Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist ¹⁷⁷Lu-Satoreotide Tetraxetan

This article is featured in Highlights of This Issue, p. 6885

Recent publications of pivotal trials and drug approvals have redefined imaging and treatment for patients with progressive metastatic neuroendocrine tumors (NET; refs. 1, 2). Diagnostically, the FDA approved ⁶⁸Ga-DOTATATE PET for imaging of NETs, which will likely replace the traditional octreotide scan (i.e., ¹¹¹In-DTPA-octreotide). Data suggest ⁶⁸Ga-DOTATATE PET scan is more sensitive at detecting NETs than conventional cross-sectional and octreotide scan (2).

The treatment of NETs includes the use of somatostatin analogues (i.e., octreotide and lanreotide) that target the SSTR for hormonal and disease control (3–5). The radiolabeled octreotate ¹⁷⁷Lu-DOTATATE was recently approved by the FDA for treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults on the basis of the NETTER1 study (1). ¹⁷⁷Lu-DOTATATE and other radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to tumors that over-express somatostatin receptors (6–11).

⁶⁸Ga-DOTATATE (i.e., the diagnostic agent) and ¹⁷⁷Lu-DOTATATE (i.e., the therapeutic agent) are somatostatin receptor (SSTR) agonists. They bind the receptor as the natural ligand somatostatin, leading to internalization of the receptor–ligand complex (12). SSTR agonists can only bind to the somatostatin receptor when in its active state (13). In contrast, somatostatin antagonists can bind to the SSTR in its active or inactive state (12). SSTR antagonists have demonstrated significantly higher tumor uptake in mice than agonists (12). Furthermore, a substantially higher number of binding sites was shown by ex vivo autoradiography of human NET samples (14).

Consistent with these preclinical data, preliminary clinical data have also indicated higher tumor uptake and retention of SSTR antagonists as compared with agonists. In a head-to-head comparison of the SSTR antagonist ¹¹¹In-DOTA-BASS and the agonist ¹¹¹In-DTPA-octreotide, the antagonist demonstrated improved image contrast and visualized significantly more metastatic lesions than the agonist, although both ligands exhibited almost identical SSTR affinity (15). Tumor uptake of ¹¹¹In-DOTA-BASS remained higher than that of ¹¹¹In-octreotide until 24 hours after injection (15), indicating that antagonists are well retained in the tumor tissue even though they do not lead to significant internalization of the SSTR. Similarly, PET/CT with the somatostatin antagonist ⁶⁸Ga-satoreotide tetraxetan detected significantly more metastases than PET/CT with the SSTR agonist ⁶⁸Ga-DOTATOC (16).

Here, we report the clinical results of a phase I study to assess the efficacy and safety of the novel therapeutic SSTR antagonist ¹⁷⁷Lu-satoreotide tetraxetan (also called ¹⁷⁷Lu-IPN01072 and previously known as ¹⁷⁷Lu-OPS201 and ¹⁷⁷Lu-DOTA-JR11; ref. 17) for therapy of patients with advanced and progressive metastatic NETs. ¹⁷⁷Lu-satoreotide tetraxetan has a similar SSTR affinity profile as the clinically approved SSTR agonist ¹⁷⁷Lu-DOTATATE (Lutathera; ref. 18). A preliminary comparison of these two SSTR ligands in four patients with metastatic NETs has indicated higher tumor doses and tumor-to-kidney dose ratios for ¹⁷⁷Lu-satoreotide tetraxetan than for ¹⁷⁷Lu-DOTATATE (17).

The study was a phase I investigator-initiated study conducted at Memorial Sloan Kettering Cancer Center (MSK) reviewed by the Institutional Review Board (ClinicalTrials.gov NCT02609737) and conducted under the auspices of an Investigational New Drug (IND) application acknowledged by the FDA. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All study participants provided written informed consent before study enrollment.

Eligibility criteria included pathologically confirmed, well-differentiated NETs with unresectable measurable disease according to RECIST version 1.1 on either CT or MRI, and progressive metastatic disease defined either by RECIST 1.1 or by increasing symptomatic disease (i.e., worsening hormonal symptoms or increased symptoms related to tumor burden). At least one metastasis had to show uptake of ¹¹¹In-DTPA-octreotide on SPECT that was higher than physiologic radiotracer uptake by the liver. Patients were further required to have an Eastern Cooperative Oncology Group performance status ≤ 2, be 18 years or older, and have an estimated life expectancy of >6 months. Adequate kidney and bone marrow function were required [creatinine ≤ 1.5× upper limit of normal (ULN), absolute neutrophil count ≥ 1.5 × 10/L, hemoglobin ≥9.0 g/dL, platelets ≥ 200 × 10/L] and adequate hepatic function, defined as total bilirubin ≤ 1.25× ULN, AST/ALT ≤ 2.5× ULN with liver metastases. Patients with a history of >20% bone marrow external beam radiotherapy and/or previous radioisotope therapy were excluded.

Medical history, MRI or CT, blood counts, and chemistry values were documented at screening and follow-ups. Tumor response was monitored by CT and MR studies, acquired as part of routine standard clinical care, approximately 3 and 6 months after the last treatment cycle. Tumor response was classified according to RECIST 1.1. Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events Version 4 (CTCAE), and the relationship to ¹⁷⁷Lu-satoreotide tetraxetan was assessed. Dose-limiting toxicity was defined as any ¹⁷⁷Lu-satoreotide tetraxetan-related AE ≥ grade 3 (G3).

Given that this was a first-in-human study with limited data on the dosimetry of ¹⁷⁷Lu-satoreotide tetraxetan, the main goal was to define safety and tolerability and characterize the AE profile. Safety, tolerability, and AEs were summarized using descriptive statistics. Overall response rate was according to RECIST 1.1. The median point estimate and 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. A stopping rule was incorporated into the trial that if we observed more than one excessive toxicity within the first 10 patients, we would stop the study; otherwise, we would proceed to enroll 10 more patients. If we saw more than two excessive toxicities within the 20 (cumulative including the one that might have been seen among the first 10), we would stop the study. Excessive toxicities were defined as treatment-related toxicities leading to an unacceptable delay in completing the two cycles of therapy as well as any delayed or irreversible grade 3 (G3) or grade 4 (G4) toxicities.

The ¹⁷⁷Lu-satoreotide tetraxetan therapeutic agent was manufactured by the MSK Radiochemistry and Molecular Imaging Probes Core Facility in compliance with the requirements specified in the Chemistry, Manufacturing, and Controls section of an FDA-acknowledged IND (No.128,082).

The treatment schema (Fig. 1) included imaging with the SSTR2 antagonist ⁶⁸Ga-DOTA-JR11, which is chemically identical to ¹⁷⁷Lu- satoreotide tetraxetan (previously known as ¹⁷⁷Lu-DOTA-JR11) except for the different radioisotope (the positron emitter ⁶⁸Ga rather than the beta emitter ¹⁷⁷Lu). Only patients with ⁶⁸Ga-DOTA-JR11 uptake greater than liver in at least one metastasis of more than 2 cm in diameter were considered for therapy. Patients with ⁶⁸Ga-DOTA-JR11–positive disease then underwent a dosimetry study with ¹⁷⁷Lu- satoreotide tetraxetan to determine the therapeutic activity that could be safely administered, based on normal tissue-absorbed radiation dose criteria. Given the worldwide clinical experience with radiolabeled SSTR agonists, we expected the kidney and bone marrow to be the main dose-limiting organs. The absorbed dose limits were set at 23 Gy total dose (i.e., combined dosimetry and therapy) for kidney, as suggested by the QUANTEC guidelines for external beam radiotherapy, and 1.5 Gy for red marrow, based on experience with ¹³¹I therapy for thyroid cancer (19), ¹³¹I-labeled antibodies (19), and ¹⁷⁷Lu-labeled SSTR agonists (20). The administered activity for the pre-therapy dosimetry study was nominally set at 1.85 GBq (50 mCi). Thereafter, the balance of activity that was predicted to deliver the lower of the two absorbed dose limits was calculated. This was split into two equal amounts to be delivered 3 months apart. However, if the first treatment resulted in estimated absorbed doses that differed from the initial predictions, the second treatment could be decreased or increased to achieve the intended dose limits. Irrespective of these calculated activities, the maximum allowable activity of ¹⁷⁷Lu- satoreotide tetraxetan was fixed at 7.4 GBq (200 mCi) per administration. The mass dose of satoreotide tetraxetan injected into the patient ranged from 50–100 μg for PET imaging, dosimetry, and both therapeutic administrations.

The study was suspended when four of seven (57%) patients unexpectedly developed G4 hematologic toxicity after the second therapeutic administration of ¹⁷⁷Lu-satoreotide tetraxetan. When the study was restarted, the treatment schema was modified such that the prescribed activity for the second therapeutic cycle was reduced to 50% of what it otherwise would have been. A dose reduction of 50% was chosen arbitrarily to ensure safety.

Full details of the methodology and results of radiation dose estimation will be presented elsewhere. Briefly, radiation dose estimates were calculated based on the analysis of serial blood counts and planar scintigraphic images together with a single SPECT/CT scan of the upper abdomen. Volumes of interest (VOI) were generated to correspond to kidney, spleen, uninvolved liver, bone, and 1–5 index lesions for each patient. The activity concentrations in VOI and the corresponding areas under the curve were estimated. It was assumed that the activity concentration in red bone marrow was equal to that in blood (21). These data were used to provide input to the radiation dose estimation software package OLINDA/EXM 1.0 (22). Radiation dose estimates to index lesions were generated, considering only the non-penetrating component (i.e., beta particles) of ¹⁷⁷Lu emissions.

From December 2015 to July 2017, 20 patients (10 female, 10 male) with an average age of 58 years were enrolled in this prospective single-center study. Patient characteristics are summarized in Table 1. The most common primary tumor site was pancreas (45%). All patients had metastatic disease, with the most common sites being liver (95%), lymph nodes (75%), and bone (35%). Ten percent (2/10) were hormone secreting, both small bowel with carcinoid syndrome. Seventy-five percent of tumors were classified as intermediate grade, 20% were low-grade, and 5% high-grade. The median number of prior treatments was three. Prior to study enrollment, 60% of the patients had undergone surgical resection, 80% somatostatin analog therapy, 45% hepatic arterial embolization, 55% cytotoxic therapy, and 55% targeted therapy.

The ⁶⁸Ga-DOTA-JR11 PET/CT scans demonstrated high tracer uptake of the known metastases in all patients (peak standardized uptake value, SUV peak, 2.5–84.0, average 18.0). Tracer uptake by the liver was markedly lower (average SUV 1.1; range, 0.7–1.9; ref. 23). Therefore, all patients went on to the dosimetry study, and received one therapeutic dose of ¹⁷⁷Lu- satoreotide tetraxetan. Fourteen patients received two therapeutic doses. Five of the six patients did not receive the second dose because of clinical or radiographic progression; the sixth patient sustained a PR with the first dose and opted to come off study and received radioembolization to the liver eight months after the first treatment dose.

The study was put on hold when four of seven patients developed G4 hematologic toxicity after their second therapeutic dose, approximately 4 to 8 weeks after treatment. The hematologic toxicities thus occurred at the typical time after the second treatment and did not delay the treatment. Because all G4 toxicities were reversible and occurred after the completion of the therapy we did not meet the stopping rules to close the study. We did, however, place the study on hold which was approved by the IRB and FDA. None of the patients with G4 toxicities had been treated with cytotoxic therapy prior to study enrollment. At the time the study was placed on hold, 19 patients had received their first therapeutic dose. The study restarted after a delay of approximately one year, and the gap between treatments for the next six patients was a median of 80 weeks (70–85 weeks). The reason for the extended gap was that we prioritized the patients that did not have a measurable response and treated them first. These patients received no additional antineoplastic treatment while awaiting the second treatment dose. Those that achieved PR were withheld treatment until the other patients were treated. The final patient entered the study after the restart and had a gap between treatments of three months. Activities for all administrations of ¹⁷⁷Lu-satoreotide tetraxetan with associated time gaps and best responses are shown in Supplementary Table S1.

Radiation dose estimates to normal tissues based on pretherapeutic dosimetry administration are shown in Table 2. The normal tissues that received the highest radiation doses were spleen (mean, 1.48 Gy/GBq; range, 0.12–4.01), kidneys (1.03 Gy/GBq; 0.15–1.52), and liver (0.47 Gy/GBq; 0.24–1.13). The estimated radiation dose to the red bone marrow was a mean of 0.09 Gy/GBq (range, 0.06–0.15). For index lesions, the estimated radiation doses on a per-patient average basis ranged from 1.6 to 11.9 Gy/GBq.

¹⁷⁷Lu-satoreotide tetraxetan targeted disease with high uptake in all known sites of disease (liver, nodes, bone). Figure 2 shows a selection of patient images illustrating intense tumor uptake of ¹⁷⁷Lu-satoreotide tetraxetan and prolonged intratumoral retention of activity. On a patient-average basis, the effective terminal half-life ranged from 66 to 117 hours with a median of 87 hours, corresponding to biological half-times of 111 to 430 hours with a median of 188 hours.

Typically, disease that was visualized on ¹⁷⁷Lu-satoreotide tetraxetan scans was also seen on the prior ⁶⁸Ga-DOTA-JR11 PET scans. A detailed comparison of lesion targeting between ⁶⁸Ga-DOTA-JR11 and ¹⁷⁷Lu-satoreotide tetraxetan will be reported elsewhere.

Nonhematologic AEs that were considered possibly, probably, or definitely related to ¹⁷⁷Lu-satoreotide tetraxetan treatment occurred in 14 patients (70%) and were all grade 1 or 2 G1 or G2). These included G2 nausea (5%) and G2 vomiting (5%), which were attributed to the concurrently infused amino acid solution and resolved once the infusions were complete. Other AEs included G1 hair loss (10%), G1 asthenia (5%), G1 tremor (5%), G2 diarrhea (10%), G1 facial edema (5%), G2 lower extremity edema (10%), and G2 mucositis (5%; Table 3). There were no renal toxic effects during the observed time frame. One of the two hormone secreting patients required octreotide short acting octreotide to control the carcinoid syndrome immediately following the infusion but neither patient had an exacerbation of the carcinoid syndrome after the treatment.

The maximum grades of hematologic toxicity are detailed in Table 4. Subacute hematologic toxicity after cycle 1 was mild-moderate [G3/4 2/19 (10%) leukopenia that reversed before cycle 2]. However, G4 thrombocytopenia occurred in four of the first seven patients (57%) who received a second therapeutic administration of ¹⁷⁷Lu-satoreotide tetraxetan. This toxicity started approximately 4 to 6 weeks after administration of the second therapeutic dose and lasted 7 to 16 weeks. Two of these patients also developed G3 anemia and three of these patients developed G3/4 neutropenia (Table 4). To examine any possible dose–response relationship with hematologic toxicity, we calculated the projected total radiation doses to red bone marrow for the combined dosimetry and therapeutic administrations. These are based on the red marrow doses estimated from the pretherapeutic dosimetry administration.

We examined the relationship between the estimated red marrow radiation dose (for all administrations combined) and the appearance of hematologic toxicity (Fig. 3). G4 thrombocytopenia was used as the toxicity endpoint, as this was the most common G4 toxicity observed. Furthermore, prior work had suggested the existence of a dose response for platelet toxicity by radionuclide therapy (19). All patients treated with two cycles of ¹⁷⁷Lu-satoreotide tetraxetan within 3 months who received ≥1.44 Gy bone marrow dose developed G4 thrombocytopenia (and G3/4 neutropenia; Fig. 3). In contrast, no patient with ≤1.08 Gy bone marrow dose experienced G4 thrombocytopenia or neutropenia.

Myelodysplastic syndrome has not been observed in this trial to date. One patient with low counts subsequently underwent a bone marrow biopsy that revealed normal trilineage hematopoiesis and his counts subsequently recovered.

Overall response rate was 45% [1 CR (1/20, 5%), 40% PR (8/20)]; 40% had SD (8/20), and 15% had PD (3/20). Supplementary Figures S4 and S5 (waterfall plot) show examples of tumor responses to ¹⁷⁷Lu- satoreotide tetraxetan. Median follow-up was 32 months. Median PFS was 21.0 months (95% CI, 13.6–NR) and 2-year PFS was 38% (20–73 months). Six deaths occurred, and median OS was not reached. Two-year overall survival was 85% (71–100) and 3-year overall survival was 69% (51–93; Fig. 4). Responses were also seen in patients for whom the second treatment dose had been reduced and/or delayed (Table 4). Supplementary Figures S1–S3 show (as examples) the tumor response for patients 19 and 20, who enrolled after the protocol was modified with dose reduction. Total red marrow dose was 1.35 and 0.88 Gy, respectively, and both achieved a partial sustained response.

In this phase I trial involving patients with progressive, heavily pretreated, well-differentiated, and mostly intermediate-grade NETs, one to two cycles of ¹⁷⁷Lu-satoreotide tetraxetan resulted in a promising clinical response rate of 45%. Median PFS was 21.0 months (95% CI, 13.6–NR) and 2-year PFS was 38% (20–73 months). Benefit was seen across all different types of gastroenteropancreatic NETs studied. High tumor uptake and slow washout resulting in high tumor radiation doses likely explain the high response rate with only one to two treatment cycles (23).

No renal toxicity was observed, consistent with other PRRT studies with ¹⁷⁷Lu-labeled somatostatin ligands (24, 25). Hematologic toxicity, however, was unexpected and more severe than reported with other radionuclide therapies and none of these patients were heavily treated (26–28). G3 or G4 hematotoxicity occurs in about 10% of patients treated with four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE, a somatostatin receptor agonist with a similar affinity for SSTR2 as ¹⁷⁷Lu-satoreotide tetraxetan (24). In about half of these patients, the hematotoxicity after ¹⁷⁷Lu-DOTATATE was prolonged (>6 months) or required transfusions. As in the current study, leukopenia and thrombocytopenia are more common after ¹⁷⁷Lu-DOTATATE therapy than anemia. Dosimetry studies have indicated that the red marrow dose for four cycles of ¹⁷⁷Lu-DOTATATE may exceed 2 Gy in up to 50% of patients (24, 29). In contrast, we observed prolonged G4 thrombocytopenia and G3 leukopenia in four of seven patients who received an estimated bone marrow radiation dose in the range of 1.5 Gy. After dose modification, there were no safety issues.

The reasons for the unexpected severity of hematotoxicity are currently unclear. At the time the protocol was designed, 1.5 Gy was considered a relatively low (and safe) limit for red marrow, especially because treatment was to be delivered over multiple cycles. Hematopoiesis did eventually recover in all patients and no patient developed myelodysplastic syndrome in 32 months of follow-up. A bone marrow aspirate performed in one patient illustrated normal tri-lineage cells and failed to identify an etiology.

The hematotoxicity is likely caused by ionizing radiation (11), because there was a relationship between the estimated red marrow radiation dose and the appearance of hematologic toxicity; all patients who received two therapeutic administrations 3 months apart of ≥1.44 Gy, and no patients who received doses ≤1.08 Gy, experienced G4 thrombocytopenia.

Furthermore, the amount of peptide administered per cycle was low (≤100 μg) and all patients received the same peptide mass. No patients developed hematotoxicity once a 50% reduced amount of ¹⁷⁷Lu was administered with the same peptide mass. This suggests that a purely pharmacologic effect of the SSTR antagonist is unlikely; however, somatostatin and other neuropeptides are involved in the regulation of hematopoiesis (30–33) and the possibility of some unknown radiation damage potentiating interaction cannot be excluded.

Increased binding capacity of ¹⁷⁷Lu-satoreotide tetraxetan to SSTRs, including bone marrow stem cells, could have increased the radiation exposure of progenitor cells, thereby causing prolonged bone marrow suppression. Two articles studied the effects of peptide receptor radiotherapy on the bone marrow. Forrer and colleagues compared radioactivity of the blood with the bone marrow aspirates in 15 patients after treatment with ¹⁷⁷Lu-DOTATATE. They noted that the radioactivity in the bone marrow was identical to that in the blood. There was no significant binding of the radiopharmaceutical to the whole marrow (21). However, Sigrid and colleagues showed that SSTRs are specifically expressed on immature (CD34⁺⁾human and murine hematopoietic progenitors and that somatostatin acts as a chemoattractant for these cells (34). Flow cytometric analysis showed that SSTR expression was restricted to CD34⁺cells and that the CD34⁺/CD117⁺subset, the most immature population of CD34⁺cells, showed the highest SSTR expression (34). Because these cells represent only a small fraction of the total bone marrow, high uptake of ¹⁷⁷Lu-satoreotide will not be detectable on whole-body imaging studies. We therefore hypothesize, because of the short path length of the beta particles emitted by ¹⁷⁷Lu, that SSTR2-positive stem cells may receive a higher radiation dose than the average for the whole bone marrow. Because clinical dosimetry studies only determine the average dose to the bone marrow, this may explain why we observed severe hematotoxicity despite the low average bone marrow dose. These results illustrate that macroscopic bone marrow radiation dose limits for one form of PRRT do not necessarily apply to other types of PRRT even if the target and radionuclide are the same. We believe these are important findings to consider when testing future radiolabeled therapies. In particular, phase I clinical trials with novel molecular targeting vectors may require a more conservative approach to starting levels of radiation dose/administered activity and toxicity monitoring. Our results show that severe toxicity can occur even when radiation dose estimates are within limits previously considered safe and that low-level marrow toxicity for the first treatment cycle does not guarantee the same for second or subsequent cycles even with a 12-week gap between cycles. However, estimated radiation dose to red marrow did seem to be a reliable guide to toxicity, albeit with tolerance doses less than expected from clinical experience with 177Lu-DOTATE.

Limitations of our study for assessment of PFS and OS include the extensive delay in treating a subgroup of patients with the second therapeutic dose, with some patients having scans that were quite delayed, which could have inflated the PFS. We therefore interpret the very long PFS in this group of patients with heavily pretreated, mostly intermediate-grade NETs with caution. In addition, our patient sample size is small, which is, however, typical for this stage of early drug development. In addition, extended follow-up was not reported to evaluate the long-term safety profile of ¹⁷⁷Lu-satoreotide tetraxetan but is ongoing.

In summary, this phase I study indicates that ¹⁷⁷Lu-satoreotide tetraxetan can deliver high radiation doses to NETs with favorable tumor-to-normal organ dose ratios. Preliminary data on tumor response rates and PFS are encouraging and overall support a potential therapeutic role for radiolabeled somatostatin antagonists in the treatment of NETs. However, the initial treatment schedule of this trial was associated with more severe hematotoxicity than expected from SSTR2 agonists at the same or higher red marrow dose. Treatment with reduced activity and longer treatment intervals drastically reduced hematologic toxicity while preserving activity.

D. Reidy-Lagunes is a consultant/advisory board member for Novartis, Ipsen, AAA (Advanced Accelerator Applications), and Lexicon and reports receiving commercial research grants from Novartis, Ipsen, and Merck. N. Pandit-Taskar is a consultant/advisory board member for Progenics and Actinium Pharma. L. Bodei is a consultant/advisory board member for AAA (Advanced Accelerator Applications), Ipsen, and Curium. W.A. Weber is a consultant/advisory board member for Bayer, Blue Earth Diagnostics, Endocyte, Ipsen, and Pentixapharm. No potential conflicts of interest were disclosed by the other authors.

Conception and design: D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, S.K. Lyashchenko, M. Gönen, W.A. Weber

Development of methodology: D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, S.K. Lyashchenko, J.S. Lewis, W.A. Weber

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, S. Krebs, K.D. Staton, J.S. Lewis, L. Bodei, W.A. Weber

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, S. Krebs, K.D. Staton, M. Gönen, C. Lohrmann, L. Bodei, W.A. Weber

Writing, review, and/or revision of the manuscript: D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, S. Krebs, K.D. Staton, J.S. Lewis, N. Raj, M. Gönen, C. Lohrmann, L. Bodei, W.A. Weber

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D. Reidy-Lagunes, J.A. O'Donoghue, S. Krebs, K.D. Staton, S.K. Lyashchenko, J.S. Lewis, C. Lohrmann

Study supervision: D. Reidy-Lagunes, N. Pandit-Taskar, J.A. O'Donoghue, W.A. Weber

This study was supported in part by the Geoffrey Beene Cancer Research Center at MSK and the MSK Radiochemistry and Molecular Imaging Probe Core, which is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. We gratefully acknowledge funding by Caring for the Carcinoid/NETRF. The precursor used in this study was provided by OctreoPharm/Ipsen. Ipsen reviewed this manuscript for scientific accuracy but had no input into the content. S. Krebs was supported in part by the NIH/NCI Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746. We gratefully acknowledge Rashid Ghani and members of the Nuclear Medicine Pharmacy; nuclear medicine nurses Ann Longing and Louise Harris for their help in patient management; RSAs Alicia Lashley, Hanh Pham, and Martha Ziolkowska and Clinical Research Manager Bolorsukh Gansukh for their excellent support with patient flow and protocol management; and the radiation safety officers and nuclear medicine technologists for their excellent technical assistance.

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