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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3644-3650 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.4569 Phase I Single-Dose Study of Intracavitary-Administered Iodine-131-TM-601 in Adults With Recurrent High-Grade Glioma
From the Cedars Sinai Medical Center, Los Angeles; City of Hope Cancer Center, Duarte, CA; University of Alabama at Birmingham; TransMolecular Inc, Birmingham, AL; and Saint Louis University, St Louis, MO Address reprint requests to Adam N. Mamelak, MD, Maxine Dunitz Neurosurgical Institute, Cedars Sinai Medical Center, 8631 W Third St, Ste 800e, Los Angeles, CA 90048, e-mail: Adam.Mamelak{at}cshs.org
PURPOSE: TM-601 binds to malignant brain tumor cells with high affinity and does not seem to bind to normal brain tissue. Preclinical studies suggest that iodine-131 (131I) –TM-601 may be an effective targeted therapy for the treatment of glioma. We evaluated the safety, biodistribution, and dosimetry of intracavitary-administered 131I-TM-601 in patients with recurrent glioma.
PATIENTS AND METHODS: Eighteen adult patients (17 with glioblastoma multiforme and one with anaplastic astrocytoma) with histologically documented recurrent glioma and a Karnofsky performance status of RESULTS: Intracavitary administration was well tolerated, with no dose-limiting toxicities observed. 131I-TM-601 bound to the tumor periphery and demonstrated long-term retention at the tumor with minimal uptake in any other organ system. Nonbound peptide was eliminated from the body within 24 to 48 hours. Only minor adverse events were reported during the 22 days after administration. At day 180, four patients had radiographic stable disease, and one had a partial response. Two of these patients further improved and were without evidence of disease for more than 30 months. CONCLUSION: A single dose of 10 mCi 131I-TM-601 was well tolerated for 0.25 to 1.0 mg TM-601 and may have an antitumoral effect. Dosimetry and biodistribution from this first trial suggest that phase II studies of 131I-TM-601 are indicated.
Despite aggressive efforts, the prognosis for survival from malignant glioma has not significantly improved in the last 20 years.1-5 The 5-year survival for glioblastoma remains approximately 3%, and the 2-year survival is approximately 8.2%.2 TM-601 is a synthetic version of a peptide (chlorotoxin) found in the venom of the giant yellow Israeli scorpion Leiurus quinquestriatus.6 This 36–amino acid peptide has been explored7,8 as a candidate for targeting gliomas. TM-601 crosses blood-brain and tissue barriers7 and binds to a phosphatidyl inositide, a phosphorylated lipid on lamellipodia of tumor cells.9 Preclinical studies demonstrated the stability, safety, efficacy, and lack of immunogenicity of radioiodinated TM-601. We performed a phase I study to evaluate the safety, biodistribution, and dosimetry of intracavitary iodine-131 (131I) –TM-601 in adult patients with recurrent high-grade glioma.
Preparation of 131I-TM-601 TM-601 (lyophilized, sterile, and pyrogen free) was radiolabeled with 10 mCi 131I via the iodogen bead method10 at the clinical site and used within 78 hours (typically < 2 hours). Release specifications required less than 5% free iodine (by instant thin-layer chromatography) and no pyrogenicity.
Patients and Treatment Protocol
Adult (> 18 years) patients with histologically documented supratentorial malignant glioma, a Karnofsky performance status (KPS) of
Magnetic Resonance Imaging
Injection of Radiolabeled Peptide Next, patients received 25% of the total dose via injection into the venous access device, were observed for 5 minutes, and then received the remainder of the study dose. Patients were monitored during drug infusion and re-evaluated on a daily basis during the immediate (days 0 to 8) postinfusion period; patients were seen again at day 22 and then observed for up to 180 days. Biodistribution and elimination were determined by urine and blood measures of radioactivity. Twenty-four hour urine collections were performed over days 1 to 2, 2 to 3, 3 to 4, and 4 to 6 or 8, with an aliquot from each 24-hour period used to determine the average amount of excreted radioactivity during that time period. Blood samples were collected 1, 2, and 4 hours after the completion of the infusion on days 2, 3, and 4 and at the time of imaging on day 6 or 8.
Gamma Camera Imaging Whole-body and two-dimensional brain single photon emission computed tomography (SPECT) scans. After intracavitary injection of 131I-TM-601, anterior and posterior whole-body planar images and two-dimensional SPECT scans were acquired as described.12 A 20-mL calibrated 131I source (approximately 100 µCi) was placed 10 cm from the feet of the patient within the field of view. Subsequent images were acquired on days 1, 2, and 3 and between 5 and 8 days after injection.
Study Design and Statistical Methods Preliminary assessment of antitumor effect was a secondary end point. Six patients were enrolled onto one of three sequential dosing panels (panel 1, 0.25 mg of TM-601; panel 2, 0.50 mg of TM-601; and panel 3, 1.00 mg of TM-601), each radiolabeled with 10 mCi (± 10%) of 131I. Treatment within a dosing panel would have been interrupted if two or more of the initial three patients experienced a DLT (grade 3 or higher according to the National Cancer Institute Common Toxicity Criteria version 3.0 and graded as at least probably related to treatment). Dose escalation similarly would have been interrupted if two or more DLTs occurred within a single dosing panel. If two patients at a given dose experienced a DLT, the previous dose level would have been identified as the maximum tolerated dose. Every patient was observed clinically for 180 days after treatment. All efficacy and safety analyses were performed on the intent-to-treat cohort of all patients who received a single dose of intracavitary 131I-TM-601.
Radiation Dosimetry Radioactivity concentrations in blood and urine were determined using a gamma well counter calibrated with a 131I standard. For blood, total radioactivity was calculated based on the area under the radioactivity-time curve, with the typical peak (µCi/mL) at 4 hours. Cumulated activity during the 0- to 4-hour window was determined by trapezoid integration, and cumulated activity after more than 4 hours was fitted with a monoexponential curve. Marrow-to-blood ratio17 was assumed to be 0.75 because of the small peptide size. Patient-specific marrow dose was estimated based on the electron radiation from the blood, the photon radiation from the remaining body and tumor cavity, and the patient's body weight.18
Histochemical Staining
Nineteen patients with recurrent high-grade glioma were enrolled onto the study; 18 had glioblastoma multiforme (GBM), and one had anaplastic astrocytoma. One GBM patient was excluded after surgery because of a diagnosis of previously undetected hepatitis C. The demographics of the patient population are listed in Table 1. All patients received at least one dose of study medication.
For unplanned reasons, two patients assigned to the 0.50-mg dose panel and one patient assigned to the 1.00-mg panel received a second dose of study medication. In one of these patients, SPECT images indicated that the first injection was accidentally delivered subcutaneously and did not enter the resection cavity. Calculated radiation doses to normal organs after this subcutaneous injection were determined to be clinically insignificant. This patient received a second injection of 10 mCi 131I-TM-601 into the reservoir, confirmed by subsequent SPECT images. Two other patients received a second dose on a compassionate use basis, with approval from the US Food and Drug Administration, at 12 and 19 weeks after initial treatment. Survival from time of injection for all patients is shown in Figure 1. Two patients demonstrated a small amount of 111In-DTPA leakage into the ventricles and spinal fluid pathways. Radiation dose estimates suggest that the radiation dose of 131I-TM-601 to the spine was in a range thought to be clinically insignificant (2.83 Gy and 3.78 Gy). In these patients, the treating physician determined that administration of 10 mCi 131I-TM-601 was still appropriate for this study.
Radiation Dosimetry Radiation doses to normal organs were clinically insignificant (Table 2). In contrast, the mean radiation dose to within 2 cm of the cavity wall was 0.81 Gy/mCi (median, 0.49 Gy/mCi), and the dose ranged from 0.12 to 2.75 Gy/mCi (Table 2). Furthermore, the biologic half-life of 131I-TM-601 in the tumor cavity margin was longer than in any other organ, indicating long-term retention of the drug in and around the injection site (Table 2). The median biologic half-life in cavity margin was 70 hours (range, 32 to 193 hours), 80 hours (range, 25 to 86 hours), and 55 hours (range, 41 to 62 hours) for patients receiving 0.25, 0.50, and 1.0 mg of peptide, respectively.
The biologic half-life, radiation dose per unit of injection dose (Gy/mCi), and radiation dose (Gy) for 131I-TM-601 within the 2-cm tumor cavity wall are listed for each patient in Table 3. These data indicate a slightly longer half-life and higher radiation dose for patients receiving 0.50 mg of peptide compared with the other groups, although this difference did not reach statistical significance. 131I-TM-601 localized to and remained primarily concentrated in and around the patients’ surgical cavity for all 5 days that the patients were imaged (a typical image is shown in Fig 2).
Patient Follow-Up, Toxicity, and Response to Therapy Eleven patients completed the 180-day observation period. There were no DLTs related to treatment during the initial 22-day observation period and no clinically significant acute adverse events during infusion of 131I-TM-601 at any dose level. The majority of events reported were mild to moderate in nature. There were no grade 3 or 4 toxicities related to the study drug or method of administration in the immediate and/or long-term follow-up period. There were 88 grade 1 and 90 grade 2 toxicities. There were no patient complaints related to the study drug or method of administration. Four patients had serious adverse events possibly or probably related to study medication reported within 22 days of administration (Table 4). Additional serious adverse events reported beyond the initial 22-day observation period included one patient with generalized seizure and increased confusion; one patient with pneumonia; one patient with somnolence, ventricular dilation, and cerebral hematoma; and one patient with headache, dysarthria, and instability. The administration of a second dose of study medication was not associated with any serious adverse events, although these events were not formally included in the toxicity evaluations because of the long time interval (12 and 19 weeks) between drug administrations.
Over the course of the 180-day observation period, there were seven deaths. Two patients in panel 2 with GBM have survived more than 30 months. Median survival time was 25.7 weeks for patients in panel 1 (0.25-mg dose), 77.6 weeks for patients in panel 2 (0.50-mg dose), 23.6 weeks for patients in panel 3 (1.00-mg dose), and 27.0 weeks for patients in all three dosing groups (Table 5). Histochemistry of the tumor tissue from all patients stained intensely positive for TM-601, as represented in Figures 3A to 3C.
Radiographic Changes Tumor volume measurements were available for 16 patients at baseline (within 48 hours of surgery), 16 patients at 22 days after treatment, 16 patients at 90 days after treatment, and five patients at 180 days after treatment. All but one patient had evidence of residual enhancing disease on baseline scans. The mean baseline residual T1 enhancing tumor volume was 28 ± 28 mL (range, 0 to 72.15 mL). On day 22 after treatment, this volume had increased to a mean of 31.8 ± 32.7 mL (range, 1.8 to 114.2 mL). The tumor volumes decreased by 10.8% in one patient and 76.7% in another patient, were unchanged in nine patients, and increased in three patients (four patients were not assessable). This translated into a radiographic interpretation of stable disease in 12 patients and progressive disease in four patients (two patients were not assessable at this time point; Table 4). For 16 patients with radiographic follow-up available at 90 days, a stable response was observed in seven patients, and progressive disease was observed in nine patients (two patients were not assessable at this time point). Long-term follow-up was available for six patients, with one patient showing a partial response (defined as at least a 50% decrease under baseline with no new lesions), four with stable disease, and one with progressive disease. Two patients (one with stable disease and one with partial response) went on to achieve a complete radiographic response (defined as complete absence of demonstrable contrast enhancement on T1-weighted MRI) without evidence of disease for 32 and 30 months. The patients (patients 203 and 204) were females and were ages 40 and 42 years. Both patients had parietal lobe GBM (one left hemisphere and one right hemisphere), a KPS of 90% after resection, and minimal residual enhancement on postoperative MRIs. Neither patient received a second dose of 131I-TM-601. An example of stable disease (patient 204) is demonstrated in Figures 3D and 3E.
In this first human trial, treatment of patients with recurrent high-grade glioma with a single intracavitary dose of 131I-TM-601 was well tolerated to the dose of 1.0 mg TM-601 radiolabeled with 10 mCi of 131I. Few adverse effects occurred during the initial 22-day observation period, which suggests the dosing level of peptide used in this study is safe and well tolerated. It is unlikely that the doses of 131I contributed to the adverse events because the doses were far below expected toxicity ranges.20 The adverse events that did occur were considered unremarkable in this patient population. Three patients received two doses without any significant adverse events, preliminarily demonstrating that repeated administration of 131I-TM-601 may be safe. Biodistribution data of 131I-TM-601 indicated that this radiopeptide rapidly penetrated through the cavity wall with, on average, 79% of the radioactivity leaving the region of cavity within 24 hours after administration. The majority of the remaining radioactivity stayed tightly localized to the tumor cavity and surrounding regions, suggesting discrete binding to the tumor. The amount of uptake and radiation doses in the stomach, kidneys, spleen, and bladder were much lower compared with those reported in the literature for other modalities.21,22 There was no observable uptake of 131I-TM-601 in the small or large intestine at any time in any patient, suggesting that the excretion route of 131I-TM-601 is mainly through the urinary tract. Uptake of 131I-TM-601 in the thyroid was greater than in other solid organs but still far below toxic levels, which are reported to be in the range of 100 Gy to cause hypothyroidism in greater than 50% of patients.23,24 Immunohistochemical studies in normal human tissues have failed to demonstrate TM-601 binding in normal thyroid gland,7 which is consistent with our observation. A detailed analysis of the imaging of this drug in the brain based on a subset of nine patients has been published,12 indicating that 131I-TM-601 diffuses into the brain at distances far greater than observed for antibodies and other large molecules.25 These observations suggest that TM-601 may be a useful means to deliver focused radiotherapy to patients with glioma. Limited by current state of the art imaging technologies and because of the nonuniform microscopic distribution of 131I-TM-601 and residual tumor cells, the current macroscopic radiation dose calculations based on imaging may not accurately represent the actual radiation dose delivered to tumor cells.26 In two GBM patients receiving 0.5 mg TM-601 plus 10 mCi 131I (± 10%), a complete radiographic response was observed. These two patients are still alive 37 and 39 months after surgery (as of March 2006) even with this low dose of peptide and expected subtherapeutic level of radiation. Of note, these patients were slightly younger than the average patient in the study (ages 40 and 42 years) but were otherwise quite representative of the remainder of the study cohort. Thus, although we acknowledge that confounding factors, such as patient age, tumor size, extent of resection, and KPS, may have contributed to this result,27 the responses certainly suggest that further investigation of this minimally toxic agent is warranted. Intracavitary-administered 131I-TM-601 is simple to deliver, well tolerated, remains highly localized to the treatment site, and preliminarily seems safe for repeated injections. Recently, a phase II trial has been initiated using escalating peptide and radiation doses with multiple injections for patients with high-grade glioma.
Although all authors completed the disclosure declaration, the following authors or their 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported by TransMolecular Inc, Birmingham, AL. Presented in part at the 20th International Advances in the Application of Monoclonal Antibodies in Clinical Oncology Conference, Latchi, Cyprus, June 30-July 2, 2003; and at the 8th Annual Meeting of the Society for Neuro-Oncology, Keystone, CO, November 13-16, 2003. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. National Cancer Institute: Adult brain tumors (PDQ): Treatment. http://www.nci.nih.gov/cancertopics/pdq/treatment/adultbrain/healthprofessional 2. Accelerate Brain Cancer Cure: Statistics. http://www.abc2.org/statistics.shtml 3. Stewart LA: Chemotherapy in adult-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomized trials. Lancet 359:1011-1018, 2002[CrossRef][Medline] 4. Grossman SA, Batara JF: Current management of glioblastoma multiforme. Semin Oncol 31:635-644, 2004[CrossRef][Medline] 5. Parney IF, Chang SM: Current chemotherapy for glioblastoma. Cancer J 9:149-156, 2003[Medline] 6. DeBin JA, Maggio JE, Strichartz GR: Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am J Physiol 264:C361-C369, 1993[Medline] 7. Soroceanu L, Gillespie Y, Khazaeli MB, et al: Use of chlorotoxin for targeting of primary brain tumors. Cancer Res 58:4871-4879, 1998 8. Shen S, Khaaeli MB, Gillespie G, et al: Radiation dosimetry of 131I-chlorotoxin for targeted radiotherapy in glioma-bearing mice. J Neurooncol 71:113-119, 2005[CrossRef][Medline] 9. Grimes CA, Gonda MA, Alvarez VL: TM-601 targets human cancer cells via a phosphatidylinositol phosphate in lamellipodia. J Clin Oncol 23:850s, 2005 (abstr 9556)[CrossRef] 10. Woltanski KP, Besch W, Keilacker H, et al: Radioiodination of peptide hormones and immunoglobulin preparations: Comparison of the chloramines T and iodogen method. Exp Clin Endocrinol 95:39-46, 1990[Medline] 11. Karnofsky D, Abelman W, Craver L, et al: The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1:634-656, 1948[CrossRef] 12. Hockaday DC, Shen S, Fiveash J, et al: Imaging glioma extent with 131I-TM-601. J Nucl Med 46:580-586, 2005 13. Shen S, Forero A, LoBuglio AF, et al: Patient-specific dosimetry of pretargeted radioimmunotherapy using CC49 fusion protein in patients with gastrointestinal malignancies. J Nucl Med 46:642-651, 2005 14. Sabin MG: MIRDOSE: Personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 37:538-546, 1996 15. Burger PC, Heinz ER, Shibata T, et al: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68:698-704, 1988[Medline] 16. Harsh GR: Management of recurrent gliomas, in Berger MS, Wilson CB (eds): The Gliomas. Philadelphia, PA, WB Saunders, 1999, p 649 17. Sgouros G: Bone marrow dosimetry for radioimmunotherapy: Theoretical considerations. J Nucl Med 34:689-694, 1993 18. Shen S, DeNardo GL, Sgouros G, et al: Practical determination of patient-specific marrow dose using radioactivity concentration in blood and body. J Nucl Med 40:2102-2106, 1999 19. Lyons SA, O'Neal J, Sontheimer H: Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39:162-173, 2002[CrossRef][Medline] 20. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-122, 1991[Medline] 21. Goldenberg DM: Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med 43:693-713, 2002 22. DeNardo GL: Treatment of non-Hodgkin's lymphoma (NHL) with radiolabeled antibodies (mAbs). Semin Nucl Med 35:202-211, 2005[CrossRef][Medline] 23. Metso S, Jaatinen P, Huhtala H, et al: Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clin Endocrinol (Oxf) 61:641-648, 2004[CrossRef][Medline] 24. Leslie WD, Ward L, Salamon EA, et al: A randomized comparison of radioiodine doses in Graves’ hyperthyroidism. J Clin Endocrinol Metab 88:978-983, 2003 25. Akabani G, Reardon DA, Coleman RE, et al: Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant glioma: A phase II study. J Nucl Med 46:1042-1051, 2005 26. Shen S, Mamelak A, Raubitschek A, et al: Dosimetry of phase I/II study of intracavitary administered I-131-TM-601 peptide in patients with recurrent high-grade glioma. Int J Radiat Oncol Biol Phys 60:S259, 2004 (suppl, abstr) 27. Lamborn KR, Chang SM, Prados MD: Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro-oncol 6:227-235, 2004[Abstract] Submitted December 21, 2005; accepted May 26, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60% who were eligible for cytoreductive craniotomy were enrolled. An intracavitary catheter with subcutaneous reservoir was placed in the tumor cavity during surgery. Two weeks after surgery, patients received a single dose of 131I-TM-601 from one of three dosing panels (0.25, 0.50, or 1.0 mg of TM-601), each labeled with 10 mCi of 131I. 
