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Phase I Trial of 90Y-DOTATOC Therapy in Children and Young Adults with Refractory Solid Tumors That Express Somatostatin Receptors

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Phase I Trial of 90Y-DOTATOC Therapy in Children and Young Adults with Refractory Solid Tumors That Express Somatostatin Receptors Phase I Trial of 90Y-DOTATOC Therapy in Children and Young Adults with Refractory Solid Tumors That Express Somatostatin Receptors Yusuf Menda1,2, M. Sue O’Dorisio2,3, Simon Kao1,2, Geetika Khanna4, Stacy Michael3, Mary Connolly5, John Babich6, Thomas O’Dorisio2,7, David Bushnell1,8, and Mark Madsen1 1Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 2Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 3Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 4Department of Radiology, Washington University School of Medicine, St. Louis, Missouri; 5Novartis Pharmaceuticals, Inc., Basel, Switzerland; 6Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts; 7Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa; and 8Iowa City VA Medical Center, Iowa City, Iowa The purpose of this study was to conduct a phase I trial of 90Y- DOTATOC to determine the dose-toxicity profile in children and Somatostatin receptor expression has been demonstrated young adults with somatostatin receptor–positive tumors. in several embryonal tumors in children, including in more Methods: A3· 3 design was used to determine the highest tolerable dose of 90Y-DOTATOC, with administered activities of than 90% of neuroblastoma and medulloblastomas and 1.11, 1.48, and 1.85 GBq/m2/cycle given in 3 cycles at 6-wk 35% of Ewing sarcomas (1,2). Similarly, bronchopulmo- intervals. An amino acid infusion was coadministered with the nary, intestinal, and pancreatic neuroendocrine tumors radiopharmaceutical for renal protection. Eligibility criteria (NETs) are known to express somatostatin receptors both included an age of 2–25 y, progressive disease, a positive lesion in vitro (3) and in vivo (4). Early observations were made 111 1 on In-diethylenetriaminepentaacetic acid-D-Phe -octreotide on excised tumor tissue using immunohistochemistry or in scanning, a glomerular filtration rate of 80 mL/min/1.73 m2 or vitro receptor-binding studies and have since been shown to more, bone marrow cellularity of 40% or more or stored autol- ogous hematopoietic stem cells, 60% or more on the Lansky correlate closely with in vivo nuclear imaging techniques 111 Play Scale, and informed consent. Results: Seventeen subjects using In-diethylenetriaminepentaacetic acid (DTPA)-D- (age, 2–24 y) received at least 1 dose of 90Y-DOTATOC; diag- Phe1-octreotide (OctreoScan; Covidien), which primarily noses included neuroblastoma, embryonal and astrocytic brain targets somatostatin receptor type 2 (5–7). These advances tumors, paraganglioma, multiple endocrine neoplasia IIB, and led to the development of somatostatin analogs labeled neuroendocrine tumors. No dose-limiting toxicities and no indi- with b-emitting radionuclides that can be used for peptide vidual dose reductions due to renal or hematologic toxicity receptor radionuclide therapy (PRRT) of NETs (8). The were noted. No complete responses were observed; 2 sub- jects experienced partial response, 5 had minor responses, 6 radiopharmaceuticals most commonly used in PRRT are 90 177 0 3 8 experienced stable disease, 2 had progressive disease, and 2 Y-DOTATOC and Lu-DOTA -Tyr -Thre -octreotide withdrew. Conclusion: Peptide receptor radionuclide therapy (9). The present phase I trial in the pediatric patient pop- with 90Y-DOTATOC is safe in children and young adults and ulation used 90Y-DOTATOC. 90Y is a pure b-emitter, with a demonstrated a 12% partial response plus 29% minor maximum energy of 2.3 MeV, a maximum range of 12 mm, response rate in patients with somatostatin receptor–positive and a half-life of 64 h. The relatively long range of the tumors. No dose-limiting toxicities were observed. The recom- b-particle allows for a bystander effect in heterogeneous mended phase II dosing is 3 cycles of 1.85 GBq/m2/dose of 90Y-DOTATOC coadministered with amino acids. tumors in which some cells may be somatostatin receptor Key Words: radiolabeled peptide; somatostatin; therapy; type 2–negative. children Both neuroblastoma and medulloblastoma are known J Nucl Med 2010; 51:1524–1531 to be responsive to external-beam and to targeted radio- DOI: 10.2967/jnumed.110.075226 therapies (10–13); thus, these tumors should be responsive to PRRT as well. On the other hand, NETs are minimally responsive to conventional radiation therapy (14), yet their response to PRRT has been promising, with phase I–II trials in adults demonstrating 25%–30% partial-response (PR) Received Feb. 25, 2010; revision accepted Jun. 25, 2010. rates (9,15). Early dose-finding clinical trials in adults For correspondence or reprints contact: Yusuf Menda, University of established the kidneys as the critical organ of toxicity, Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242. E-mail: [email protected] followed by bone marrow toxicity at high doses (16). Renal ª COPYRIGHT 2010 by the Society of Nuclear Medicine, Inc. failure was observed in subjects who received up to 7.4 1524 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 51 • No. 10 • October 2010 GBq/m2 in the absence of kidney protection with infusion no surgery or chemotherapy was allowed within 4 wk of the of cationic amino acids (17). Current practice in adults now study drug administration. A glomerular filtration rate greater than includes infusion of amino acid solution, beginning 30 min 80 mL/min/1.73 m2 was required as measured by plasma clear- 99m before and continuing 90 min after the administration of ance of Tc-DTPA. Hematopoietic status requirements included 3 90Y-DOTATOC (18). This therapeutic advance, combined an absolute neutrophil count greater than 1,000/mm , a platelet count greater than 100,000/mm3, and a bone marrow cellularity of with limiting the renal dose to less than 25 Gy, has consid- 40% or more or the availability of 1 · 106 or more CD34-positive erably reduced renal toxicity (18). Severe bone marrow hematopoietic stem cells per kilogram. Stem cell availability was toxicity has also been rare in adults treated with radiola- required for any subject who had received cranial–spinal irradia- beled somatostatin analogs (19). With its low-toxicity pro- tion of 12 Gy or more. Adequate cardiac function with a short- file, significant improvement in symptoms and quality of ening fraction of 30% or more and adequate liver function with life, and lack of effective alternative therapies, PRRT has bilirubin less than 1.5 times and aspartate aminotransferase and been suggested as a possible first-line therapy in adult alanine aminotransferase 2.5 or less times the upper limit of normal patients with gastroenteropancreatic NETs (20). Recent were also required. All subjects were required to have provided data have also demonstrated a significant survival benefit written informed consent for the protocol, which was conducted with PRRT in this population, compared with historical under Investigational New Drug no. 61,907 and approved by the controls (21). Institutional Review Board of the University of Iowa. This study was undertaken to test the hypothesis that Exclusion Criteria PRRT would be safe and effective in children and young Concomitant therapy was not allowed except for somatostatin adults with refractory solid tumors that express somatosta- analogs or bisphosphonates; somatostatin therapy was limited to tin receptors. short-acting subcutaneous doses between cycles, with discontin- uation 24 h before each dose of 90Y-DOTATOC. Potential sub- jects were excluded if they were pregnant or breast-feeding, if they MATERIALS AND METHODS had more than 1 concurrent malignancy, or if they had received Design external-beam radiation to both kidneys (scatter doses of ,0.5 Gy The 90Y-DOTATOC was administered in 3 cycles, 6 wk apart, to a single kidney or radiation to ,50% of a single kidney was starting with 1.11 GBq/m2/cycle in cohort 1 and escalating to 1.48 acceptable). and then to 1.85 GBq/m2/cycle, using 3 subjects per cohort. Each cohort included at least 3 subjects who received 3 complete cycles Kidney, Liver, and Bone Marrow Dosimetry of the drug, with no intrapatient dose escalation (22). If 1 of 3 Individual kidney, liver, and bone marrow dosimetric analyses 90 subjects in any cohort developed grade 3 toxicity or above, 3 were performed for 8 administrations of Y-DOTATOC in 5 sub- 2 additional subjects were entered in the cohort; if 2 of 6 subjects jects in cohort 3, each of whom received 1.85 GBq/m per cycle. 111 1 2 in the cohort developed grade 3 toxicity or above, no further In-DTPA-D-Phe -octreotide (222 MBq/1.73 m ) was administered 90 subjects were enrolled in that dose cohort, and the dose in the concurrently with Y-DOTATOC and used as a surrogate for indi- 111 1 previous cohort was considered as the maximum-tolerable dose. vidual kidney and liver dosimetry. In-DTPA-D-Phe -octreotide Because this was the first, to our knowledge, use of 90Y-DOTA- SPECT/CT images of the abdomen—along with a 1.85-MBq 111 TOC in children, the starting administered activity was based on a In standard in a 30-mL plastic bottle included in the field— requirement of the Food and Drug Administration that the initial were obtained at 4–6, 20–28, and 44–52 h after injection. All dose be limited to less than 50% of the dose used in the phase II imaging studies were acquired on a low-power dual-detector trial in adults and that the total estimated dose to the kidneys— SPECT/CT system with 25-mm-thick NaI(Tl) crystals (Hawkeye; including from both 90Y-DOTATOC and any prior direct or scatter GE Healthcare). Multiple energy windows were set to capture the 111 doses from external-beam radiotherapy—be limited to 21 Gy for 172- and 247-keV g-rays of In as well as a window from 300 to 90 children and 23 Gy for young adults (23).
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