Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma

Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent... Abstract Context No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting Three centers. Patients Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg. Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from adrenal medullary chromaffin cells and extra-adrenal sympathetic neurons, respectively. Paraganglioma can also arise from parasympathetic neurons, largely in the head and neck, but these are not the subject of this report. The reported overall incidence varies between two and eight cases per million per year (1–4). Approximately 10% to 35% of PPGLs have been reported to present as metastatic at the time of diagnosis and primary treatment; metastases typically develop after a median interval of ∼5.5 years (5–7). The most common sites of metastasis are lymph nodes, bone, lung, and liver (6). Five-year survival rates vary (24% to 60%) according to the location of metastatic lesions, with the worst prognosis reported for patients with liver and/or lung metastases (8). Shorter survival has also recently been correlated with older age at the time of primary tumor, synchronous metastases, larger primary tumor size, and unresectable disease (5). Once metastasis has occurred, treatment options are limited; there are currently no approved pharmacological treatments in the United States for recurrent and/or metastatic (or previously referred to as malignant by World Health Organization 2004 classification) PPGLs. Conventional low-specific-activity I-131 meta-iodobenzylguanidine (MIBG) therapy at high doses and cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine have been used in patients with recurrent and/or metastatic disease (9, 10). Tyrosine kinase inhibitors such as sunitinib and stable and/or radiolabeled octreotide derivatives are also being explored (11–13). MIBG is a guanethidine derivative and a substrate for the norepinephrine (NE) transporter present in the chromaffin cells of PPGLs. MIBG has been labeled with radioactive isotopes of iodine for both diagnostic and therapeutic applications. Conventional low-specific-activity I-131 MIBG has been commercially available in the United States and Europe for the imaging of neuroendocrine tumors, including PPGL, since the 1990s. However, studies have reported that >99% of the MIBG molecules are not radiolabeled in conventional commercial preparations (14, 15). A major drawback of using high doses of conventional I-131 MIBG is the large amount of unlabeled MIBG that competes for NET binding sites, lowering uptake of the therapeutically active I-131–labeled MIBG while also disrupting the NE-reuptake mechanism (15). The resulting increase in circulating NE can elevate the risk of major cardiovascular side effects such as acute hypertensive crisis during or shortly after the infusion of conventional I-131 MIBG therapy (16, 17). To improve the benefit to risk profile of I-131 MIBG, a manufacturing process (Ultratrace®) has been developed to produce AZEDRA® (iobenguane I 131; Progenics Pharmaceuticals, Inc., New York, NY). This drug product has high-specific-activity and little to no unlabeled MIBG, thus potentially providing advantages over conventional I-131 MIBG in safety and efficacy for the treatment of patients with PPGL (18). This open-label, multicenter, dose-escalation phase 1 study was undertaken to determine the maximum-tolerated dose (MTD) of high-specific-activity I-131 MIBG in the treatment of metastatic and/or recurrent PPGL. Secondary measures included estimated radiation absorbed doses, objective radiographic tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, biochemical response, survival, and safety and tolerability. Patients and Methods Patients The study protocol (NCT00458952) and all procedures were approved by local institutional review boards and the US Food and Drug Administration. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice. All subjects provided written informed consent before study entry. To be eligible, patients 18 years of age or older had to have histologically confirmed evidence of PPGL with at least one measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) that was also confirmed as visible on a diagnostic MIBG scan. Patients had disease that was metastatic or recurred after prior surgery. Key exclusion criteria were radiographic evidence for active central nervous system lesions within 3 months of study entry, previous systemic radiotherapy within 6 months or chemotherapy within 30 days of study entry, nursing or pregnant status, and concurrent use of medications known to interfere with MIBG uptake. Study design and assessments This was a phase 1, open-label, single-arm, multicenter, dose-finding study in patients with histologically confirmed PPGL that was metastatic and/or recurrent, regardless of disease progression status, designed to establish the MTD of high-specific-activity I-131 MIBG. To determine the MTD, sequential dose-escalation cohorts began with three patients at 222 MBq/kg (6 mCi/kg) and proceeded according to a standard modified Fibonacci 3 + 3 trial design, with dose increases at 37-MBq/kg (1-mCi/kg) increments until the MTD was established (19). To guard against inadvertently administering high levels of radioactivity, an upper limit for administered activity was based on a body weight of 75 kg. Therefore, the first three dose levels were not to exceed 16.65, 19.43, or 22.2 GBq (450, 525, or 600 mCi). The 222-MBq/kg (6-mCi/kg) starting dose was less than the calculated maximum administered activity, resulting in 23 Gy of absorbed dose to the kidneys according to a prior dosimetry study (20). Toxicities were graded according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE version 3). Potential dose limiting toxicities (DLTs) consisted of CTCAE grade 4 hematologic toxicity of >1 week’s duration or the occurrence of any grade 3 or 4 nonhematologic toxicity. Key secondary objectives were to assess the radiation dose estimates, safety and tolerability, and preliminary efficacy of high-specific-activity I-131 MIBG with regard to objective tumor response (OTR) by radiographic assessment, biochemical response, and survival. Patients were evaluated at 3, 6, 9, and 12 months after treatment. Safety was evaluated by collection of treatment-emergent adverse events (AEs), electrocardiograms (ECGs), physical examination findings, vital sign measurements, and clinical laboratory data. The biodistribution of I-131 MIBG was assessed by determination of total body residence time and by visual examination of whole body planar images. Radiographic OTR was based on RECIST v1.0 and was assessed by two blinded independent central reviewers and an adjudicator using CT or MRI scans of the chest, abdomen, and pelvis performed at each assessment time point after investigational treatment. For the assessment of biochemical response, serum chromogranin A (CgA) and 24-hour levels of urinary catecholamines/metanephrines were collected at baseline and every 3 months for 1 year after treatment. Complete response (CR) was defined as a tumor marker value above the upper limit of normal (ULN) at baseline and at or below the ULN at the assessed time point; partial response (PR) was defined as a value that was above ULN at baseline and decreased by at least 50% from the baseline value but was still above the ULN. Best overall tumor response by RECIST and best biochemical response were evaluated for treated patients during the 12-month efficacy period. After the first year, patients were followed up every 6 months or until death (or withdrawal from the study) for overall survival and late radiation toxicity. Late radiation toxicity was assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Scoring Scheme (21). Imaging For imaging, each patient received a single intravenous bolus of approximately 185 MBq (5 mCi) of high-specific-activity I-131 MIBG as the dosimetry (imaging) dose (20). After the dosimetry dose, serial anterior and posterior whole body images were taken 30 to 60 minutes after injection and before patient voiding and again at 2 to 4 days and after patient voiding. The geometric mean count of the first whole body studies represented 100% of administered activity. An imaging standard was prepared and placed in the field of view for all images and as a reference for correcting decay and camera sensitivity changes. Tumor uptake on the diagnostic MIBG scan was confirmed to correspond to a designated target lesion seen on CT or MRI. If at least one lesion observed on baseline CT or MRI was also visualized on the MIBG scan and the dosimetry dose showed typical biodistribution, the patient was administered a therapeutic dose 7 to 28 days after the dosimetry dose. Data were evaluated to determine human radiation absorbed dose estimates to target lesions and normal organs in accordance with the Medical Internal Radiation Dose schema to account for patient-to-patient variation in radiation absorbed doses to individual organs (22). Absorbed radiation dose was calculated using OLINDA/EXM software (Vanderbilt University, Nashville, TN) (23). Study drug administration For the therapeutic dose administration of high-specific-activity I-131 MIBG, all patients were pretreated with a saturated solution of potassium iodide for thyroid protection per standard practice. The recommended infusion rate of intravenous administration of the therapeutic dose was 50 mL over a period of 15 to 30 minutes. Because of the theoretical risk for hypertensive crisis during and after therapeutic administration of I-131 MIBG, investigators had phentolamine available during each infusion. ECGs and vital signs were obtained before and after each dose, Holter monitoring was initiated 1 hour pretherapeutic dose and continued through approximately 23 hours posttherapeutic dose. A 12-lead ECG was performed upon the patient’s release from isolation and before discharge. Any clinically significant ECG changes and findings were captured as reported AEs. The radioactive drug product was handled only by trained personnel with proper shielding and monitoring following institutional standard operating procedures and/or applicable guidance. Statistical analyses The sample size was dictated by the 3 + 3 study design. Patients who received any dose of high-specific-activity I-131 MIBG were included in the safety analysis. The intent-to-treat population was all patients who received a therapeutic dose; this was the primary analysis set for the determination of the MTD and efficacy measures. Quantitative values were reported as means ± standard deviation or median and range, as appropriate. For categorical endpoints, Jonckheere-Terpstra test statistics were computed and P values presented (P < 0.05 was considered significant). Regression models for dose-response relationships were fit to the study data, and tests for the statistical significance of the association between dose level and response were conducted. Overall survival was defined as the time from the date of enrollment to the date of death from any cause or was censored at the date the patient was last known to be alive. All statistical analyses were performed using SAS Statistical Software (version 9.2; SAS Institute Inc., Cary, NC). Results Baseline characteristics of patients Of the 24 patients with metastatic and/or recurrent PPGL who consented for the trial, three patients did not meet all of the eligibility criteria at screening and did not receive study drug. The baseline characteristics of the 21 patients who were enrolled and dosed are presented in Table 1. Table 1. Baseline Characteristics of 21 Treated Patients Characteristics  Value  Age, y     Median  49   Range  30–72  Male, n (%)  13 (61.9)  Race, n (%)     White/Caucasian  16 (76.2)   Black  3 (14.3)   Asian  2 (9.5)  Height, cm     Median  172.7   Range  145–201  Weight, kg     Median  80.7   Range  42–126  Primary diagnosis, n (%)     Pheochromocytoma  10 (47.6)   Paraganglioma  11 (52.4)  Prior anticancer therapies for PPGL, n (%)     Radiation therapya  12 (57.1)   Chemotherapy (e.g., CVD)  6 (28.6)   Octreotide  3 (14.3)  Characteristics  Value  Age, y     Median  49   Range  30–72  Male, n (%)  13 (61.9)  Race, n (%)     White/Caucasian  16 (76.2)   Black  3 (14.3)   Asian  2 (9.5)  Height, cm     Median  172.7   Range  145–201  Weight, kg     Median  80.7   Range  42–126  Primary diagnosis, n (%)     Pheochromocytoma  10 (47.6)   Paraganglioma  11 (52.4)  Prior anticancer therapies for PPGL, n (%)     Radiation therapya  12 (57.1)   Chemotherapy (e.g., CVD)  6 (28.6)   Octreotide  3 (14.3)  Abbreviation: CVD, cyclophosphamide, vincristine, and dacarbazine. a Includes external beam radiation therapy and conventional I-131 MIBG. View Large Radiation absorbed doses The median dosimetry dose administered was 189 MBq (5.1 mCi), and the range was 181 to 196 MBq (4.9 to 5.3 mCi). Target organ radiation dose estimates are presented in descending order of mean absorbed radiation dose in Table 2. One patient was excluded from the dosimetry analyses because no imaging standard was used. The highest mean radiation absorbed dose estimates were observed in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). All other target organ mean radiation absorbed dose estimates were <1 mGy/MBq. The total mean radiation doses for kidneys, liver, and lungs were 0.42, 0.48, and 0.32 mGy/MBq, respectively. Even at the highest dose level in our study, the radiation dose levels did not exceed critical organ radiation dose limits used in external beam radiation therapy (24). Estimated tumor radiation absorbed dose varied from 0.14 to 17 mGy/MBq, with tumor volumes ranging from 5.9 cm3 (mL) to 343 mL (mean, 79 mL). Table 2. Radiation Absorbed Dose Estimates by Target Organ After Dosimetry Doses of High-Specific-Activity I-131 MIBG in 20 Dosimetry-Evaluable Patients Target Organ  Mean 
(mGy/MBq)  Minimum 
(mGy/MBq)  Maximum 
(mGy/MBq)  Thyroid  1.2  0.44  2.0  Lower large intestine wall  1.2  0.74  1.7  Salivary glands  0.87  0.28  1.9  Urinary bladder wall  0.67  0.62  0.71  Upper large intestine wall  0.51  0.34  0.71  Liver  0.48  0.16  2.7  Spleen  0.47  0.23  0.99  Kidneys  0.42  0.14  0.73  Heart wall  0.35  0.20  0.48  Lungs  0.32  0.13  0.63  Small intestine  0.19  0.14  0.26  Osteogenic cells  0.14  0.070  0.26  Gallbladder wall  0.13  0.065  0.36  Ovaries  0.13  0.094  0.20  Uterus  0.12  0.082  0.18  Pancreas  0.11  0.053  0.20  Adrenals  0.11  0.049  0.22  Total body  0.10  0.053  0.17  Stomach wall  0.094  0.050  0.16  Thymus  0.078  0.038  0.14  Muscle  0.077  0.041  0.13  Red marrow  0.074  0.041  0.13  Testes  0.072  0.042  0.13  Breasts  0.065  0.031  0.12  Skin  0.058  0.030  0.11  Brain  0.049  0.016  0.081  Target Organ  Mean 
(mGy/MBq)  Minimum 
(mGy/MBq)  Maximum 
(mGy/MBq)  Thyroid  1.2  0.44  2.0  Lower large intestine wall  1.2  0.74  1.7  Salivary glands  0.87  0.28  1.9  Urinary bladder wall  0.67  0.62  0.71  Upper large intestine wall  0.51  0.34  0.71  Liver  0.48  0.16  2.7  Spleen  0.47  0.23  0.99  Kidneys  0.42  0.14  0.73  Heart wall  0.35  0.20  0.48  Lungs  0.32  0.13  0.63  Small intestine  0.19  0.14  0.26  Osteogenic cells  0.14  0.070  0.26  Gallbladder wall  0.13  0.065  0.36  Ovaries  0.13  0.094  0.20  Uterus  0.12  0.082  0.18  Pancreas  0.11  0.053  0.20  Adrenals  0.11  0.049  0.22  Total body  0.10  0.053  0.17  Stomach wall  0.094  0.050  0.16  Thymus  0.078  0.038  0.14  Muscle  0.077  0.041  0.13  Red marrow  0.074  0.041  0.13  Testes  0.072  0.042  0.13  Breasts  0.065  0.031  0.12  Skin  0.058  0.030  0.11  Brain  0.049  0.016  0.081  View Large MTD Because of the protocol-mandated dose ceilings for therapeutic doses relative to body weight, 12 of the 21 patients (57%) received doses lower than the planned levels on a per–body weight basis. The weight limit rendered a body weight–based dose analysis unfeasible because essentially all of the patients in the later dose levels were above the upper body weight limit of 75 kg. The median therapeutic dose administered was 21.13 GBq (571 mCi), with a range of 12 to 25.8 GBq (325 to 696 mCi), which resulted in a median activity by actual body weight of 240 MBq/kg [(6.5 mCi/kg); range, 167 to 311 MBq/kg (4.5 to 8.4 mCi/kg)]. To assess the results according to a fixed therapeutic dose in the study population, patients were grouped and analyzed by total administered activity: two activity groups of ≤18.5 GBq (500 mCi) and >18.5 GBq. Four patients experienced DLTs, all of which were hematologic events. All of these patients received >18.5 GBq. Figure 1 shows the administration of high-specific-activity I-131 MIBG at sequential dose-escalating levels and the occurrence of DLTs in the treated patients. Actual administered activities for the four patients who experienced DLTs were between 19.4 GBq (524 mCi) and 25.2 GBq (680 mCi). The DLTs were neutropenia (n = 2), thrombocytopenia (n = 1), and concurrent febrile neutropenia and thrombocytopenia (n = 1). All observed DLTs resolved within a month. On the basis of the occurrence of DLTs in the planned 333 MBq/kg (9 mCi/kg) cohort, the MTD was determined to be 296 MBq/kg (8 mCi/kg). Six patients were treated in the MTD cohort. Figure 1. View largeDownload slide Administration of high-specific-activity I-131 MIBG at sequential escalating dose levels and occurrence of DLTs in 21 treated patients. AZEDRA® and Ultratrace® are registered trademarks of Progenics Pharmaceuticals, Inc. Figure 1. View largeDownload slide Administration of high-specific-activity I-131 MIBG at sequential escalating dose levels and occurrence of DLTs in 21 treated patients. AZEDRA® and Ultratrace® are registered trademarks of Progenics Pharmaceuticals, Inc. Safety The most frequently reported AEs were nausea (76%); fatigue (67%); dry mouth and vomiting (62% each); leukopenia, neutropenia, and thrombocytopenia (48% each); and anemia and salivary gland pain (43% each). The majority of AEs (84%) were CTCAE grade 1 or 2 in severity. Grade 3 or 4 AEs were reported in 16 of the 21 patients (76%), including 5 of 7 patients (71%) who received ≤18.5 GBq and 11 of 14 patients (79%) who received >18.5 GBq (no statistically significant difference was observed between the dose groups). Overall, the most common (≥10%) grade 3/4 events were neutropenia, leukopenia, thrombocytopenia, nausea, and vomiting; most of these were considered related to study drug. No patients were discontinued from the study because of AEs. During the study, five deaths occurred from approximately 2.5 months up to 22 months after treatment, and all were assessed as unrelated to treatment. In addition, the majority of serious AEs were not considered related to study drug. Hypertensive crises or cardiovascular risks were not observed in any patient. There was no evidence of a dose effect on ECG changes or clinically significant vital sign changes. Tachycardia was reported in four patients and was not considered related to study drug. During the long-term follow-up period of up to 3.5 years, most patients did not experience radiation toxicity as assessed by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Scoring Scheme. The most clinically significant symptoms showing possible radiation toxicity were moderate bone pain/tenderness and/or moderate joint stiffness/pain reported by a total of 3 patients at 3 to 3.5 years after treatment. Tumor response OTR Overall, 14 patients (58%) completed the 12-month efficacy phase. Table 3 presents the best confirmed overall OTR to treatment during the efficacy phase as assessed by RECIST for each dose group and for all patients. The majority of patients had a PR or stable disease (SD) at 12 months. No patient had a CR to treatment, but four patients, all of whom received >18.5 GBq of high-specific-activity I-131 MIBG, had a best confirmed overall OTR of PR. The proportion of patients with evaluable responses (n = 19) who were successful overall (PR or CR) was 21% (95% confidence interval: 0, 0.42). However, the Jonckheere-Terpstra test for dose response in the evaluable population indicated there was no trend in OTR by dose group at any time point. Table 3. Best Overall Objective Tumor Response as Assessed by RECIST, Categorized by Total Administered Activity of High-Specific-Activity I-131 MIBG Overall Response by RECIST  Total Administered Activity  Overall (N = 21)  ≤18.5 GBq (N = 7)  >18.5 GBq (N = 14)  CR  0  0  0  PR  0  4 (28.6)  4 (19.0)  Stable disease  6 (85.7)  7 (50.0)  13 (61.9)  Progressive disease  0  2 (14.3)  2 (9.5)  Not evaluable  1a (14.3)  1b (7.1)  2 (9.5)  Overall Response by RECIST  Total Administered Activity  Overall (N = 21)  ≤18.5 GBq (N = 7)  >18.5 GBq (N = 14)  CR  0  0  0  PR  0  4 (28.6)  4 (19.0)  Stable disease  6 (85.7)  7 (50.0)  13 (61.9)  Progressive disease  0  2 (14.3)  2 (9.5)  Not evaluable  1a (14.3)  1b (7.1)  2 (9.5)  Data are presented as n (%). a Not evaluated because patient died of hepatic failure before any efficacy assessments. b Not evaluated because patient was discontinued from the study for starting alternative chemotherapy. View Large Biochemical tumor response Analyses of biochemical tumor response to treatment were performed only on patients whose baseline blood and urine tumor markers were ≥1.5 × ULN. For most serum and urine (24-hour) tumor markers, mean baseline and mean maximum change values differed because of high patient variability. Jonckheere-Terpstra tests for dose response at each time point indicated there were no trends by dose group for any of the tumor markers at any time point during the 12-month posttreatment period (P > 0.05). Tumor markers NE, normetanephrine, epinephrine, metanephrine, dopamine, total metanephrines, CgA and vanillylmandelic acid were assessed. Table 4 presents the overall best biochemical responses for CgA and total urine metanephrines observed during the 12-month period. On the basis of the best biochemical response for CgA, 80% of patients with evaluable responses were successful overall (CR or PR). On the basis of the best biochemical response for total metanephrines, 64% of patients with evaluable responses (95% confidence interval: 0.36, 0.93) were successful overall. Table 4. Best Biochemical Tumor Response During 12 Months After Treatment, Categorized by Total Administered Activity of I-131 MIBG and Overall Biochemical Tumor Response, Best Overall  Total Administered Activity    ≤18.5 GBq (N = 7)   >18.5 GBq (N = 14)   Total (N = 21)   CgA         CR   3 (42.9)  4 (28.6)  7 (33.3)   PR   1 (14.3)  4 (28.6)  5 (23.8)   SD   0  3 (21.4)  3 (14.3)   Progressive disease   0  0  0   Normal at baseline   2 (28.6)  3 (21.4)  5 (23.8)   Not evaluable   1 (14.3)  0  1 (4.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.75 (0.51, 0.99)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.80 (0.56, 1.04)  Jonckheere-Terpstra test for dose responsea,b  0.284  Total metanephrines, 24 h         CR  2 (28.6)  3 (21.4)  5 (23.8)   PR  0  4 (28.6)  4 (19.0)   SD  2 (28.6)  3 (21.4)  5 (23.8)   Progressive disease   0  0  0   Normal at baseline   1 (14.3)  1 (7.1)  2 (9.5)   Not evaluable   2 (28.6)  3 (21.4)  5 (23.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.47 (0.22, 0.72)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.64 (0.36, 0.93)  Jonckheere-Terpstra test for dose responsea,b  1.000  Biochemical Tumor Response, Best Overall  Total Administered Activity    ≤18.5 GBq (N = 7)   >18.5 GBq (N = 14)   Total (N = 21)   CgA         CR   3 (42.9)  4 (28.6)  7 (33.3)   PR   1 (14.3)  4 (28.6)  5 (23.8)   SD   0  3 (21.4)  3 (14.3)   Progressive disease   0  0  0   Normal at baseline   2 (28.6)  3 (21.4)  5 (23.8)   Not evaluable   1 (14.3)  0  1 (4.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.75 (0.51, 0.99)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.80 (0.56, 1.04)  Jonckheere-Terpstra test for dose responsea,b  0.284  Total metanephrines, 24 h         CR  2 (28.6)  3 (21.4)  5 (23.8)   PR  0  4 (28.6)  4 (19.0)   SD  2 (28.6)  3 (21.4)  5 (23.8)   Progressive disease   0  0  0   Normal at baseline   1 (14.3)  1 (7.1)  2 (9.5)   Not evaluable   2 (28.6)  3 (21.4)  5 (23.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.47 (0.22, 0.72)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.64 (0.36, 0.93)  Jonckheere-Terpstra test for dose responsea,b  1.000  Data are presented as n (%) unless otherwise noted. Abbreviations: CI, confidence interval; ITT, intent-to-treat. a Excludes nonevaluable responses. b P-value is exact and two-sided. View Large Survival Survival time was calculated from the date of enrollment to the date of death from any cause or was censored at the date the patient was last known to be alive. Overall survival was 85.7% (18 of 21) at 1 year after treatment and 61.9% (13 of 21) at 2 years after treatment. Discussion The objectives of this phase 1 study were to determine the MTD of high-specific-activity carrier-free I-131 MIBG for the treatment of metastatic and/or recurrent PPGL, evaluate safety and tolerability, estimate radiation absorbed doses to target lesions and organs after dosimetry, and assess tumor response, biochemical response, and survival after treatment. Overall, four patients experienced DLTs, and all were hematologic events. Actual administered activities for these four patients were all >18.5 GBq (500 mCi). Of these four patients, three patients with the highest activity levels demonstrated the best radiographic tumor response to treatment, with PR as the best overall response. Tumor response for the other patient was not evaluated because of early discontinuation from the study. Because two patients experienced dose-limiting neutropenia in the 333 MBq/kg (9 mCi/kg) cohort, the MTD was determined to be 296 MBq/kg (8 mCi/kg). Treatment success appeared to be related to total administered activity. The majority of patients had PR or SD by radiographic tumor response at 12 months. Four patients had best confirmed overall tumor response of PR, all of whom had received >18.5 GBq (500 mCi) of high-specific-activity I-131 MIBG. Overall, best treatment responses were also observed at doses >18.5 GBq, and no patients who received ≤18.5 GBq achieved PR by RECIST. For most tumor markers, mean baseline and mean maximum change values differed because of high patient variability and small sample size. There were no dose-relationship trends for any of the tumor markers. Because hypertension is one of the symptoms in patients who have primarily NE-secreting tumors, the use of antihypertensive medications was also analyzed as an exploratory endpoint evaluating clinical benefit in 15 patients who had documented use of baseline antihypertensive medications. Of these patients, five (33.3%) had either a decrease in or discontinuation of the medications within 12 months of study drug treatment. The majority of AEs in the phase 1 study were grade 1 or 2 in severity. Grade 3 or 4 AEs were consistent with anticipated toxicities after radiotherapy and the expected pattern of AEs described in I-131 MIBG therapeutic studies (18, 23). Limitations of this study are related to its small size, particularly with respect to interpretation of efficacy, which was also impacted by differences in therapeutic dose levels. Nonetheless, the preliminary safety and efficacy data from this phase 1 study support the clinical development of high-specific-activity I-131 MIBG in patients with metastatic and/or recurrent PPGLs. On the basis of the MTD of 296 MBq/kg (8 mCi/kg) determined from this study, a target therapeutic administered activity of 18.5 GBq (500 mCi) was selected in the open-label, multicenter phase 2b study, which is currently ongoing in the long-term follow-up phase (NCT00874614). There are no other comparative studies for any systemic therapeutic options in this ultra-rare disease. Only one phase 2 clinical trial with high-dose conventional I-131 MIBG has been published, and no phase 3 clinical trials exist (25). Van Hulsteijn et al. (10) conducted a meta-analysis of radiographic and biochemical tumor response on 17 I-131 MIBG studies in a total of 243 patients with metastatic and/or recurrent PPGL. Response rates showed high variability; treatment regimens, administered doses, and duration of follow-up also differed widely across studies. Individual tumor dosimetry was not routinely performed to optimize dose delivery, and a version(s) of RECIST criteria was used in only four studies to assess OTR. The analysis suggests that most patients experienced either PR (27% radiographic, 40% biochemical) or SD (52% radiographic, 21% biochemical) responses (mostly not by RECIST). An older meta-analysis by Loh et al. (17) reported similar radiographic response rates of 26% PR and 57% SD, whereas 13% of patients experienced progressive disease. The large proportion of patients with SD was also observed in untreated patients with metastatic and/or recurrent PPGL, perhaps owing to the indolent nature of the disease (26). A single-arm, investigator-initiated, phase 2 study with sunitinib in locally advanced or metastatic PPGL has been published with interim results up to 12 weeks. The study reported that of 14 patients with evaluable radiological response, three patients (21.4%) had PR at 12 weeks with one unconfirmed response (27). Thus, on the basis of the reported safety and tolerability and efficacy of radiological response at 12 months, high-specific-activity I-131 MIBG may be an effective therapeutic option for patients with iobenguane-avid, metastatic, and/or recurrent PPGL for which there are no approved therapies. Abbreviations: AE adverse event CgA serum chromogranin A CR complete response CT computed tomography CTCAE Common Terminology Criteria for Adverse Events DLT dose limiting toxicity ECG electrocardiogram MIBG meta-iodobenzylguanidine MRI magnetic resonance imaging MTD maximum tolerated dose NE norepinephrine OTR objective tumor response PPGL pheochromocytoma or paraganglioma PR partial response RECIST Response Evaluation Criteria in Solid Tumors SD stable disease ULN upper limit of normal. Acknowledgments We thank John W. Babich, R. Edward Coleman, and Shankar Vallabhajosula for their contributions to the study. Financial Support: Research funding was provided by Molecular Insight Pharmaceuticals, Inc., a wholly owned subsidiary of Progenics Pharmaceuticals, Inc. The writing of the manuscript was not supported by any grant. Clinical Trial Information: ClinicalTrials.gov no. NCT00458952 (registered 9 April 2007). Disclosure Summary: The authors report no conflicts of interest in this work. R.B.N. has research funding and a consulting role with Eli Lilly and Avid Radiopharmaceuticals. D.A.P. consults for 511 Pharma. D.A.P. has received research funding from Progenics, Siemens, and 511 Pharma. J.J., T.L., N.S., T.S., and V.W. are employed by Progenics Pharmaceuticals, Inc. S.J.G. receives royalties from Cornell University. References 1. National Institutes of Health, National Cancer Institute. Pheochromocytoma and Paraganglioma Treatment (PDQ®) – health professional version. Available at: https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/stoc_h2_0. Accessed 7 September 2017. 2. Stenström G, Svärdsudd K. Pheochromocytoma in Sweden 1958-1981 : an analysis of the National Cancer Registry data. Acta Med Scand . 1986; 220( 3): 225– 232. Google Scholar CrossRef Search ADS PubMed  3. Hartley L, Perry-Keene D. Phaeochromocytoma in Queensland--1970-83. Aust N Z J Surg . 1985; 55( 5): 471– 475. Google Scholar CrossRef Search ADS PubMed  4. Fernández-Calvet L, García-Mayor RV. Incidence of pheochromocytoma in South Galicia, Spain. J Intern Med . 1994; 236( 6): 675– 677. Google Scholar CrossRef Search ADS PubMed  5. Hamidi O, Young WF, Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S, Bancos I. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab . 2017; 102( 9): 3296– 3305. Google Scholar CrossRef Search ADS PubMed  6. Pacak K, Lenders JWM, Eisenhofer G. Pheochromocytoma: Diagnosis, Localization, and Treatment . Oxford, UK: Blackwell Publishing Ltd; 2007: 93– 108. 7. Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev . 1994; 15( 3): 356– 368. Google Scholar CrossRef Search ADS PubMed  8. Mornex R, Badet C, Peyrin L. Malignant pheochromocytoma: a series of 14 cases observed between 1966 and 1990. J Endocrinol Invest . 1992; 15( 9): 643– 649. Google Scholar CrossRef Search ADS PubMed  9. Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) . 2014; 81( 5): 642– 651. Google Scholar CrossRef Search ADS PubMed  10. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EPM. 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) . 2014; 80( 4): 487– 501. Google Scholar CrossRef Search ADS PubMed  11. Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging . 2008; 52( 4): 334– 340. Google Scholar PubMed  12. van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, Wolbers JG, Kwekkeboom DJ. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med . 2006; 47( 10): 1599– 1606 Google Scholar PubMed  13. Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, Caramella C, Anderson P, Al Ghuzlan A, Waguespack SG, Deandreis D, Baudin E, Jimenez C. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab . 2012; 97( 11): 4040– 4050. Google Scholar CrossRef Search ADS PubMed  14. Vallabhajosula S, Nikolopoulou A. Radioiodinated metaiodobenzylguanidine (MIBG): radiochemistry, biology, and pharmacology. Semin Nucl Med . 2011; 41( 5): 324– 333. Google Scholar CrossRef Search ADS PubMed  15. Vaidyanathan G, Zalutsky MR. No-carrier-added synthesis of meta-[131I]iodobenzylguanidine. Appl Radiat Isot . 1993; 44( 3): 621– 628. Google Scholar CrossRef Search ADS PubMed  16. Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, Damon L, Linker C, Sznewajs A, Shiboski S, Fitzgerald P. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol . 2009; 27( 25): 4162– 4168. Google Scholar CrossRef Search ADS PubMed  17. Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest . 1997; 20( 11): 648– 658. Google Scholar CrossRef Search ADS PubMed  18. Barrett JA, Joyal JL, Hillier SM, Maresca KP, Femia FJ, Kronauge JF, Boyd M, Mairs RJ, Babich JW. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother Radiopharm . 2010; 25( 3): 299– 308. Google Scholar CrossRef Search ADS PubMed  19. Storer BE. Design and analysis of phase I clinical trials. Biometrics . 1989; 45( 3): 925– 937. Google Scholar CrossRef Search ADS PubMed  20. Coleman RE, Stubbs JB, Barrett JA, de la Guardia M, Lafrance N, Babich JW. Radiation dosimetry, pharmacokinetics, and safety of ultratrace Iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid. Cancer Biother Radiopharm . 2009; 24( 4): 469– 475. Google Scholar CrossRef Search ADS PubMed  21. RTOG Foundation Inc. RTOG/EORTC late radiation morbidity scoring schema. Available at: https://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx. Accessed 3 October 2017. 22. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, Robertson JS, Howell RW, Wessels BW, Fisher DR, Weber DA, Brill AB. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med . 1999; 40( 2): 37S– 61S. Google Scholar PubMed  23. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med . 2005; 46( 6): 1023– 1027. Google Scholar PubMed  24. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys . 1991; 21( 1): 109– 122. Google Scholar CrossRef Search ADS PubMed  25. Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND, Baudin E, Jimenez C. Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Horm Metab Res . 2012; 44( 5): 390– 399. Google Scholar CrossRef Search ADS PubMed  26. Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, de la Fouchardiere C, Libé R, Do Cao C, Niccoli P, Tabarin A, Raingeard I, Chougnet C, Giraud S, Gimenez-Roqueplo AP, Young J, Borson-Chazot F, Bertherat J, Wemeau JL, Bertagna X, Plouin PF, Schlumberger M, Baudin E; French group of Endocrine and Adrenal tumors (Groupe des Tumeurs Endocrines-REseau NAtional des Tumeurs ENdocrines and COrtico-MEdullo Tumeurs Endocrines networks). One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab . 2013; 98( 10): 4006– 4012. Google Scholar CrossRef Search ADS PubMed  27. Leibowitz-Amit R, Joshua AM, Ezzat S, Bourdeau I, Olney H, Oosting S, Seah J-A, Ruether JD, Chin S, Asa SL, Krzyzanowska MK, Knox JJ. A single-arm, phase II, multicenter trial of sunitinib in locally advanced or metastatic pheochromocytoma/paraganglioma (PC/PG): updated interim results. J Clin Oncol . 2014; 32( 4 Suppl): 431. Abstract 431. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma

Loading next page...
 
/lp/ou_press/phase-1-study-of-high-specific-activity-i-131-mibg-for-metastatic-and-gKOVdfEECf
Publisher
Oxford University Press
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-02030
Publisher site
See Article on Publisher Site

Abstract

Abstract Context No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting Three centers. Patients Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg. Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from adrenal medullary chromaffin cells and extra-adrenal sympathetic neurons, respectively. Paraganglioma can also arise from parasympathetic neurons, largely in the head and neck, but these are not the subject of this report. The reported overall incidence varies between two and eight cases per million per year (1–4). Approximately 10% to 35% of PPGLs have been reported to present as metastatic at the time of diagnosis and primary treatment; metastases typically develop after a median interval of ∼5.5 years (5–7). The most common sites of metastasis are lymph nodes, bone, lung, and liver (6). Five-year survival rates vary (24% to 60%) according to the location of metastatic lesions, with the worst prognosis reported for patients with liver and/or lung metastases (8). Shorter survival has also recently been correlated with older age at the time of primary tumor, synchronous metastases, larger primary tumor size, and unresectable disease (5). Once metastasis has occurred, treatment options are limited; there are currently no approved pharmacological treatments in the United States for recurrent and/or metastatic (or previously referred to as malignant by World Health Organization 2004 classification) PPGLs. Conventional low-specific-activity I-131 meta-iodobenzylguanidine (MIBG) therapy at high doses and cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine have been used in patients with recurrent and/or metastatic disease (9, 10). Tyrosine kinase inhibitors such as sunitinib and stable and/or radiolabeled octreotide derivatives are also being explored (11–13). MIBG is a guanethidine derivative and a substrate for the norepinephrine (NE) transporter present in the chromaffin cells of PPGLs. MIBG has been labeled with radioactive isotopes of iodine for both diagnostic and therapeutic applications. Conventional low-specific-activity I-131 MIBG has been commercially available in the United States and Europe for the imaging of neuroendocrine tumors, including PPGL, since the 1990s. However, studies have reported that >99% of the MIBG molecules are not radiolabeled in conventional commercial preparations (14, 15). A major drawback of using high doses of conventional I-131 MIBG is the large amount of unlabeled MIBG that competes for NET binding sites, lowering uptake of the therapeutically active I-131–labeled MIBG while also disrupting the NE-reuptake mechanism (15). The resulting increase in circulating NE can elevate the risk of major cardiovascular side effects such as acute hypertensive crisis during or shortly after the infusion of conventional I-131 MIBG therapy (16, 17). To improve the benefit to risk profile of I-131 MIBG, a manufacturing process (Ultratrace®) has been developed to produce AZEDRA® (iobenguane I 131; Progenics Pharmaceuticals, Inc., New York, NY). This drug product has high-specific-activity and little to no unlabeled MIBG, thus potentially providing advantages over conventional I-131 MIBG in safety and efficacy for the treatment of patients with PPGL (18). This open-label, multicenter, dose-escalation phase 1 study was undertaken to determine the maximum-tolerated dose (MTD) of high-specific-activity I-131 MIBG in the treatment of metastatic and/or recurrent PPGL. Secondary measures included estimated radiation absorbed doses, objective radiographic tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, biochemical response, survival, and safety and tolerability. Patients and Methods Patients The study protocol (NCT00458952) and all procedures were approved by local institutional review boards and the US Food and Drug Administration. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice. All subjects provided written informed consent before study entry. To be eligible, patients 18 years of age or older had to have histologically confirmed evidence of PPGL with at least one measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) that was also confirmed as visible on a diagnostic MIBG scan. Patients had disease that was metastatic or recurred after prior surgery. Key exclusion criteria were radiographic evidence for active central nervous system lesions within 3 months of study entry, previous systemic radiotherapy within 6 months or chemotherapy within 30 days of study entry, nursing or pregnant status, and concurrent use of medications known to interfere with MIBG uptake. Study design and assessments This was a phase 1, open-label, single-arm, multicenter, dose-finding study in patients with histologically confirmed PPGL that was metastatic and/or recurrent, regardless of disease progression status, designed to establish the MTD of high-specific-activity I-131 MIBG. To determine the MTD, sequential dose-escalation cohorts began with three patients at 222 MBq/kg (6 mCi/kg) and proceeded according to a standard modified Fibonacci 3 + 3 trial design, with dose increases at 37-MBq/kg (1-mCi/kg) increments until the MTD was established (19). To guard against inadvertently administering high levels of radioactivity, an upper limit for administered activity was based on a body weight of 75 kg. Therefore, the first three dose levels were not to exceed 16.65, 19.43, or 22.2 GBq (450, 525, or 600 mCi). The 222-MBq/kg (6-mCi/kg) starting dose was less than the calculated maximum administered activity, resulting in 23 Gy of absorbed dose to the kidneys according to a prior dosimetry study (20). Toxicities were graded according to the US National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE version 3). Potential dose limiting toxicities (DLTs) consisted of CTCAE grade 4 hematologic toxicity of >1 week’s duration or the occurrence of any grade 3 or 4 nonhematologic toxicity. Key secondary objectives were to assess the radiation dose estimates, safety and tolerability, and preliminary efficacy of high-specific-activity I-131 MIBG with regard to objective tumor response (OTR) by radiographic assessment, biochemical response, and survival. Patients were evaluated at 3, 6, 9, and 12 months after treatment. Safety was evaluated by collection of treatment-emergent adverse events (AEs), electrocardiograms (ECGs), physical examination findings, vital sign measurements, and clinical laboratory data. The biodistribution of I-131 MIBG was assessed by determination of total body residence time and by visual examination of whole body planar images. Radiographic OTR was based on RECIST v1.0 and was assessed by two blinded independent central reviewers and an adjudicator using CT or MRI scans of the chest, abdomen, and pelvis performed at each assessment time point after investigational treatment. For the assessment of biochemical response, serum chromogranin A (CgA) and 24-hour levels of urinary catecholamines/metanephrines were collected at baseline and every 3 months for 1 year after treatment. Complete response (CR) was defined as a tumor marker value above the upper limit of normal (ULN) at baseline and at or below the ULN at the assessed time point; partial response (PR) was defined as a value that was above ULN at baseline and decreased by at least 50% from the baseline value but was still above the ULN. Best overall tumor response by RECIST and best biochemical response were evaluated for treated patients during the 12-month efficacy period. After the first year, patients were followed up every 6 months or until death (or withdrawal from the study) for overall survival and late radiation toxicity. Late radiation toxicity was assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Scoring Scheme (21). Imaging For imaging, each patient received a single intravenous bolus of approximately 185 MBq (5 mCi) of high-specific-activity I-131 MIBG as the dosimetry (imaging) dose (20). After the dosimetry dose, serial anterior and posterior whole body images were taken 30 to 60 minutes after injection and before patient voiding and again at 2 to 4 days and after patient voiding. The geometric mean count of the first whole body studies represented 100% of administered activity. An imaging standard was prepared and placed in the field of view for all images and as a reference for correcting decay and camera sensitivity changes. Tumor uptake on the diagnostic MIBG scan was confirmed to correspond to a designated target lesion seen on CT or MRI. If at least one lesion observed on baseline CT or MRI was also visualized on the MIBG scan and the dosimetry dose showed typical biodistribution, the patient was administered a therapeutic dose 7 to 28 days after the dosimetry dose. Data were evaluated to determine human radiation absorbed dose estimates to target lesions and normal organs in accordance with the Medical Internal Radiation Dose schema to account for patient-to-patient variation in radiation absorbed doses to individual organs (22). Absorbed radiation dose was calculated using OLINDA/EXM software (Vanderbilt University, Nashville, TN) (23). Study drug administration For the therapeutic dose administration of high-specific-activity I-131 MIBG, all patients were pretreated with a saturated solution of potassium iodide for thyroid protection per standard practice. The recommended infusion rate of intravenous administration of the therapeutic dose was 50 mL over a period of 15 to 30 minutes. Because of the theoretical risk for hypertensive crisis during and after therapeutic administration of I-131 MIBG, investigators had phentolamine available during each infusion. ECGs and vital signs were obtained before and after each dose, Holter monitoring was initiated 1 hour pretherapeutic dose and continued through approximately 23 hours posttherapeutic dose. A 12-lead ECG was performed upon the patient’s release from isolation and before discharge. Any clinically significant ECG changes and findings were captured as reported AEs. The radioactive drug product was handled only by trained personnel with proper shielding and monitoring following institutional standard operating procedures and/or applicable guidance. Statistical analyses The sample size was dictated by the 3 + 3 study design. Patients who received any dose of high-specific-activity I-131 MIBG were included in the safety analysis. The intent-to-treat population was all patients who received a therapeutic dose; this was the primary analysis set for the determination of the MTD and efficacy measures. Quantitative values were reported as means ± standard deviation or median and range, as appropriate. For categorical endpoints, Jonckheere-Terpstra test statistics were computed and P values presented (P < 0.05 was considered significant). Regression models for dose-response relationships were fit to the study data, and tests for the statistical significance of the association between dose level and response were conducted. Overall survival was defined as the time from the date of enrollment to the date of death from any cause or was censored at the date the patient was last known to be alive. All statistical analyses were performed using SAS Statistical Software (version 9.2; SAS Institute Inc., Cary, NC). Results Baseline characteristics of patients Of the 24 patients with metastatic and/or recurrent PPGL who consented for the trial, three patients did not meet all of the eligibility criteria at screening and did not receive study drug. The baseline characteristics of the 21 patients who were enrolled and dosed are presented in Table 1. Table 1. Baseline Characteristics of 21 Treated Patients Characteristics  Value  Age, y     Median  49   Range  30–72  Male, n (%)  13 (61.9)  Race, n (%)     White/Caucasian  16 (76.2)   Black  3 (14.3)   Asian  2 (9.5)  Height, cm     Median  172.7   Range  145–201  Weight, kg     Median  80.7   Range  42–126  Primary diagnosis, n (%)     Pheochromocytoma  10 (47.6)   Paraganglioma  11 (52.4)  Prior anticancer therapies for PPGL, n (%)     Radiation therapya  12 (57.1)   Chemotherapy (e.g., CVD)  6 (28.6)   Octreotide  3 (14.3)  Characteristics  Value  Age, y     Median  49   Range  30–72  Male, n (%)  13 (61.9)  Race, n (%)     White/Caucasian  16 (76.2)   Black  3 (14.3)   Asian  2 (9.5)  Height, cm     Median  172.7   Range  145–201  Weight, kg     Median  80.7   Range  42–126  Primary diagnosis, n (%)     Pheochromocytoma  10 (47.6)   Paraganglioma  11 (52.4)  Prior anticancer therapies for PPGL, n (%)     Radiation therapya  12 (57.1)   Chemotherapy (e.g., CVD)  6 (28.6)   Octreotide  3 (14.3)  Abbreviation: CVD, cyclophosphamide, vincristine, and dacarbazine. a Includes external beam radiation therapy and conventional I-131 MIBG. View Large Radiation absorbed doses The median dosimetry dose administered was 189 MBq (5.1 mCi), and the range was 181 to 196 MBq (4.9 to 5.3 mCi). Target organ radiation dose estimates are presented in descending order of mean absorbed radiation dose in Table 2. One patient was excluded from the dosimetry analyses because no imaging standard was used. The highest mean radiation absorbed dose estimates were observed in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). All other target organ mean radiation absorbed dose estimates were <1 mGy/MBq. The total mean radiation doses for kidneys, liver, and lungs were 0.42, 0.48, and 0.32 mGy/MBq, respectively. Even at the highest dose level in our study, the radiation dose levels did not exceed critical organ radiation dose limits used in external beam radiation therapy (24). Estimated tumor radiation absorbed dose varied from 0.14 to 17 mGy/MBq, with tumor volumes ranging from 5.9 cm3 (mL) to 343 mL (mean, 79 mL). Table 2. Radiation Absorbed Dose Estimates by Target Organ After Dosimetry Doses of High-Specific-Activity I-131 MIBG in 20 Dosimetry-Evaluable Patients Target Organ  Mean 
(mGy/MBq)  Minimum 
(mGy/MBq)  Maximum 
(mGy/MBq)  Thyroid  1.2  0.44  2.0  Lower large intestine wall  1.2  0.74  1.7  Salivary glands  0.87  0.28  1.9  Urinary bladder wall  0.67  0.62  0.71  Upper large intestine wall  0.51  0.34  0.71  Liver  0.48  0.16  2.7  Spleen  0.47  0.23  0.99  Kidneys  0.42  0.14  0.73  Heart wall  0.35  0.20  0.48  Lungs  0.32  0.13  0.63  Small intestine  0.19  0.14  0.26  Osteogenic cells  0.14  0.070  0.26  Gallbladder wall  0.13  0.065  0.36  Ovaries  0.13  0.094  0.20  Uterus  0.12  0.082  0.18  Pancreas  0.11  0.053  0.20  Adrenals  0.11  0.049  0.22  Total body  0.10  0.053  0.17  Stomach wall  0.094  0.050  0.16  Thymus  0.078  0.038  0.14  Muscle  0.077  0.041  0.13  Red marrow  0.074  0.041  0.13  Testes  0.072  0.042  0.13  Breasts  0.065  0.031  0.12  Skin  0.058  0.030  0.11  Brain  0.049  0.016  0.081  Target Organ  Mean 
(mGy/MBq)  Minimum 
(mGy/MBq)  Maximum 
(mGy/MBq)  Thyroid  1.2  0.44  2.0  Lower large intestine wall  1.2  0.74  1.7  Salivary glands  0.87  0.28  1.9  Urinary bladder wall  0.67  0.62  0.71  Upper large intestine wall  0.51  0.34  0.71  Liver  0.48  0.16  2.7  Spleen  0.47  0.23  0.99  Kidneys  0.42  0.14  0.73  Heart wall  0.35  0.20  0.48  Lungs  0.32  0.13  0.63  Small intestine  0.19  0.14  0.26  Osteogenic cells  0.14  0.070  0.26  Gallbladder wall  0.13  0.065  0.36  Ovaries  0.13  0.094  0.20  Uterus  0.12  0.082  0.18  Pancreas  0.11  0.053  0.20  Adrenals  0.11  0.049  0.22  Total body  0.10  0.053  0.17  Stomach wall  0.094  0.050  0.16  Thymus  0.078  0.038  0.14  Muscle  0.077  0.041  0.13  Red marrow  0.074  0.041  0.13  Testes  0.072  0.042  0.13  Breasts  0.065  0.031  0.12  Skin  0.058  0.030  0.11  Brain  0.049  0.016  0.081  View Large MTD Because of the protocol-mandated dose ceilings for therapeutic doses relative to body weight, 12 of the 21 patients (57%) received doses lower than the planned levels on a per–body weight basis. The weight limit rendered a body weight–based dose analysis unfeasible because essentially all of the patients in the later dose levels were above the upper body weight limit of 75 kg. The median therapeutic dose administered was 21.13 GBq (571 mCi), with a range of 12 to 25.8 GBq (325 to 696 mCi), which resulted in a median activity by actual body weight of 240 MBq/kg [(6.5 mCi/kg); range, 167 to 311 MBq/kg (4.5 to 8.4 mCi/kg)]. To assess the results according to a fixed therapeutic dose in the study population, patients were grouped and analyzed by total administered activity: two activity groups of ≤18.5 GBq (500 mCi) and >18.5 GBq. Four patients experienced DLTs, all of which were hematologic events. All of these patients received >18.5 GBq. Figure 1 shows the administration of high-specific-activity I-131 MIBG at sequential dose-escalating levels and the occurrence of DLTs in the treated patients. Actual administered activities for the four patients who experienced DLTs were between 19.4 GBq (524 mCi) and 25.2 GBq (680 mCi). The DLTs were neutropenia (n = 2), thrombocytopenia (n = 1), and concurrent febrile neutropenia and thrombocytopenia (n = 1). All observed DLTs resolved within a month. On the basis of the occurrence of DLTs in the planned 333 MBq/kg (9 mCi/kg) cohort, the MTD was determined to be 296 MBq/kg (8 mCi/kg). Six patients were treated in the MTD cohort. Figure 1. View largeDownload slide Administration of high-specific-activity I-131 MIBG at sequential escalating dose levels and occurrence of DLTs in 21 treated patients. AZEDRA® and Ultratrace® are registered trademarks of Progenics Pharmaceuticals, Inc. Figure 1. View largeDownload slide Administration of high-specific-activity I-131 MIBG at sequential escalating dose levels and occurrence of DLTs in 21 treated patients. AZEDRA® and Ultratrace® are registered trademarks of Progenics Pharmaceuticals, Inc. Safety The most frequently reported AEs were nausea (76%); fatigue (67%); dry mouth and vomiting (62% each); leukopenia, neutropenia, and thrombocytopenia (48% each); and anemia and salivary gland pain (43% each). The majority of AEs (84%) were CTCAE grade 1 or 2 in severity. Grade 3 or 4 AEs were reported in 16 of the 21 patients (76%), including 5 of 7 patients (71%) who received ≤18.5 GBq and 11 of 14 patients (79%) who received >18.5 GBq (no statistically significant difference was observed between the dose groups). Overall, the most common (≥10%) grade 3/4 events were neutropenia, leukopenia, thrombocytopenia, nausea, and vomiting; most of these were considered related to study drug. No patients were discontinued from the study because of AEs. During the study, five deaths occurred from approximately 2.5 months up to 22 months after treatment, and all were assessed as unrelated to treatment. In addition, the majority of serious AEs were not considered related to study drug. Hypertensive crises or cardiovascular risks were not observed in any patient. There was no evidence of a dose effect on ECG changes or clinically significant vital sign changes. Tachycardia was reported in four patients and was not considered related to study drug. During the long-term follow-up period of up to 3.5 years, most patients did not experience radiation toxicity as assessed by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Scoring Scheme. The most clinically significant symptoms showing possible radiation toxicity were moderate bone pain/tenderness and/or moderate joint stiffness/pain reported by a total of 3 patients at 3 to 3.5 years after treatment. Tumor response OTR Overall, 14 patients (58%) completed the 12-month efficacy phase. Table 3 presents the best confirmed overall OTR to treatment during the efficacy phase as assessed by RECIST for each dose group and for all patients. The majority of patients had a PR or stable disease (SD) at 12 months. No patient had a CR to treatment, but four patients, all of whom received >18.5 GBq of high-specific-activity I-131 MIBG, had a best confirmed overall OTR of PR. The proportion of patients with evaluable responses (n = 19) who were successful overall (PR or CR) was 21% (95% confidence interval: 0, 0.42). However, the Jonckheere-Terpstra test for dose response in the evaluable population indicated there was no trend in OTR by dose group at any time point. Table 3. Best Overall Objective Tumor Response as Assessed by RECIST, Categorized by Total Administered Activity of High-Specific-Activity I-131 MIBG Overall Response by RECIST  Total Administered Activity  Overall (N = 21)  ≤18.5 GBq (N = 7)  >18.5 GBq (N = 14)  CR  0  0  0  PR  0  4 (28.6)  4 (19.0)  Stable disease  6 (85.7)  7 (50.0)  13 (61.9)  Progressive disease  0  2 (14.3)  2 (9.5)  Not evaluable  1a (14.3)  1b (7.1)  2 (9.5)  Overall Response by RECIST  Total Administered Activity  Overall (N = 21)  ≤18.5 GBq (N = 7)  >18.5 GBq (N = 14)  CR  0  0  0  PR  0  4 (28.6)  4 (19.0)  Stable disease  6 (85.7)  7 (50.0)  13 (61.9)  Progressive disease  0  2 (14.3)  2 (9.5)  Not evaluable  1a (14.3)  1b (7.1)  2 (9.5)  Data are presented as n (%). a Not evaluated because patient died of hepatic failure before any efficacy assessments. b Not evaluated because patient was discontinued from the study for starting alternative chemotherapy. View Large Biochemical tumor response Analyses of biochemical tumor response to treatment were performed only on patients whose baseline blood and urine tumor markers were ≥1.5 × ULN. For most serum and urine (24-hour) tumor markers, mean baseline and mean maximum change values differed because of high patient variability. Jonckheere-Terpstra tests for dose response at each time point indicated there were no trends by dose group for any of the tumor markers at any time point during the 12-month posttreatment period (P > 0.05). Tumor markers NE, normetanephrine, epinephrine, metanephrine, dopamine, total metanephrines, CgA and vanillylmandelic acid were assessed. Table 4 presents the overall best biochemical responses for CgA and total urine metanephrines observed during the 12-month period. On the basis of the best biochemical response for CgA, 80% of patients with evaluable responses were successful overall (CR or PR). On the basis of the best biochemical response for total metanephrines, 64% of patients with evaluable responses (95% confidence interval: 0.36, 0.93) were successful overall. Table 4. Best Biochemical Tumor Response During 12 Months After Treatment, Categorized by Total Administered Activity of I-131 MIBG and Overall Biochemical Tumor Response, Best Overall  Total Administered Activity    ≤18.5 GBq (N = 7)   >18.5 GBq (N = 14)   Total (N = 21)   CgA         CR   3 (42.9)  4 (28.6)  7 (33.3)   PR   1 (14.3)  4 (28.6)  5 (23.8)   SD   0  3 (21.4)  3 (14.3)   Progressive disease   0  0  0   Normal at baseline   2 (28.6)  3 (21.4)  5 (23.8)   Not evaluable   1 (14.3)  0  1 (4.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.75 (0.51, 0.99)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.80 (0.56, 1.04)  Jonckheere-Terpstra test for dose responsea,b  0.284  Total metanephrines, 24 h         CR  2 (28.6)  3 (21.4)  5 (23.8)   PR  0  4 (28.6)  4 (19.0)   SD  2 (28.6)  3 (21.4)  5 (23.8)   Progressive disease   0  0  0   Normal at baseline   1 (14.3)  1 (7.1)  2 (9.5)   Not evaluable   2 (28.6)  3 (21.4)  5 (23.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.47 (0.22, 0.72)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.64 (0.36, 0.93)  Jonckheere-Terpstra test for dose responsea,b  1.000  Biochemical Tumor Response, Best Overall  Total Administered Activity    ≤18.5 GBq (N = 7)   >18.5 GBq (N = 14)   Total (N = 21)   CgA         CR   3 (42.9)  4 (28.6)  7 (33.3)   PR   1 (14.3)  4 (28.6)  5 (23.8)   SD   0  3 (21.4)  3 (14.3)   Progressive disease   0  0  0   Normal at baseline   2 (28.6)  3 (21.4)  5 (23.8)   Not evaluable   1 (14.3)  0  1 (4.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.75 (0.51, 0.99)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.80 (0.56, 1.04)  Jonckheere-Terpstra test for dose responsea,b  0.284  Total metanephrines, 24 h         CR  2 (28.6)  3 (21.4)  5 (23.8)   PR  0  4 (28.6)  4 (19.0)   SD  2 (28.6)  3 (21.4)  5 (23.8)   Progressive disease   0  0  0   Normal at baseline   1 (14.3)  1 (7.1)  2 (9.5)   Not evaluable   2 (28.6)  3 (21.4)  5 (23.8)  Proportion (of ITT) with overall response of CR or PR (95% CI)  0.47 (0.22, 0.72)  Proportion (of evaluable) with overall response of CR or PR (95% CI)a  0.64 (0.36, 0.93)  Jonckheere-Terpstra test for dose responsea,b  1.000  Data are presented as n (%) unless otherwise noted. Abbreviations: CI, confidence interval; ITT, intent-to-treat. a Excludes nonevaluable responses. b P-value is exact and two-sided. View Large Survival Survival time was calculated from the date of enrollment to the date of death from any cause or was censored at the date the patient was last known to be alive. Overall survival was 85.7% (18 of 21) at 1 year after treatment and 61.9% (13 of 21) at 2 years after treatment. Discussion The objectives of this phase 1 study were to determine the MTD of high-specific-activity carrier-free I-131 MIBG for the treatment of metastatic and/or recurrent PPGL, evaluate safety and tolerability, estimate radiation absorbed doses to target lesions and organs after dosimetry, and assess tumor response, biochemical response, and survival after treatment. Overall, four patients experienced DLTs, and all were hematologic events. Actual administered activities for these four patients were all >18.5 GBq (500 mCi). Of these four patients, three patients with the highest activity levels demonstrated the best radiographic tumor response to treatment, with PR as the best overall response. Tumor response for the other patient was not evaluated because of early discontinuation from the study. Because two patients experienced dose-limiting neutropenia in the 333 MBq/kg (9 mCi/kg) cohort, the MTD was determined to be 296 MBq/kg (8 mCi/kg). Treatment success appeared to be related to total administered activity. The majority of patients had PR or SD by radiographic tumor response at 12 months. Four patients had best confirmed overall tumor response of PR, all of whom had received >18.5 GBq (500 mCi) of high-specific-activity I-131 MIBG. Overall, best treatment responses were also observed at doses >18.5 GBq, and no patients who received ≤18.5 GBq achieved PR by RECIST. For most tumor markers, mean baseline and mean maximum change values differed because of high patient variability and small sample size. There were no dose-relationship trends for any of the tumor markers. Because hypertension is one of the symptoms in patients who have primarily NE-secreting tumors, the use of antihypertensive medications was also analyzed as an exploratory endpoint evaluating clinical benefit in 15 patients who had documented use of baseline antihypertensive medications. Of these patients, five (33.3%) had either a decrease in or discontinuation of the medications within 12 months of study drug treatment. The majority of AEs in the phase 1 study were grade 1 or 2 in severity. Grade 3 or 4 AEs were consistent with anticipated toxicities after radiotherapy and the expected pattern of AEs described in I-131 MIBG therapeutic studies (18, 23). Limitations of this study are related to its small size, particularly with respect to interpretation of efficacy, which was also impacted by differences in therapeutic dose levels. Nonetheless, the preliminary safety and efficacy data from this phase 1 study support the clinical development of high-specific-activity I-131 MIBG in patients with metastatic and/or recurrent PPGLs. On the basis of the MTD of 296 MBq/kg (8 mCi/kg) determined from this study, a target therapeutic administered activity of 18.5 GBq (500 mCi) was selected in the open-label, multicenter phase 2b study, which is currently ongoing in the long-term follow-up phase (NCT00874614). There are no other comparative studies for any systemic therapeutic options in this ultra-rare disease. Only one phase 2 clinical trial with high-dose conventional I-131 MIBG has been published, and no phase 3 clinical trials exist (25). Van Hulsteijn et al. (10) conducted a meta-analysis of radiographic and biochemical tumor response on 17 I-131 MIBG studies in a total of 243 patients with metastatic and/or recurrent PPGL. Response rates showed high variability; treatment regimens, administered doses, and duration of follow-up also differed widely across studies. Individual tumor dosimetry was not routinely performed to optimize dose delivery, and a version(s) of RECIST criteria was used in only four studies to assess OTR. The analysis suggests that most patients experienced either PR (27% radiographic, 40% biochemical) or SD (52% radiographic, 21% biochemical) responses (mostly not by RECIST). An older meta-analysis by Loh et al. (17) reported similar radiographic response rates of 26% PR and 57% SD, whereas 13% of patients experienced progressive disease. The large proportion of patients with SD was also observed in untreated patients with metastatic and/or recurrent PPGL, perhaps owing to the indolent nature of the disease (26). A single-arm, investigator-initiated, phase 2 study with sunitinib in locally advanced or metastatic PPGL has been published with interim results up to 12 weeks. The study reported that of 14 patients with evaluable radiological response, three patients (21.4%) had PR at 12 weeks with one unconfirmed response (27). Thus, on the basis of the reported safety and tolerability and efficacy of radiological response at 12 months, high-specific-activity I-131 MIBG may be an effective therapeutic option for patients with iobenguane-avid, metastatic, and/or recurrent PPGL for which there are no approved therapies. Abbreviations: AE adverse event CgA serum chromogranin A CR complete response CT computed tomography CTCAE Common Terminology Criteria for Adverse Events DLT dose limiting toxicity ECG electrocardiogram MIBG meta-iodobenzylguanidine MRI magnetic resonance imaging MTD maximum tolerated dose NE norepinephrine OTR objective tumor response PPGL pheochromocytoma or paraganglioma PR partial response RECIST Response Evaluation Criteria in Solid Tumors SD stable disease ULN upper limit of normal. Acknowledgments We thank John W. Babich, R. Edward Coleman, and Shankar Vallabhajosula for their contributions to the study. Financial Support: Research funding was provided by Molecular Insight Pharmaceuticals, Inc., a wholly owned subsidiary of Progenics Pharmaceuticals, Inc. The writing of the manuscript was not supported by any grant. Clinical Trial Information: ClinicalTrials.gov no. NCT00458952 (registered 9 April 2007). Disclosure Summary: The authors report no conflicts of interest in this work. R.B.N. has research funding and a consulting role with Eli Lilly and Avid Radiopharmaceuticals. D.A.P. consults for 511 Pharma. D.A.P. has received research funding from Progenics, Siemens, and 511 Pharma. J.J., T.L., N.S., T.S., and V.W. are employed by Progenics Pharmaceuticals, Inc. S.J.G. receives royalties from Cornell University. References 1. National Institutes of Health, National Cancer Institute. Pheochromocytoma and Paraganglioma Treatment (PDQ®) – health professional version. Available at: https://www.cancer.gov/types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq#link/stoc_h2_0. Accessed 7 September 2017. 2. Stenström G, Svärdsudd K. Pheochromocytoma in Sweden 1958-1981 : an analysis of the National Cancer Registry data. Acta Med Scand . 1986; 220( 3): 225– 232. Google Scholar CrossRef Search ADS PubMed  3. Hartley L, Perry-Keene D. Phaeochromocytoma in Queensland--1970-83. Aust N Z J Surg . 1985; 55( 5): 471– 475. Google Scholar CrossRef Search ADS PubMed  4. Fernández-Calvet L, García-Mayor RV. Incidence of pheochromocytoma in South Galicia, Spain. J Intern Med . 1994; 236( 6): 675– 677. Google Scholar CrossRef Search ADS PubMed  5. Hamidi O, Young WF, Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S, Bancos I. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab . 2017; 102( 9): 3296– 3305. Google Scholar CrossRef Search ADS PubMed  6. Pacak K, Lenders JWM, Eisenhofer G. Pheochromocytoma: Diagnosis, Localization, and Treatment . Oxford, UK: Blackwell Publishing Ltd; 2007: 93– 108. 7. Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev . 1994; 15( 3): 356– 368. Google Scholar CrossRef Search ADS PubMed  8. Mornex R, Badet C, Peyrin L. Malignant pheochromocytoma: a series of 14 cases observed between 1966 and 1990. J Endocrinol Invest . 1992; 15( 9): 643– 649. Google Scholar CrossRef Search ADS PubMed  9. Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) . 2014; 81( 5): 642– 651. Google Scholar CrossRef Search ADS PubMed  10. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EPM. 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) . 2014; 80( 4): 487– 501. Google Scholar CrossRef Search ADS PubMed  11. Forrer F, Riedweg I, Maecke HR, Mueller-Brand J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q J Nucl Med Mol Imaging . 2008; 52( 4): 334– 340. Google Scholar PubMed  12. van Essen M, Krenning EP, Kooij PP, Bakker WH, Feelders RA, de Herder WW, Wolbers JG, Kwekkeboom DJ. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J Nucl Med . 2006; 47( 10): 1599– 1606 Google Scholar PubMed  13. Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, Caramella C, Anderson P, Al Ghuzlan A, Waguespack SG, Deandreis D, Baudin E, Jimenez C. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab . 2012; 97( 11): 4040– 4050. Google Scholar CrossRef Search ADS PubMed  14. Vallabhajosula S, Nikolopoulou A. Radioiodinated metaiodobenzylguanidine (MIBG): radiochemistry, biology, and pharmacology. Semin Nucl Med . 2011; 41( 5): 324– 333. Google Scholar CrossRef Search ADS PubMed  15. Vaidyanathan G, Zalutsky MR. No-carrier-added synthesis of meta-[131I]iodobenzylguanidine. Appl Radiat Isot . 1993; 44( 3): 621– 628. Google Scholar CrossRef Search ADS PubMed  16. Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, Damon L, Linker C, Sznewajs A, Shiboski S, Fitzgerald P. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol . 2009; 27( 25): 4162– 4168. Google Scholar CrossRef Search ADS PubMed  17. Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest . 1997; 20( 11): 648– 658. Google Scholar CrossRef Search ADS PubMed  18. Barrett JA, Joyal JL, Hillier SM, Maresca KP, Femia FJ, Kronauge JF, Boyd M, Mairs RJ, Babich JW. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother Radiopharm . 2010; 25( 3): 299– 308. Google Scholar CrossRef Search ADS PubMed  19. Storer BE. Design and analysis of phase I clinical trials. Biometrics . 1989; 45( 3): 925– 937. Google Scholar CrossRef Search ADS PubMed  20. Coleman RE, Stubbs JB, Barrett JA, de la Guardia M, Lafrance N, Babich JW. Radiation dosimetry, pharmacokinetics, and safety of ultratrace Iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid. Cancer Biother Radiopharm . 2009; 24( 4): 469– 475. Google Scholar CrossRef Search ADS PubMed  21. RTOG Foundation Inc. RTOG/EORTC late radiation morbidity scoring schema. Available at: https://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx. Accessed 3 October 2017. 22. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, Robertson JS, Howell RW, Wessels BW, Fisher DR, Weber DA, Brill AB. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med . 1999; 40( 2): 37S– 61S. Google Scholar PubMed  23. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med . 2005; 46( 6): 1023– 1027. Google Scholar PubMed  24. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys . 1991; 21( 1): 109– 122. Google Scholar CrossRef Search ADS PubMed  25. Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND, Baudin E, Jimenez C. Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Horm Metab Res . 2012; 44( 5): 390– 399. Google Scholar CrossRef Search ADS PubMed  26. Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, de la Fouchardiere C, Libé R, Do Cao C, Niccoli P, Tabarin A, Raingeard I, Chougnet C, Giraud S, Gimenez-Roqueplo AP, Young J, Borson-Chazot F, Bertherat J, Wemeau JL, Bertagna X, Plouin PF, Schlumberger M, Baudin E; French group of Endocrine and Adrenal tumors (Groupe des Tumeurs Endocrines-REseau NAtional des Tumeurs ENdocrines and COrtico-MEdullo Tumeurs Endocrines networks). One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab . 2013; 98( 10): 4006– 4012. Google Scholar CrossRef Search ADS PubMed  27. Leibowitz-Amit R, Joshua AM, Ezzat S, Bourdeau I, Olney H, Oosting S, Seah J-A, Ruether JD, Chin S, Asa SL, Krzyzanowska MK, Knox JJ. A single-arm, phase II, multicenter trial of sunitinib in locally advanced or metastatic pheochromocytoma/paraganglioma (PC/PG): updated interim results. J Clin Oncol . 2014; 32( 4 Suppl): 431. Abstract 431. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Jan 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off