Thema: News: Salvage radioimmunotherapy with I131-antitenascin-AB81C6

Journal of Clinical Oncology, Vol 24, No 1 (January 1), 2006: pp. 115-122

Salvage Radioimmunotherapy With Murine Iodine-131-Labeled Antitenascin Monoclonal Antibody 81C6 for Patients With Recurrent Primary and Metastatic Malignant Brain Tumors: Phase II Study Results

David A. Reardon, Gamal Akabani, R. Edward Coleman, Allan H. Friedman, Henry S. Friedman, James E. Herndon, II, Roger E. McLendon, Charles N. Pegram, James M. Provenzale, Jennifer A. Quinn, Jeremy N. Rich, James J. Vredenburgh, Annick Desjardins, Sri Guruangan, Michael Badruddoja, Jeanette M. Dowell, Terence Z. Wong, Xiao-Guang Zhao, Michael R. Zalutsky, Darell D. Bigner

From the Departments of Surgery, Medicine, Pathology, Radiology, and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC.


PURPOSE:
To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients.

PATIENTS AND METHODS:
In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy.

RESULTS:
With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis.

CONCLUSION:
In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Outcome for adults with primary malignant brain tumors remains unacceptable. Although temozolomide plus radiotherapy has recently been shown to improve outcome for newly diagnosed glioblastoma multiforme (GBM) patients,1 tumor progression occurs within 1 to 2 years in most patients. After recurrence, outcome is dismal due to ineffective salvage therapies.2 Most tumors recur at or adjacent to the site of origin indicating that failure to eradicate local tumor growth is a major factor contributing to poor outcome.3 For this reason, we have focused on augmenting local control to improve overall outcome by administering tumor-associated radiolabeled monoclonal antibodies (mAbs) directly into spontaneous tumor cysts, surgically created resection cavities (SCRCs), the intrathecal space, and solid tumors.4-7

Tenascin, an extracellular matrix hexabrachion glycoprotein, is expressed ubiquitously in high-grade gliomas and in breast, lung, and squamous cell carcinomas, but not normal brain.8,9 81C6, a murine immunoglobulin G2b mAb that binds an epitope within the alternatively spliced fibronectin type III region of tenascin,9-11 specifically reacts with tenascin-expressing tumors12 and can delay tumor growth and induce apparent cures in flank and intracranial xenograft models.13-15 Prior phase I studies established the maximum-tolerated dose (MTD) of iodine-131-labeled murine 81C6 (131I-m81C6) mAb injected into the SCRC of patients with newly diagnosed and recurrent malignant brain tumors to be 120 and 100 mCi, respectively.5,6 In a subsequent phase II study for newly diagnosed patients, administration of 120 mCi of 131I-m81C6 followed by conventional radiotherapy and chemotherapy achieved median survivals of 87 and 79 weeks among all patients (n = 33) and those with GBM (n = 27), respectively. Toxicity was limited to reversible hematologic events in 27% of patients and neurologic deficits in 15% of patients.7 We now report a phase II study using 100 mCi of 131I-m81C6 in adults with recurrent malignant brain tumors.

Patient Eligibility and Treatment

Eligible patients had a confirmed histologic diagnosis of recurrent supratentorial primary malignant tumor and were candidates for resection. Patients with tumors that were infratentorial, diffusely infiltrating, multifocal, or that had intraventricular access or subependymal spread were ineligible. Histopathologic samples from initial surgery were centrally reviewed at Duke University Medical Center (DUMC), and underwent immunoreactivity testing for tenascin as previously described.7 Patients were required to be older than 3 years, have a Karnofsky performance status (KPS) of 60%, and satisfy additional, previously described, eligibility requirements.7

Patients underwent a gross total resection (GTR) and placement of a Rickham reservoir and catheter into the SCRC. Contrast-enhanced magnetic resonance imaging (MRI) was obtained within 48 hours of resection to confirm that residual tumor did not extend more than 1.0 cm beyond the SCRC margin. Rickham catheter patency and SCRC integrity were confirmed by injecting technetium-99m (99mTc) -labeled albumin or diethylenetriamine pentaacetic acid into the Rickham reservoir and obtaining gamma camera images immediately, then 4 and 24 hours later. Patients with subgaleal or subarachnoid leakage were not eligible. A baseline [18F]fluorodeoxyglucose positron emission tomography (FDG PET) scan was obtained postresection. Before and 30 to 120 days after treatment, patients were tested for circulating antibodies to m81C6 as previously described.16

Eligible patients received four drops of a saturated solution of potassium iodine and 75 µg of liothyronine sodium (Cytomel; SmithKline Beecham, Pittsburgh, PA) daily from 48 hours before to 16 days after 131I-m81C6. The Rickham reservoir was accessed with a 25-gauge needle using sterile technique and up to 6 mL of SCRC cyst fluid was removed when possible. A volume of 6 mL of 81C6 mAb (20 mg) labeled with 100 mCi of 131I was injected into the reservoir. The reservoir and catheter were then flushed with the previously aspirated, sterile SCRC fluid. Patients remained in radiation isolation until the whole-body retention of 131I was 30 mCi, as measured by a cross-calibrated radiation survey meter. Before discharge, a brain MRI was performed and radionuclide gamma imaging as well as serial blood samples were obtained to assess the biodistribution of 131I.

The DUMC Investigational Review Board approved this study. Investigational review board-approved informed consent was obtained from each patient.

Antibody Production and Labeling

The 81C6, grown in athymic mice ascites, was purified over a Sepharose-staphylococcal protein-A (Amersham Biosciences Corporation, Piscataway, NJ) column followed by polyethylenimine ion exchange chromatography. US Food and Drug Administration manufacturing and testing guidelines for mAb products were followed for each clinical batch.17 The 81C6 was radiolabeled using a modified Iodo-Gen procedure (Pierce Chemical Co, Rockford, IL). All preparations had 75% immunoreactivity, with 95% of the label eluting as immunoglobulin G on high-pressure liquid chromatography and precipitating with trichloroacetic acid.

Pharmacokinetics and Dosimetry

Absorbed dose calculations for the SCRC, whole body, and bone marrow were performed using a serial, two-compartment system to model 131I-m81C6 pharmacokinetics, where the SCRC and the whole body (not including the SCRC) were assumed to be the first and second compartments, respectively.18 Postoperative MRI images (2-mm-thick slices, noninterleaved, 0-mm spacing) were used to generate a three-dimensional reconstruction of the head and SCRC (VoxelView 2.5.4; Vital Images, St Paul, MN). The calculated SCRC volume was used to estimate the initial SCRC activity, where a uniform activity concentration was assumed. Depth-dose calculations of the SCRC interface, 2-cm-thick margin, and normal brain were then performed.18

Toxicity and Response Determinations

After 131I-m81C6, patients were monitored continually with initial follow-up within 1 month of treatment and CBCs were monitored weekly for 8 weeks. Adjuvant chemotherapy was prescribed for 1 year beginning approximately 4 weeks after 131I-m81C6. Because of variability in chemotherapy regimens administered before study enrollment, chemotherapy after 131I-m81C6 was prescribed on an individualized, best clinical management basis using standard dosing schedules of conventional salvage chemotherapeutics such as temozolomide, lomustine, irinotecan, and etoposide. Patients were re-evaluated before chemotherapy was initiated and every 8 to 12 weeks during chemotherapy. Evaluations continued every 3 months for year 1, every 4 months for year 2, and biannually thereafter. At each evaluation, a complete physical examination, KPS rating, CBC, biochemical profile, and contrast MRI were performed. FDG PET scans were obtained as clinically indicated. Thyroid function was assessed within 1 to 2 months of 131I-m81C6 and every 6 to 12 months thereafter. Human antimouse antibody (HAMA) titers were measured within 6 months of 131I-m81C6.

National Cancer Institute Common Toxicity Criteria, version 2.0 (Bethesda, MD), were used to score toxicity. Although seizures were recorded, they were not considered an indication of neurotoxicity because of their expected frequency in this disease setting. The precise etiology of neurotoxicity following 131I-m81C6 was difficult to define because neither clinical features nor radiographic findings reliably distinguished recurrent tumor from treatment-induced necrosis. Although stereotactic biopsy is limited by volume sampling, it remains the definitive diagnostic tool of focal brain lesions. Therefore, the etiology of observed neurotoxicity was based on stereotactic biopsy whenever possible.

Progressive disease was defined by more than 25% increase in the enhancing tumor cross-sectional area or radiographically new lesions that were also hypermetabolic on FDG PET scan; clinical deterioration and a more than 25% increase in enhancing tumor or radiographically new lesions; or biopsy-proven recurrent tumor.

Statistical Analysis

In this single-stage phase II study of recurrent malignant brain tumor patients, 1-year survival after 131I-m81C6 was the primary end point. Our design provided 90% power at the .1 significance level to detect a 1-year survival of 40% to 60%, based on outcome achieved among recurrent GBM patients treated with iodine-125 (125I) brachytherapy.19

The method of Kaplan and Meier20 was used to estimate survival distributions measured from 131I-m81C6 administration to death or last contact. Subgroup differences in survival were assessed with log-rank tests.21 The Cox proportional hazards model22 was also used to investigate various prognostic factors, including age (< 50 v 50 years), KPS (< 90 v 90), SCRC volume (< 14 v 14 cm3), and SCRC dose (< 40 v 40 to 48 v > 48 Gy). Logistic regression was used to examine the effect of cavity size as well as 131I-m81C6 absorbed doses to the 2-cm SCRC interface on toxicity.


Patient Characteristics

The study population included 43 patients treated at DUMC between October 1996 and October 2003 (Table 1). Approximately 5% of screened patients were excluded because of subgaleal leakage on the postoperative flow study. This problem appeared to relate to SCRC proximity to the ventricular system rather than SCRC size.

Forty-one patients received 100 mCi of 131I conjugated to 20 mg of 81C6 mAb. Two patients had SCRC volumes less than 5 mL and received a proportionally decreased dose of 131I-m81C6 (67 and 75 mCi, respectively). After 131I-m81C6, 25 patients (58%) received systemic chemotherapy. Three patients, who had not received external-beam radiotherapy (XRT) before 131I-m81C6, underwent XRT after 131I-m81C6. Five patients remain alive and 38 have died.

HAMA immunoassays, obtained on 34 patients within 2 to 26.1 weeks of treatment, were positive in 27 of 34 patients (79%; Table 2). No observed toxicity was related to HAMA reactivity.

Dosimetry Results

Although a separate manuscript describing dosimetry findings of this study is in preparation, Table 3 provides an overview of the dosimetry results per patient. As previously demonstrated,6 131I-m81C6 retention in the SCRC and in the whole body varied significantly although the average absorbed dose to the 2-cm-thick cavity interface was 46 Gy (range, 18 to 186 Gy).

Toxicity

Toxicity was limited primarily to reversible hematologic and neurologic events (Table 4). Grade 3 or 4 hematologic toxicity developed within 8 weeks of 131I-m81C6 in 10 patients (23%) and resolved in all but one patient within a median of 25 days (range, 5 to 76 days). Six patients received platelet transfusions and two patients received granulocyte colony stimulating factor support. One patient with available, stored, autologous peripheral-blood stem cells received a peripheral-blood stem cell reinfusion with full hematologic recovery. One heavily pretreated patient, who developed grade 4 thrombocytopenia, was noncompliant with follow-up. Acute hematologic toxicity did not correlate with either prior chemotherapy administration or radiation exposures to the whole body or SCRC (Table 3).

Five patients (12%) developed grade 3 neurotoxicity within 4 months of 131I-m81C6, including two patients with headache, one patient with aphasia, and two patients with weakness. These events resolved completely either spontaneously or with corticosteroids. One patient with pre-existing grade 2 hemiparesis worsened to grade 3 weakness within 2 weeks of 131I-m81C6 and did not improve despite corticosteroid and hyperbaric oxygen therapies. There were no grade 4 neurologic events. All other neurologic events were attributable to tumor progression.
Additional significant toxicities included thrombosis (grade 3, n = 5 [12%]; grade 4, n = 4 [9%]), wound infection (grade 3, n = 5 [12%]), and hypothyroidism (grade 2, n = 2 [5%]).

Biopsies and Reoperation

Nineteen (44%) patients underwent surgical procedures after 131I-m81C6, including 15 stereotactic biopsies and four craniotomies. Six biopsies (40%) showed gliosis and necrosis, and nine biopsies (60%) demonstrated recurrent tumor. Recurrent tumor was documented in the four patients who underwent repeat craniotomy.

Response/Survival Data

With a median follow-up of 172 weeks, five patients (12%) are alive, including three (37.5%) with anaplastic astrocytoma/anaplastic oligodendroglioma (AA/AO) (median follow-up, 161 weeks) and two (6%) with GBM/gliosarcoma (GS; 100.3- and 123-week follow-up, respectively). Median overall survival (OS) for all patients, those with GBM/GS, and those with AA/AO, was 68.6 weeks (95% CI, 38.8 to 98.0 weeks), 63.9 weeks (95% CI, 38.8 to 90.0 weeks), and 98.6 weeks (95% CI, 27.8 to infinity), respectively (P for GBM/GS v AA/AO = .11; Fig 1). One-year survival probability for all patients, those with GBM/GS and those with AA/AO was 60% (95% CI, 46 to 76), 59% (95% CI, 44 to 78), and 63% (95% CI, 37 to 100), respectively.

Kaplan and Meier curves were generated for each variable (age, KPS, SCRC size, and SCRC dose) subgroup. None of the variables had a significant relationship with patient survival (Table 5), although this analysis was limited by our sample size. Established prognostic variables, including age younger than 50 years and KPS more than 90%, trended toward significance. Similarly, median OS was two-fold higher among patients who received a 40- to 48-Gy SCRC dose compared with those who received less than 40 Gy.

Progressive disease occurred at the primary tumor site in all patients except two patients with contralateral hemisphere progression; one patient with progression in a noncontiguous, isolateral site; and the patient with metastatic adenocarcinoma who experienced disease progression at both the original brain site and leptomeninges.

The primary objective of the current phase II study was to assess the impact on survival of 100 mCi of 131I-m81C6 administered into the SCRC of recurrent malignant brain tumor patients. A secondary objective was to assess further the feasibility and toxicity of this approach among such patients. Patients were previously treated with XRT (93%) and/or chemotherapy (51%). After 131I-m81C6, most patients received systemic chemotherapy (58%); however, 35% received no additional therapy. Median OS was 64 and 99 weeks for recurrent GBM/GS (n = 34) and AA/AO (n = 8) patients, respectively, and 60% of all patients were alive at 1 year.

We demonstrated previously that 131I-m81C6 administered into the SCRC of newly diagnosed malignant glioma patients is well tolerated in a phase I study that established the 131I-m81C6 MTD to be 120 mCi. Delayed neurologic toxicity was dose limiting, and the only significant non-neurologic toxicity was hematologic, consisting of grade 3 or grade 4 events in 12% and 2.5% of patients, respectively.6 Despite the dose-escalation design, the median OS for all patients and those with GBM was 79 and 69 weeks, respectively. In a follow-up phase II study in which newly diagnosed malignant glioma patients received 120 mCi of 131I-m81C6 followed by conventional XRT and systemic chemotherapy, the median OS was 89 and 79 weeks for all patients and those with GBM, respectively.7 Only two patients (2.7%) combined from our phase I and II trials required debulking resection for radionecrosis.

Similarly, we established the 131I-m81C6 MTD of among recurrent malignant brain tumor patients to be 100 mCi in a prior phase I study. Dose-limiting toxicity was neurologic. The median survival for all patients (n = 34) and those with recurrent GBM (n = 26) was 60 and 56 weeks, respectively.5

This study confirms that 100 mCi of 131I-m81C6 administered into the SCRC is well tolerated among recurrent malignant glioma patients. Acute, primarily reversible, hematologic toxicity was the most common significant adverse event (23% of patients). Acute neurologic toxicity developed in six patients (12%) and resolved spontaneously or after short-term corticosteroid administration in all but one patient. No patients required surgery to debulk radiation necrosis. In contrast, up to half of patients treated with alternative strategies to boost radiation therapy to the primary tumor bed, including stereotactic radiosurgery (SRS) and the implantation of 125I-radiolabeled beads (125I brachytherapy), may require secondary craniotomy to debulk radionecrosis.23-33

The median OS achieved in this study compares favorably with that reported for other salvage systemic therapies. The median OS for patients with GBM treated with temozolomide at first relapse was approximately 32 weeks.34 Similarly, the median OS achieved with eight consecutive investigational salvage therapies for recurrent malignant glioma patients was 47 weeks for patients with grade 3 anaplastic gliomas and only 25 weeks for those with GBM.2 Furthermore, our results compare favorably with those achieved with alternative strategies to boost radiation delivered to the primary tumor site, including SRS and 125I-brachytherapy.19,23-33 Shrieve et al30 reported median OS of 46 and 41 weeks for patients with recurrent GBM treated with 125I-brachytherapy and SRS, respectively, whereas Larson reported a median OS of 52 weeks for recurrent GBM patients who received 125I-brachytherapy after a GTR.19 The latter group most likely represents the closest comparative group to the GBM patients treated during the current study. Finally, the results of the current trial also compare favorably to the administration of interstitial chemotherapy using carmustine-loaded polymers (Gliadel; Guilford Pharmaceuticals Inc, Baltimore, MD). Among 110 treated patients, the median survival was 31 weeks.16

The encouraging results of this study must be interpreted cautiously because of several potential limitations. Specifically, this was a single-institutional effort involving a modest number of patients with overall favorable KPS who underwent GTR. This study was conducted with a fixed dose of 131I-m81C6 (100 mCi) as required by the US Food and Drug Administration. Perhaps the most important lesson learned from this approach is that fixed millicurie dosing leads to a wide range of absorbed radiation doses to the 2-cm SCRC margin. For example, the absorbed dose to the 2-cm SCRC margin in our prior phase II study in which newly diagnosed patients received a fixed, 120-mCi 131I-m81C6 dose, ranged between 2 and 119 Gy.7 Similarly, the administration of a fixed 100-mCi 131I-m81C6 dose in the current study resulted in a 2-cm SCRC margin dose between 18 and 186 Gy.

On the basis of analysis of the relationship between progressive tumor and radionecrosis, we have determined that 44 Gy (± 10%) is the optimal dose to the 2-cm SCRC margin. Specifically, patients who receive less than 44 Gy have a higher rate of tumor recurrence, whereas those who receive significantly more than 44 Gy have a higher rate of radionecrosis.18 The findings of the current study support this relationship, although they require validation in a larger trial designed to assess this hypothesis. Specifically, the low rate of neurotoxicity observed in this study most likely reflects that the majority of patients received less than 48 Gy. Furthermore, patients who received 40 to 48 Gy had a two-fold higher OS compared with those who received less than 40 Gy. The variables determining absorbed dose are SCRC volume, SCRC residence time, and administered dose. One can calculate SCRC residence time from a dosimetry study in which a small dose of 123I- or 131I-labeled 81C6 is administered before a therapeutic 131I-m81C6 dose. By taking into account SCRC volume, measured on pretreatment MRI, one can then calculate a patient-specific 131I-m81C6 therapeutic dose, to achieve an absorbed radiation dose of 44 Gy to the 2-cm SCRC margin consistently. Our ongoing trial, as well as planned multi-institutional, randomized phase III studies in both newly diagnosed and patients with recurrent disease, will incorporate patient-specific dosimetry planning and 131I-m81C6 dosing, as well as standardized chemotherapy.35

Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO´s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other

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Conception and design: David A. Reardon, R. Edward Coleman, Henry S. Friedman, James E. Herndon II, James M. Provenzale, Michael A. Badruddoja, Michael R. Zalutsky, Darell D. Bigner
Provision of study materials or patients: David A. Reardon, R. Edward Coleman, Allan H. Friedman, Henry S. Friedman, Charles N. Pegram, Jennifer A. Quinn, James J. Vredenburgh, Annick Desjardins, Terence Z. Wong, Michael R. Zalutsky, Darell D. Bigner

Collection and assembly of data: David A. Reardon, Gamal Akabani, Roger E. McLendon, Jennifer A. Quinn, Jeremy N. Rich, Michael A. Badruddoja, Xiao-Guang Zhao

Data analysis and interpretation: David A. Reardon, Henry S. Friedman, James E. Herndon II, Jeremy N. Rich, Jeanette M. Dowell, Darell D. Bigner

Manuscript writing: David A. Reardon, James E. Herndon II, James M. Provenzale, Sri Guruangan, Michael R. Zalutsky, Darell D. Bigner

Final approval of manuscript: David A. Reardon, Gamal Akabani, R. Edward Coleman, Allan H. Friedman, Henry S. Friedman, James E. Herndon II, Roger E. McLendon, Charles N. Pegram, James M. Provenzale, Jennifer A. Quinn, Jeremy N. Rich, James J. Vredenburgh, Annick Desjardins, Sri Guruangan, Jeanette M. Dowell, Terence Z. Wong, Michael R. Zalutsky, Darell D. Bigner

Supported by National Institutes of Health Grants No. 1-P50-CA108786-01, NS20023 and CA11898 and by Grant No. MO1 RR 30 through the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.


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Reardon DA, Akabani G, Friedman AH, et al: Phase II study of 131-iodine-labeled antitenascin murine monoclonal antibody 81C6 (M81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors, in Bigner DD (ed): Ninth Annual Meeting of the Society of Neuro-Oncology. Toronto, Ontario, Canada, Duke University Press, 2004, p 381
Submitted July 11, 2005; accepted October 14, 2005.


© 2006 American Society of Clinical Oncology


Address reprint requests to David A. Reardon, MD, Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Box 3624, Durham, NC, 27710; e-mail: reard003@mc.duke.edu