trials in general, was limited to myelotoxicity. The MTD of a single dose of 177Lu-J591 was 70 mCi/m2. This MTD is significantly higher than the MTD of 17.5 mCi/m2 we observed with 90Y using the same J591-DOTA preparation in a similar patient population. This finding likely relates to the lower energy and range of 177Lu, resulting in less bystander radiation to the bone marrow. Ultimately of course, a higher MTD is irrelevant unless it results in an improved therapeutic ratio. Prior published experience with 177Lu-labeled antibody is very limited. Only three previous trials have been reported, all of which used murine mAb CC49, targeting the TAG72 antigen, and the PA-DOTA chelate.15-17 Only one of these trials used intravenous administration,14 while the other two trials used an intraperitoneal approach.16,17 In the trial using the intravenous route, patients with breast, colon or lung cancer received 177Lu-PA-DOTA-CC49 (177Lu-CC49) with the finding of a MTD of 15 mCi/m2, as compared with our MTD of 70 mCi/m2. The significantly lower MTD in this 177Lu-CC49 trial was likely due to the labeling of CC49 up to a week before administration. The resulting radiolytic damage to the CC49 led to high reticuloendothelial uptake, including the bone marrow, of the radiopharmaceutical. In the two intraperitoneal trials, ovarian cancer patients given 177Lu-CC49 monotherapy16 exhibited an MTD of 45 mCi/m2, while those given 177Lu-CC49 in combination with paclitaxel and IFN17 had an MTD of 40 mCi/m2. There is limited prior experience with RIT in PC, and no previous RIT trials have studied 177Lu-labeled antibodies in PC. The MTD of 70 mCi/m2, however, compares well with that of 131I-labeled mAbs in other RIT trials in PC20,21 and other cancers. 131I is another beta/gamma emitter with similar physical characteristics to 177Lu (t1/2: 8 v 6.7 days; average energy: 0.2 v 0.15 MeV; average range: 0.4 v 0.25 mm, respectively). While 177Lu and 131I have similar decay characteristics, use of the latter is compromised in this antigenic system, as after internalization, 131I-labeled antibody is rapidly dehalogenated and diffuses out of tumor cells, while radiometals such as 177Lu or 90Y remain sequestered within the targeted tumor cells. In this study, as in our 90Y-J591 trial, we found no clear relationship between a history of prior chemotherapy treatment and the degree of toxicity. Similarly, we found no correlation between prior radiotherapy and toxicity. In addition, we found that there was no relationship between the extent of bone marrow involvement by cancer and toxicity. While this observation is somewhat different from that seen in NHL, a similar observation in PC was made by Knox et al22 and O'Donnell et al.23 This difference may be due to the fact that NHL involves the marrow much more diffusely than PC where the disease tends to be more focal. As a result, radiolabeled-antibody localization in NHL may radiate the marrow more diffusely than in PC.
The nonhematologic toxicity in RIT trials, in general, and in this 177Lu-J591 trial, was minimal and not dose limiting. Radiation dosimetry calculations indicate a radiation dose to liver of 7.7 cGy/mCi or approximately 1,088 cGy at the MTD of 70 mCi/m2. This is well below the acceptable radiation limits to the liver. In this trial, 11 patients had transaminase elevations, 10 of which were Sixteen of 35 patients in the trial received multiple doses. To our knowledge, this represents the largest experience with multiple dosing of RIT yet reported. Two doses of 45 or 60 mCi/m2, totaling 90 to 120 mCi/m2, proved to be quite toxic, with three of five patients experiencing prolonged and incomplete platelet recovery. Two or more doses of 30 mCi/m2, however, were well tolerated, and four patients received cumulative doses of 90 mCi/m2, almost 30% higher than the single-dose MTD. In this study, each dose was administered after allowing for hematologic recovery from the prior dose. It therefore took 3 to 4 months to administer the three doses, resulting in a higher cumulative dose, but lower dose-rate. While there may be advantages to the higher cumulative dose, the time required to deliver this dose using this regimen may be offset by unrelenting tumor progression. Given the kinetics of platelet decline and recovery, a dose interval of 14 to 17 days may allow a two-dose regimen that might result in a higher cumulative dose (than a single-dose regimen) to be given over a shorter period than attempted in this trial. Such a schedule would result in the onset of platelet recovery from the first dose to coincide with platelet decline from the second dose, thereby resulting in a longer but shallower nadir than with a single MTD dose. Such a dose schedule remains to be explored.
Although no patients in this trial had an objective measurable disease response (PR or CR), in our 90Y trial, there was a correlation of PSA response with measurable disease response,11 indicating that PSA was a reasonable measure of antitumor activity in patients with PC treated with RIT. In the current trial, four patients had PSA declines of
There are limited comparisons that can be drawn between our trials of 177Lu-J591 and 90Y-J591. Both radiopharmaceuticals were dose limited by myelosuppression with little nonhematologic toxicity. Both demonstrated biologic activity. In the case of 90Y-J591, the two PSA declines seen could be corroborated by measurable regressions.11 With 177Lu-J591, the four PSA declines occurred in patients without measurable disease. This may be explained by the responses to 177Lu-J591, with the optimum tumor size for 177Lu treatment of 1.2 to 3.0 mm being more likely to occur in small-volume unmeasurable disease sites, whereas responses to 90Y-J591 would be more likely to occur in bulkier disease sites,14 or it may simply be an artifact of the small sample size in these phase I trials. There appeared to be more uniformity of myelotoxicity grades among patients at any given dose of 177Lu-J591 than with 90Y-J591. This may reflect the higher energy and range of 90Y and the greater difficulty in calibrating the dose of 90Y combined with its narrower tolerable dose range. Approval of administering repeat doses came relatively late in the course of the 90Y-J591 trial, and, as a result, only four patients received multiple doses of 90Y-J591 compared with 16 patients in the 177Lu-J591 trial. Interestingly, in the 90Y-J591 study in which the MTD was 17.5 mCi/m2, three patients tolerated two to three doses at 17.5 mCi/m2, and the fourth patient tolerated two doses of 20 mCi/m2. That is, the repeat dosing in the 90Y-J591 trial resulted in patients receiving, and tolerating, multiples of the MTD. Conversely, in the 177Lu-J591 trial, there seemed to be more cumulative myelotoxicity, such that repeated dosing was poorly tolerated at doses In conclusion, 177Lu-J591 is well-tolerated, nonimmunogenic, can be administered in multiple doses, and targets PC metastases with sensitivity and specificity. Having determined the single-dose MTD of 70 mCi/m2 and the tolerability of multiple doses of 177Lu-J591, phase II trials are have begun to assess antitumor activity in both the single- and multiple-dose formats. Additional studies can evaluate the combination of radiolabeled J591 plus chemotherapy such as docetaxel, an agent active in PC also known to have radiosensitizing properties. Preclinical data in human PC xenografts applying RIT in combination with taxanes have demonstrated therapeutic synergy without excess toxicity.24
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Neil H. Bander, BZL Biologics Inc; Shankar Vallabhajosula, BZL Biologics Inc. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
We thank the following for their substantial contribution to this trial: Marta Cobham, RN; Felicia Berger, RN; Maureen Joyce, NP; Alyssa S. Rosmarin, NP; Jodi Kaplan, NP, Sae Kim, He Liu, MD; Christine Larned, Mark R. Navarro, Lana Winter, Heather Orkin, and the General Clinical Research Center staff.
Supported in part by National Institutes of Health General Clinical Research Center Program (NCRR grant M01RR00047); the Cancer Research Institute; the David H. Koch Foundation; the Peter Sacerdote Foundation; the Robert H. McCooey Memorial Cancer Research Fund; BZL Biologics Inc; and Millennium Pharmaceuticals Inc. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Bander NH, Nanus DM, Milowsky MI, et al: Targeted systemic therapy of prostate cancer with a monoclonal antibody to prostate specific membrane antigen (PSMA). Semin Oncol 30:667-677, 2003[CrossRef][Medline] 2. Bostwick DG, Pacelli A, Blute M, et al: Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: A study of 184 cases. Cancer 82:2256-2261, 1998[CrossRef][Medline]
3. Israeli RS, Powell CT, Fair WR, et al: Expression of the prostate-specific membrane antigen. Cancer Res 54:1807-1811, 1994 4. Wright GL Jr, Haley C, Beckett ML, et al: Expression of prostate-specific membrane antigen (PSMA) in normal, benign and malignant prostate tissues. Urol Oncol 1:18-28, 1995 5. Wright GL Jr, Grob BM, Haley C, et al: Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 48:326-334, 1996[CrossRef][Medline] 6. Sweat SD, Pacelli A, Murphy GP, et al: PSMA expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology 52:637-640, 1998[CrossRef][Medline]
7. Liu H, Rajasekaran AK, Moy P, et al: Constitutive and antibody-induced internalization of prostate-specific membrane antigen. Cancer Res 58:4055-4060, 1998
8. Rajasekaran SA, Anilkuman G, Oshima E, et al: A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Molec Biol Cell 14:4835-4845, 2003
9. Liu H, Moy P, Kim S, et al: Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res 57:3629-3634, 1997
10. Smith-Jones PM, Vallabahajosula S, Goldsmith SJ, et al: In vitro characterization of radiolabeled monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen. Cancer Res 60:5237-5243, 2000
11. Milowsky MI, Nanus DM, Kostaglou L, et al: Phase I trial of Y-labeled anti-PSMA monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 22:2522-2531, 2004
12. Smith-Jones PM, Vallabhajosula S, Navarro V, et al: Radiolabeled monoclonal antibodies specific to the extracellular domain of prostate-specific membrane antigen: Preclinical studies in nude mice bearing LNCaP human prostate tumor. J Nucl Med 44:610-617, 2003 13. Vallabahajosula S, Smith-Jones PM, Navarro V, et al: Radioimmunotherapy of prostate cancer in human xenografts using monoclonal antibodies specific to prostate specific membrane antigen (PSMA): Studies in nude mice. Prostate 58:145-155, 2004[CrossRef][Medline]
14. O'Donoghue JA, Bardies M, Wheldon TE: Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med 36:1902-1909, 1995 15. Mulligan T, Carrasquillo JA, Chung Y, et al: Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma. Clin Cancer Res 1:1447-1454, 1995[Abstract] 16. Alvarez RD, Partridge EE, Khazaeli MB, et al: Intraperitoneal radioimmunotherapy of ovarian cancer with 177Lu-CC49: A phase I/II study. Gynecol Oncol 65:94-101, 1997[CrossRef][Medline] 17. Meredith R, Alvarez RD, Partridge EE, et al: Intraperitoneal radioimmunochemotherapy of ovarian cancer: A phase I study. Cancer Biother Radiopharm 16:305-315, 2001[CrossRef][Medline]
18. Vallabhajosula S, Kuji I, Hamacher KA, et al: Radiolabeled J591 monoclonal antibody to PSMA, pharmacokinetics and biodistribution studies with 111In-J591 and 177Lu-J591. J Nuc Med 46:634-641, 2005 19. Bander NH, Trabulsi E, Kostakoglu L, et al: Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate-specific membrane antigen. J Urol 170:1717-1721, 2003[CrossRef][Medline] 20. Meredith RF, Khazaeli MB, Macey DJ, et al: Phase II study of interferon enhanced131I-CC49 in patients with prostate cancer. Clin Cancer Res 5:3254s-3258s, 1999 21. Slovin S, Scher H, Divgi C, et al: Interferon-gamma and 131I-CC49 in patients with prostate cancer. Clin Cancer Res 4:643-651, 1998[Abstract] 22. Knox SJ, Goris ML, Trisler K, et al: Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res 2:457-470, 1996[Abstract]
23. O'Donnell RT, DeNardo SJ, Yuan A, et al: Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer. Clin Cancer Res 7:1561-1568, 2001 24. O'Donnell RT, DeNardo SJ, Miers LA, et al: Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90Yttrium-DOTA-peptide-ChL6. Prostate 50:27-37, 2002[CrossRef][Medline] Submitted May 21, 2004; accepted October 12, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
