Dave Yamauchi

Phase II Trial of a Transplantation Regimen of Yttrium-90 Ibritumomab Tiuxetan and High-Dose Chemotherapy in Patients With Non-Hodgkin's Lymphoma

PURPOSE This phase II trial evaluated the safety and efficacy of combining yttrium-90 (90Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkins lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy. PATIENTS AND METHODS Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkins lymphoma received standard-dose 90Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM. RESULTS The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients. CONCLUSION Adding 90Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.

Pilot Trial Evaluating an 123I-Labeled 80-Kilodalton Engineered Anticarcinoembryonic Antigen Antibody Fragment (cT84.66 Minibody) in Patients with Colorectal Cancer

Purpose: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (VL-linker-VH-CH3; 80 kDa) that demonstrates bivalent and high affinity (4 × 1010 m−1) binding to carcinoembryonic antigen (CEA). The variable regions (VL and VH) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the CH3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab′)2 fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether 123I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. Experimental Design: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5–10 mCi (1 mg) of 123I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48–72 h. Surgery was performed immediately after the last nuclear scan. Results: Tumor imaging was observed with 123I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. 123I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9–65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. Conclusion: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as 111In.

Effects of allogeneic bone marrow transplantation on recipient bone mineral density: A prospective study

Allogeneic bone marrow transplant (BMT) recipients have many known risk factors for developing decreased bone mineral density (BMD) after transplantation. We performed a prospective sequential evaluation of BMD in the lumbar spine and nondominant hip using dual-energy x-ray absorptiometry (DEXA) in a cohort of 47 adult patients (median age, 43 years) who were undergoing radiation-based BMT for hematologic malignancies. Baseline DEXA studies were performed before BMT and repeated at 3 to 4 months, 6 to 8 months, and 12 to 14 months after BMT. The majority of patients (60%) had been minimally treated with combination cytotoxic chemotherapy, having received no more than 1 treatment regimen before BMT. Graft-versus-host disease prophylaxis consisted of cyclosporine in combination with either methotrexate or prednisone, or both. Mean lumbar spine and hip BMD were normal before BMT (spine: 1.01 g/cm2, z score = 96%; hip: 0.86 g/cm2, z score = 100%) and gradually decreased (spine: 0.98 g/cm2, z score = 94%; hip: 0.76 g/cm2, z score = 91%) at 12 to 14 months. These declines were statistically significant (P < .006 and < .002 for lumbar spine; P < .001 and < .001 for hip). In addition, the sharpest decline occurred during the first 6 months after BMT and was more marked in the hip than the lumbar spine. These data suggest that BMT adversely affects BMD in this patient population.

The two types of correction of absorbed dose estimates for internal emitters.

Two types of correction for absorbed dose (D̄) estimates are described for clinical applications of internal emitters. The first is appropriate for legal and scientific reasons involving phantom‐based estimates; the second is patient‐specific and primarily intended for radioimmunotherapy (RIT).

A Pretherapy Biodistribution and Dosimetry Study of Indium-111-Radiolabeled Trastuzumab in Patients with Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer

PURPOSE The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of (111)Indium ((111)In)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether (90)Y-MxDTPA-trastuzumab should be evaluated in subsequent clinical therapy trials. EXPERIMENTAL DESIGN Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4-8 mg/kg IV), followed 4 hours later by 5 mCi (111)In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days. RESULTS Eight (8) patients received (111)In-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with (90)Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi. CONCLUSIONS In summary, results from this study indicate that (90)Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to (111)In-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other (90)Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity.

High-dose radioimmunotherapy with yttrium 90 (90Y) ibritumomab tiuxetan with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous hematopoietic cell transplant (AHCT) for poor-risk or relapsed B-cell non-Hodgkin's lymphoma (NHL): Update of a phase I/II trial

6504 Background: A phase I/II trial investigated whether high-dose ibritumomab tiuxetan (Zevalin [Z]) can be safely combined with high-dose VP-16 40-60 mg/kg and CY 100 mg/kg as a conditioning regimen for AHCT. METHODS Patients undergo dosimetry study (day -21) with 5 mCi 111In-ibritumomab tiuxetan following 250 mg/m2of rituximab to confirm favorable biodistribution followed by (day -14) 40-100 mCi to deliver a target dose of 1000 cGy to highest normal organ and then VP-16 (day -4) and CY (day -2). Bone marrow biopsy is done on day-7 to estimate radiation dose and stem cells are reinfused when the radiation dose to reinfused cells is estimated to be < 5 cGy. RESULTS Between 5/00 and 11/03, 31 patients (17 M: 14 F), median age 51 (range, 25-59.6) with follicular (n=9), diffuse large B-cell (n=17) and mantle cell (n=5) were treated. Disease status at AHCT: 1stCR/PR=7, REL/IF = 14 and ≥2ndCR=10. Median number of prior chemo regimens was 2 (range, 1-6). All but two had received rituximab either alone (8), or in combination with chemotherapy (21). Six received VP-16 40 mg/kg while 25 received 60 mg/kg. The median dose was 70.8 mCi (range 36.6-105). The treatment was well tolerated with no transplant-related death. Mucositis, neutropenic fever and skin rash were the most common acute toxicities. All but one patient engrafted; median time to reach ANC > 500/μl and platelet > 20,000/μl was 10 days (range 8-17) and 19 days (range 12-123), respectively. There were 4 relapses at 3, 4, 12 and 24 months post AHCT. At a median follow-up of 21 months (range 1.4-43), the 2-year estimated OS and DFS is 93%(95% CI, 86-96%), and 80% (95% CI, 64-96%), respectively. CONCLUSION High-dose can be safely combined with high-dose VP-16 and CY without increase in transplant-related toxicity or delay engraftment. This novel preparative regimen is well tolerated and is effective in patients with refractory B-cell NHL. Further studies and longer follow-up are required to determine the curative potential of this regimen [Table: see text].

Truncation of blood curves to enhance imaging and therapy with monoclonal antibodies

Targeting of monoclonal antibody (Mab) to solid tumor sites is a function of the blood curve of activity versus time. It has been suggested that the blood curve be artificially reduced to approach zero so that the contrast between tumor and blood uptake is maximized. We analyzed tumor uptake as a function of the time tc of blood curve truncation. By using a convolution approach, we were able to find the optimal times for setting the blood curve to zero in either diagnostic or therapeutic animal examples. Two iodinated cT84.66 anti-CEA engineered fragments, diabody and minibody, were considered using previous data from nude mouse studies involving the LS174T colorectal tumor model. Figures of merit (FOMs) were used to compare ordinary and truncated blood curves and their associated tumor accumulations. Using a 1231 label, it was seen that the appropriate time for diagnostic truncation occurred when tumor uptake, as measured, was a maximum. The corresponding point for therapy (with 1311 as a label) was at infinite time. We also demonstrated that the use of traditional indices led to ambiguities in the choice of truncation times. The traditional therapy index, the ratio of the integral of the tumor uptake to the integral of the blood uptake, was found to be a numerical constant independent of tc. This ratio was proved to be the integral of the tumor impulse response function. Use of such convolution techniques to assess truncation of the perfused material is probably also applicable to multistep processes as well as to lesion targeting with other tumor-specific pharmaceuticals.

Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology

Standard-dose 90yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20+ non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.

Modification of a motel-type room to accommodate patients receiving radioiodine therapy: reduction of environmental exposure.

AbstractPatients receiving 131I-based therapies are generally restricted in leaving the medical institution. In the U.S., the U.S. Nuclear Regulatory Commission (U.S. NRC) has developed the rule that a ⩽7 mR h−1 reading at 1 m from the patient (or 33 mCi) is sufficient to allow unrestricted release. Because of home situations and other constraints, it is preferable that a patient-specific release level be determined by the radiation safety staff. Locally, the City of Hope has instituted a general release criterion of ⩽ 2 mR h−1 at 1 m. While contributing to a reduction in public exposure, this as low as reasonably achievable (ALARA) approach is difficult to justify on a cost basis due to the expense of maintaining the radioactive individual in a hospital room. Instead, it was determined that a motel-type room already on the campus be modified to allow the patient to remain on-site until at or below a locally permitted release level. By adding lead to the bathroom area and sealing the tile surfaces, the room may be converted for less than

SU‐E‐T‐288: Prediction of Initial Thyroid Therapy Clinical Exposure Rates Given the Amount of I‐131 Activity and the Patient Habitus

5,000. Daily cost for the patient is