Inr J Radmion Oncology Binl. Phrr. Vol Prmted m the U.S.A. All rights resened.

22. pp.

225-230 CopyrIght

0360.3016192 $5.00 + .Ml 0 1991 Pergamon Press plc

??Rapid Communication

MALIGNANT ASTROCYTOMAS TREATED WITH IODINE-125 LABELED MONOCLONAL ANTIBODY 425 AGAINST EPIDERMAL GROWTH FACTOR RECEPTOR: A PHASE II TRIAL LUTHER W.

BRADY, M.D.,’

CURTIS MIYAMOTO,

M.D. ,I DAVID V. Woo,

PH.D.,’

MICHAEL RACKOVER, P.A. -C., ’ JACQUELINE EMRICH, M. S . , ’ HANS BENDER, M.D., SIMIN DADPARVAR, M.D.,’

ZENON STEPLEWSKI, M.D.,*

PERRY BLACK, M.D. ,3 BETTE LAZZARO, M.D. JOSEPH NIEVES, M.D.,

HILARY KOPROWSKI, M.D.,*

,* SOMNATH NAIR, M.D.

’ MARK MORABITO,

M.S.,



,3 THOMAS MCCORMACK,

’ JEFFREY ESHLEMAN, B.A.

M.D.

,3



‘Department of Radiation Oncology, Hahnemann University, Philadelphia, PA, ‘The Wistar Institute, Philadelphia, PA, ‘Department of Neurosurgery, Hahnemann University, Philadelphia, PA Twenty-five patients with primary presentation

of malignant astrocytoma, astrocytoma with anaplastic foci, and glioblastoma multiforme were treated with surgical resection and definitive radiation therapy followed by intravenous or in&a-arterial administration of Iodine-125 labeled monoclonal antibody-425, which binds specifically to human epidermal growth factor receptor. The patients presented with primary untreated disease, positive contrast enhanced computed tomography scans of the brain, and compatible clinical symptoms. In this Phase II clinical trial, the patients had surgical debulking or biopsy followed by definitively administered external beam radiation therapy and one or multiple doses (35 to 90 mCi per infusion) of radiolabeled antibody. The total cumulative doses ranged from 40 to 224 mCi. The administrations of the radiolabeled antibody were performed in most cases 4-6 weeks following completion of the primary surgery and radiation therapy. Ten patients had astrocytoma with anaplastic foci and 15 had glioblastoma multiforme. No significant life-threatening toxicities were observed during this trial. At 1 year 60% of the patients with astrocytoma with anaplastic foci or glioblastoma multiforme are alive. The median survival for both groups was 15.6 months. Monoclonal antibody, notherapy, Human.

Epidermal growth factor, Iodine-125,

High grade astrocytoma,

Brain neoplasm,

Immu-

causing down regulation of the EGFr without stimulation of tyrosine kinase activity. Rakowicz-Szulczynska et al. (23) suggest that there is a specific nuclear component that directly binds the 425 antibody. Epidermal growth factor receptors are found in high concentration on a majority of high grade gliomas, but, infrequently, on normal brain (17, 28). These characteristics make the 425 antibody a potential effective means of delivering 1-125 into malignant astrocytomas. Astrocytoma with anaplastic foci (AAF) and Glioblastoma Multiforme (GBM) have a poor prognosis despite aggressive and often novel therapies. In 1991, the American Cancer Society estimates that 16,700 new cases of brain and CNS tumors will be diagnosed, resulting in a projected death rate of 11,500 (1). Of these, a significant number will be malignant astrocytomas and the majority (60-80%) will be high grade. The first treatment is often surgical re

INTRODUCTION

Radioactive iodine- 125 is a highly effective therapeutic agent (5, 6, 8) when internalized into tumor cells. The decay is mostly by electron capture (93%) emitting a cascade of Auger electrons and low energy photons (3.8-31 kev). It has a high linear energy transfer (LET) that decreases sublethal and potentially lethal damage repair and is less affected by hypoxia and cell cycle changes. Subcellular damage in chromosomes by I-125 labeled nucleotide precursors has been documented (4, 6, 13). The monoclonal antibody-425, which was developed at the Wistar Institute (Philadephia, PA) using the A-431 cell line, binds to human epidermal growth factor receptors (EGFr). It is an IgG 2a and its properties have been previously described (20). When bound to the membrane-receptor complex, it becomes internalized with the receptor Work supported in part by the Mary L. Smith Lead Trust, the Brady Cancer Research Institute, and the American Cancer Society, Philadelphia, PA. Reprint requests to Luther W. Brady, Department of Radiation Oncology, Hahnemann University, Philadelphia, PA 19102.

- Work supported in part by the Mary L. Smith Lead Trust, the Brady Cancer Research Institute, and the American Cancer Society, Philadelphia, PA. Accepted for publication 12 September 1991.

Acknowledgements

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I. J. Radiation Oncology ??Biology ??Physics

section. Unfortunately, 50% of these patients will die from disease at 6 months, and almost 100% at 2 years (3). Postoperative radiation therapy has improved these results and a dose response has been observed. Salazar (24) reported median survivals at 56, 42, and 30 weeks with postoperative doses of 70-80 Gy, 50-65 Gy, and 50-55 Gy, respectively. The addition of chemotherapy has been of little benefit. The Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) published the results of a combined trial (RTOG 74-01 and ECOG 137) in 1983 (9). This compared a 60 Gy whole brain control arm with 60 Gy to the whole brain followed by a 10 Gy boost, methyl CCNU, and DTIC or BCNU. The results were not significantly different between the arms. Brachytherapy has been employed for small lesions with promising results. However, few patients are candidates for this mode of therapy. Altered fraction schemes have also been used. The RTOG has an ongoing trial (90-01) comparing hyperfractionation (1.2 Gy per fraction twice daily to 72 Gy) and conventional fractionation (2 Gy per fraction to 60 Gy) plus BCNU. We have previously published our Phase I treatment results for recurrent malignant gliomas. No significant toxicities were observed (7). The average survival of these patients was 8 2 6.6 months. The objectives of the Phase II clinical trial was to evaluate the effects of systemically administered (intravenous or intra-arterially) I- 125 labeled monoclonal antibody-425 as an adjuvant to primary treatment for patients with AAF or GBM. EXPERIMENTAL

METHODS

Monoclonal antibod) The 425 monoclonal antibody used murine IgG 2a derived from the A431 carcinoma cell line (20). The antibody Wistar Institute and supplied to us in a free solution.

in these studies is a human epidermoid was produced at the sterile and pyrogen-

Radioiodination To provide sufficient quantities of I-125 labeled antibody for these studies, methods were developed for producing constant high specific activity material. The radioiodination was performed in a closed system glove box with HEPA filtered air and activated charcoal cannisters to prevent release of the radioiodine into the room. The Iodogen method (11, 12) was used for radiolabeling. Test tubes were coated with 312 pg of Iodogen by evaporation of 0.625 ml of a chloroform solution containing 0.5 mg/ml of Iodogen. The 425 monoclonal antibody was added in a phosphate buffered saline solution (0.1 M at pH 7.0) containing 2 mg of the antibody. This was immediately followed with the addition of 25 mCi of Na I-125 (100 mCi/ml) to the reaction tube. The tube was gently shaken and the iodination allowed to proceed for 10 min at

Volume 22, Number I, 1992 Table 1. Patient characteristics

# of Patients Male Female Average Age Age Range Mean Karnofsky (KPS) Karnofsky Range

AAF

GBM

Total

10 8 2 45 I I-70 80 60-100

15 6 9 54 27-68 80 60-90

25 14 I1 50 I l-70 80 60-100

temperature. The reaction was terminated with the addition of 0.5 ml of an ascorbic acid solution ( 10 mg/ml). The radioiodinated protein was then passed through a gel column (G25, PD-lo), which was prewashed with 15 ml of a sterile 1% HSA saline solution. The final product was eluted off the column with 3.5 ml of the HSA saline solution. After filtering the product through a 0.22 micron filter into a sterile vial, the final radioactive concentration was about 4 mCi/ml. Serial dilutions of the final product were made and assayed for their radioactivity in a multichannel analyzer to determine the exact radioactive concentration. Radiolabeling yields averaged about 85-95s per 25 mCi of I-125 activity. Instant thin layer chromatography (developed in saline solution) indicated less than 1% free iodide. The immunoreactivity was determined by the method of Lindmo and Boven (18). Final HPLC (High Performance Liquid Chromatography) analysis (gel filtration using PBS) indicated a single protein peak with no evidence of aggregates. The I- 125 labeled-425 monoclonal antibody product was used within 24 hr after labeling. However, TLC (Thin Layer Chromatography) analysis of the I-125 labeled-425 indicated less than 1% free iodide between 24 and 96 hr. room

Patient selection Patients enrolled into this Phase II trial had presentations of primary malignant astrocytomas, AAF or GBM. All patients had received no prior treatment and were accepted after appropriate consent (Table I). All patients had an appropriate workup including history, physical examination, laboratory studies, computed tomography, and/or magnetic resonance imaging of the brain. Patients had surgical debulking or biopsy and definitive postoperative radiation therapy. A total of 25 patients with malignant astrocytomas were treated, 10 with AAF and 15 with GBM (Tables 1 and 2). The average age was 50 years with the range being 11 to 70 years. Five patients were under 40 years of age (3 AAF, 2 GBM), 13 patients between 40 and 59 years (6 AAF, 7 GBM), while seven patients were sixty years of age or above (1 AAF, 6 GBM). The Kamofsky Performance Status (KPS) at presentation to our department ranged from 60 to 100 with an average Kamofsky score of 80.

Malignant astrocytomas ??L. W.

227

BRADY et al.

Table 2. Summary of treatments AAF

GBM

Total

8 2 0

5 8 2

13 IO 2

Therapy I. Surgery Biopsy Debulking Complete Resection

2

Il. Radiation Therapy Mean Total Dose Range Ill. Average Total mCi

61 Gy 62 Gy 60 GY 54465 Gy 45-65 Gy 45-65 Gy 141 mCi 158 mCi 151 mCi

Dose of l-125 labeled-425

30. 20. 10, “.

0

i

i

9

i2

is

is

ItDlTHS

Infusion procedure Patients were treated on an outpatient basis. The radioactive antibody solution in a volume of 15-20 ml was administered using a shielded syringe injection system. Appropriate and proper care was given to the administration of the material to prevent spillage. The infusion rate was 1.5-2.0 ml/min. After the infusion had been completed, the injection syringe was back flushed with saline and the infusion catheter flushed with 25 ml of saline. In all cases radioactivity was immediately detected in the head at the onset of the injection procedure using a hand held Geiger-Mueller counter. This confirmed that the infused dose reached the brain. After injection, the catheter was removed and the patient returned to the waiting room. In the absence of any reaction, patients receiving intravenous injections were allowed to leave after 2 hr and those receiving intra-arterial injections after 4 hr. Ideally, the first antibody administration was carried out 3-4 weeks after completion of the definitively administered external beam radiation therapy and repeated on a 7-14 day interval for three injections. The dose at each injection was 35-90 mCi (average dose 50 mCi) for a total of 40224 mCi (average total dose 151 mCi) for the complete treatment regimen. Standard Lug01 potassium iodide solution was given 24-36 hr prior to the treatment with the antibody to block the thyroid from taking up disassociated radioactive iodine. Complete blood counts with differentials and biochemical profile were routinely obtained prior to and after treatment and repeated at follow-ups. Blood specimens were drawn for determination of Human Antimouse Antibody (HAMA) which may alter the pharmocokinetics of the treatment regimen. No significant changes attributable to the antibody infusion were observed in the complete blood counts with differentials or biochemical profiles. Some patients did, however, have changes compatible with steroid use such as elevations in glucose levels. RESULTS The radiolabeling of large quantities of I-125 labeled425 was efficient and simple resulting in high yields and

Figure 1. Actuarial survival for patients with Grade Ill astrocytomas treated adjuvantly with EGF-425-l”5.

immunoreactive antibody. Routine 25 mCi batch sizes resulted in 20-24 mCi of final radiolabeled product. The specific activity of the I-125 labeled-425 was calculated to be lo-15 mCi/mg. At this specific activity, there was 0.7 to 0.9 I-125 atoms per molecule. This procedure was repeated numerous times to provide quantities of up to 200 mCi of radiolabeled product. Surgical biopsy (13 patients) or debulking (12 patients) was carried out on all patients. Postoperative radiation therapy was administered in all cases with a mean dose of 61 Gy delivered in 6.5 weeks. Most patients were treated initially with parallel opposed large fields followed by cone down fields at 45-50 Gy. The average total doses can be seen in Table 2. The average total dose administered of the I-125 labeled-425 antibody was 15 1 mCi. At 1 year, 60% of patients continued to survive and at 18 months 48% continued to survive. Of the patients under the age of 40, four out of five (80%) are still alive with an average follow-up of 8 months. For the group 60 years or above, all but one patient was followed to death with the average survival of the deceased patients being 9.3 months (one patient continues to survive at 21 months). The 18 month actuarial survival rates for patients (both AAF and GBM) ages < 40, 40-60, and 2 60 were 60.0%, 30.8%, and 21.4%, respectively. The projected median survival was 15.6 months. In the 10 patients with AAF, eight were male and two were female. Four of these patients continue to survive while six patients have died. Of the four patients who continue to survive, their mean survival is 21 months with the range being 11 to 35 months. This includes the only two patients to have debulking surgery. At one year, 60% of the AAF patients continued to survive (Fig. 1 - survival graph). The projected median survival was 15.6 months. The KPS ranged from 60 to 100 with the average being 80. In the 15 patients with GBM, six were male and nine were female. Of this group, seven patients continue to survive and eight patients have died. Again, 60% of patients

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J. Radiation Oncology 0 Biology 0 Physics

IOO-

90. 80. 5

70.

i 60. I ; 50. L 40. 2

30. eo10. 01 0

3

6

9

12

15

18

NONTHS

Figure 2. Actuarial survival for patients with Grade IV astrocytomas treated adjuvantly with EGF-425-I”5.

were alive at 1 year (Fig. 2 - survival graph). The projected median survival was 15.6 months. KPS ranged from 60 to 90 with the average being 80. The treatment with I-125 labeled-425 was well-tolerated with a minimum of side effects. No toxicities were observed after the first few hours following the injection. Subsequent infusions of the antibody, as a part of the primary treatment regimen, did not show overt immunologic or toxic reactions.

DISCUSSION Adult patients with high grade astrocytomas have a high failure rate after surgical resection. Adjuvant radiation therapy has improved survival, but the vast majority of patients continue to fail. Chemotherapy adds very little to local control or survival (9). Interstitial brachytherapy with or without hyperthermia is being explored at this time (15). Unfortunately, many patients are not candidates for this procedure, and new treatment approaches are needed. One approach is to specifically deliver a radioisotope to the tumor utilizing monoclonal antibodies. We have previously presented (19), but have not published, a study which indicates that nuclear imaging carried out in selected patients presenting with malignant gliomas shows positive localization after injection of Indium’ ’‘-425 antibody. The localization of radioactivity 3 days after injection indicated that uptake of the Indium’ ” radionuclide was due to the 425 antibody, which was capable of diffusing across the blood brain barrier at the site of the tumor. The localization at the tumor site due to specific antibody-antigen (425 binding to EGF receptor) interaction was not determined during these preliminary imaging studies. The question of whether the antibody could diffuse into a tumor within the brain compartment was answered, which was a justification for the I-125 labeled-425 therapy trials. We have previously published our experience treating patients with recurrent, malignant astrocytomas with I- 125

Volume 22, Number I, 1992 labeled-425 monoclonal antibody alone (7). In that study 15 patients were treated with one to three intra-arterial infusions. The total dose was 25 to 130 mCi. No significant life threatening reactions were observed. The average survival time from antibody treatment was 8 -+ 6.6 months. We concluded that this therapy alone was probably not adequate and its use in the adjuvant setting should be evaluated. This study reports our initial experience with the adjuvant treatment of malignant astrocytomas (AAF and GBM) with I-125 labeled-425 monoclonal antibody against the epidermal growth factor receptor. All patients received postoperative radiation therapy prior to receiving the radiolabeled 425. It has recently been shown that radiotherapy enhances breakdown of the blood brain barrier (22). In one study, 30-40 Gy caused an average increase in the penetration of Tc-99, of 24.7% in the normal brain and 74.7% in the tumor. The presence of tumor with no prior treatment caused an average enhancement of Tc-99 activity of 22.1%. This breakdown of the blood brain barrier should allow greater penetration of 1-125 labeled-425 into the tumor area making it more effective. However, this effect is lost over time (22). Thus, the time interval between the completion of radiation therapy and the initiation of monoclonal antibody treatments should be relatively short (4-6 weeks). In fact, we found that patients who were treated within 4-6 weeks after radiation therapy tended to do better. There is evidence that high grade astrocytomas generally are radioresistant as shown by the broad shoulder of the survival curve (26). This is thought to be a result of accumulation of sublethal damage. The use of a high LET isotope like I-125 should decrease sublethal damage repair and result in more effective cytotoxicity. In early studies the clonogenic survival of mammalian cells exposed to 5-(I- 125)-iododeoxyuridine showed no shoulder effect and was relatively independent of oxygenation (4, 16, 27). This differs from the molecular lesions caused by conventional external beam radiation therapy. Bloomer and Adelstein (4) reported that I- 125 was highly efficient with nearly every decay producing a double-strand break in coliphage DNA. They found no detectable repair of DNA single strand breaks. Therefore, the use of I-125 as an adjuvant to fractionated x-ray therapy has significant theoretical advantages. Clinical Human Antimouse Antibody (HAMA) reactions did not develop in any of the patients. Human Antimouse Antibody is well-documented in patients receiving murine monoclonal antibodies. It blocks and removes circulating antibodies, decreasing the time the targeted cells are exposed to them. This exposure time is important for internalization and ultimately for cytotoxicity. The clinical absence of the HAMA response may be related to the small amount of monoclonal antibody utilized in each treatment. It may also be influenced by the immunosuppression secondary to long term corticosteroid use. We routinely sampled patients’ blood to access HAMA in the serum. This

Malignant

astrocytomas

will be the subject of a future publication. However, therapy is still a point of debate. Others have utilized anti-epidermal growth factor antibodies against high grade gliomas. Epenetos et al. published a report in 1985 of a patient presenting with a recurrent GBM treated intraarterially with I-13 1 labeled 9A antibody (10). The patient had both a regression of tumor by computerized tomography and a sustained clinical improvement. Kalofonos and Epenetos (14) later reported on the treatment of 10 patients with recurrent AAF and GBM. All patients showed good localization of the I-131 radiolabeled anti-epidermal growth factor receptor antibody (EGFr). Treatments were given intravenously or infused into the internal carotid artery. Six patients showed clinical improvement, and one patient remained in remission 3 years after treatment. For patients with high grade gliomas, previously found important prognostic factors include age, histology of tumor, extent of surgery, and Kamofsky Performance Status (2, 9, 21, 25). Although the numbers are too small to detect significant survival advantages, in this study the most important prognostic factors were patient’s age and extent of surgery. Younger patients and patients with major debulking tended to do better. Although histology of the tumor has often been an important prognostic factor in patients with high grade gliomas, our study revealed similar survival advantages for both groups, AAF and GBM. No relationship was found between Kamofsky Performance Status and survival. The RTOG and ECOG have reported (9, 21) median survivals of 27 and 36.2 months for AAF patients treated with radiotherapy. The 18 month survival rate was 64%. The extent of surgery and age were both reported as sig-

0 L. W. BRADYer al.

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nificant prognostic factors. They found median survivals of 47.5, 26.2, and 9.1 months for the age groups 18-39, 4059, and 60-70, respectively. Forty-three percent of their patients were under 40 years of age. In our study only 3 of 10 patients were in this age group with two of the three alive and doing well. They also reported a 15.2 month median survival for AAF patients receiving biopsy and 46.8 months for those with debulking. In our study, the two patients with AAF surgically debulked had good responses and are surviving at 12 and 24 months. The RTOG and ECOG have also reported (9, 21) median survivals of 8 and 8.6 months for patients with GBM. In our group, the projected median survival was 15.6 months, which appears to be an improvement. Our results, although the numbers are small, are encouraging with a 60% survival at one year for both AAF and GBM. It should be noted that all patients with small implantable lesions received brachytherapy and were not included among this group of patients. Also, only 2 patients had what was considered by the surgeons to be a complete resection and 13 patients had biopsy alone. We chose survival as the endpoint when analyzing the data. We feel survival is a better measure of treatment efficacy than computerized axial tomography or magnetic resonance imaging because of the many questions raised in the interpretation of these scans. The survival of these patients is sufficiently short, allowing us to obtain meaningful results in a reasonably short period of time. We are currently preparing a randomized Phase III study of conventional surgery and radiation therapy versus conventional surgery, radiation therapy, and anti-epidermal growth factor receptor radiolabeled with I-125 for primary high grade gliomas.

REFERENCES 1. American Cancer Society. Cancer Facts & Figures-1991.

Atlanta, Georgia: American Cancer Society, Inc. 90-500MNo. 5008.91-LE. 1991. 2. Bleehen, N. M. Studies on high grade cerebral gliomas. Int. J. Radiat. Oncol. Biol. Phys. 18:811-813; 1990. 3. Bloom, H. J. G. Intracranial tumors: Response and resistance to therapeutic endeavors, 1970-1980. lnt. J. Radiat. Oncol. Biol. Phys. 8:1083-l 113; 1982. 4. Bloomer, W. D.; Adelstein, S. J. Iodine-125 cytotoxicity: Implications for therapy and estimation of radiation risk. lnt. J. Nut. Med. Biol. 8:171-178; 1981. 5. Bloomer, W. D.; McLaughlin, W. H.; Weichselbaum, R. R.; Hanson, R. N.; Adelstein, S. J.; Seitz, D. E. The role of subcellular localization in assessing the cytotoxicity of iodine- 125 labelled iododeoxyuridine , iodotamoxifen, and iodoantipyrine. J. Radioanal. Chem. 65:209; 1981. 6. Bradley, E. W.; Chan, P. C.; Adelstein, S. J. The radiotoxicity of iodine-125 in mammalian cells. I. Effects on the survival curve of radioiodine incorporated into DNA. Radiat. Res. 641555; 1975. 7. Brady, L. W.; Woo, D. V.; Markoe, A.; Dadparvar, S.; Karlsson, U.; Rackover, M.; Peyster, R.; Emrich, J.;

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Miyamoto, C.; Steplewski, Z.; Koprowski, H. Treatment of malignant gliomas with 125-l-labeled monoclonal antibody against epidermal growth factor receptor. Antibody, lmmunoconjugates and Radiopharmaceuticals. 3:169-179; 1990. Chan, P. C.; Lisco, E.; Lisco, H.; Adelstein, S. J. The radiotoxicity of iodine-125 in mammalian cells. Il. A comparative study on cell survival and cytogenetic responses to ‘=IUdR, r3’lUdR and ‘HTdR. Radiat. Res. 67:332; 1976. Chang, C. H.; Horton, J.; Schoenfeld, D.; Salazar, 0.; Perez-Tamayo, R.; Kramer, S.; Weinstein, A.; Nelson, J. S.; Tsukada, Y. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint radiation therapy oncology group and eastern cooperative oncology group study. Cancer. 52(6):997-1007; 1983. Epenetos, A. A.; Courtenay-Luck, N.; Pickering, D.; Hooker, G.; Durbin, H.; Lavender, J. P.; McKenzie, C. G. Antibody guided irradiation of brain glioma by arterial infusion of radioactive monoclonal antibody against epidermal growth factor receptor and blood group A antigen. Br. Med. J. 290:1463-1466; 1985. Fraker, P. J.; Speck, J. C. Protein and cell membrane iodi-

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Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial.

Twenty-five patients with primary presentation of malignant astrocytoma, astrocytoma with anaplastic foci, and glioblastoma multiforme were treated wi...
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