Somatostatin Receptor-positive Tumors Research Articles

685TiP A phase I, multicenter trial (“KinLET”) of [177Lu]Lu-edotreotide for treatment of somatostatin receptor positive solid tumors or lymphoma, in patients two to less than 18 years of age

685TiP A phase I, multicenter trial (“KinLET”) of [177Lu]Lu-edotreotide for treatment of somatostatin receptor positive solid tumors or lymphoma, in patients two to less than 18 years of age

A phase II randomized control trial of triapine plus lutetium 177 DOTATATE versus lutetium 177 DOTATATE alone for well-differentiated somatostatin receptor-positive neuroendocrine tumors.

TPS4202 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 14% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals. Methods: This study is an investigator initiated, NCI sponsored, multicenter randomized phase 2 trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive neuroendocrine tumor. A total of 94 patients will be equally randomized to either Lu-177 dotatate or Triapine + Lu-177 dotatate arm. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Triapine will be administered orally from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate overall response rate (ORR). Secondary endpoint is to evaluate median PFS. We are also evaluating triapine PK, plasma deoxyribonucleosides, circulating DNA and plasma hPG80, a novel blood based diagnostic biomarker. Clinical trial information: 05724108.

DOTATATE PET/MR Imaging Differentiates Secondary-Progressive from de Novo World Health Organization Grade 3 Meningiomas.

WHO grade 3 meningiomas are rare and poorly understood and have a higher propensity for recurrence, metastasis, and worsened clinical outcomes compared with lower-grade meningiomas. The purpose of our study was to prospectively evaluate the molecular profile, PET characteristics, and outcomes of patients with World Health Organization grade 3 meningiomas who were imaged with gallium 68 (68Ga) DOTATATE PET/MR imaging. Patients with World Health Organization grade 3 meningiomas enrolled in our prospective observational cohort evaluating the utility of (68Ga) DOTATATE PET/MR imaging in somatostatin receptor positive brain tumors were included. We stratified patients by de novo-versus-secondary-progressive status and evaluated the differences in the PET standard uptake value, molecular profiles, and clinical outcomes. Patients met the inclusion criteria (secondary-progressive: 7/14; de novo: 7/14). The secondary-progressive cohort had a significantly higher per-patient number of surgeries (4.1 versus 1.6; P = .011) and trended toward a higher number of radiation therapy courses (2.4 versus 1.6; P = .23) and cumulative radiation therapy doses (106Gy versus 68.3Gy; P = .31). The secondary-progressive cohort had a significantly lower progression-free survival compared with the de novo cohort (4.8 versus 37.7 months; P = .004). Secondary-progressive tumors had distinct molecular pathology profiles with higher numbers of mutations (3.5 versus 1.2; P = .024). Secondary-progressive tumors demonstrated higher PET standard uptake values (17.1 versus 12.4; P = .0021). Our study confirms prior work illustrating distinct clinical outcomes in secondary-progressive and de novo World Health Organization grade 3 meningiomas. Furthermore, our findings support (68Ga) DOTATATE PET/MR imaging as a useful management strategy in World Health Organization grade 3 meningiomas and provide insight into meningioma biology, as well as clinical management implications.

Abstract LB222: Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy

Abstract Radioligand therapy (RLT) is emerging as a safe and effective targeted approach for treating several types of cancers. Lutathera® (177Lu-Dotatate) and Pluvicto® (177Lu-PSMA-617) are two examples of FDA-approved 177Lu-based RLT drugs for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), respectively. Despite the clinical success of 177Lu-RLT, there are still patients lacking complete, durable responses. Arguably, elucidating the cellular responses to 177Lu-RLT and its mechanism of action could reveal potential opportunities for the improvement of therapy and outcome for patients. We have investigated the phenotypes and responses of multiple 177Lu- RLT-treated cell lines and observed that 177Lu-RLT induces a plethora of DNA Damage Response (DDR) markers, especially those indicative of double-strand break (DSB) repair by either non-homologous end-joining (NHEJ) or homologous recombination (HR). Furthermore, 177Lu-RLT leads to cell-cycle alterations, accumulation of micronuclei and cell death. In agreement with published reports, we have observed that either the knock-out or inhibition of NHEJ core factors such as the catalytic subunit of DNA-PK (PRKDC) renders cells sensitive to 177Lu-RLT and the combination of both the 177Lu-RLT and DNA-PK inhibitor provides a beneficial tumor growth inhibition in vivo. To further unravel the mechanism of action of 177Lu-RLT, we have conducted ‘DDR-ome’ targeted genetic screens, which also suggest that DSBs are the most cytotoxic form of 177Lu-RLT-induced DNA damage. In addition to DNA-PK, we have identified novel DDR targets that could sensitize to 177Lu-RLT. We are currently testing whether inhibiting these targets in combination with certain 177Lu-RLT could, in addition to potentially achieving greater antitumor response, allow for lower dosing to reduce radiation exposure. Taken together, our work provides better understanding of the cellular responses to 177Lu-based RLT and pinpoints NHEJ as a critical pathway promoting survival to this treatment, which could set the basis for novel combination therapies. Citation Format: Marco Ranzani, Sravanth Hindupur, Alessandro Cicconi, Guillermo Sastre-Moreno, Alexander Kristian, Barbara Schacher Engstler, Benika Pinch, Charlene Hartnagel, Delphine Gorses, Elise Simon, Emeline Mandon, Emilien Schramm, Fanny Schaeffer, Josefine Reber, Louise Barys, Luisa Deberle, Milene Walter, Ralph Bessey, Riccardo Destefani, Xavier Miot, Elias Elinati, Nan Shao, Marie Boursier, Joseph Barlow, Asmita Thapa, Alessandro Galbiati, Diego Grande, Eeson Rajendra, Niall Martin, Graeme Smith, Tobias Schmelzle, Markus Reschke, Helen Robinson, Marta Cortes-Cros. Elucidating the cellular responses and mechanism of action of 177Lu-based radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB222.

18F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs)

A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60-80%, non-decay corrected) and high radiochemical purity (>95%). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/μmol. At 30min and 60min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47±0.97%/105 cells and 12.11±0.32%/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77±1.14nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

ETCTN 10388: A first in human Phase I Trial of Triapine and Lutetium Lu 177 DOTATATE in Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

ETCTN 10388: A first in human Phase I Trial of Triapine and Lutetium Lu 177 DOTATATE in Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

THU529 Challenges In The Management Of Biochemically Silent Paraganglioma

Abstract Disclosure: S. Dewan: None. A. Farooqi: None. J. Jun: None. Biochemically silent Pheochromocytoma and Paraganglioma (PPGL) are rare neuro-endocrine tumors because of which there is low quality evidence and insufficient guidelines for their management. 74-year-old Female was referred to our Endocrine clinic for incidentally discovered Retroperitoneal mass on MRI. On evaluation patient reported having concerns of escalating anxiety, difficult to control HTN and episodic flushing after physical activity in the last one year. A CT abdomen and pelvis with contrast was ordered which showed 1.7 x 1.8 cm mass anterior to the L5 vertebral body just caudal to the aortic bifurcation. The biochemical work up including 24-hour urine Metanephrines (104 ug/24 hr; n 52-341), Normetanephrines (479 ug/24 hr; n 88-444), Total Metanephrines (583 ug/24 hr; n 88-444), 3 Methoxytyramine (166 mcg/24 hr; n &amp;lt;242) was inconclusive. For further evaluation PET CT DOTATATE scan was ordered which showed the lesion to be DOTATAE somatostatin analogue avid, consistent with somatostatin receptor positive neuroendocrine tumor. Patient was scheduled for surgery in 2 weeks and was started on Terazosin in addition to her anti HTN medications Amlodipine, Losartan and HCTZ. The surgery had to be rescheduled due to inadequate blood pressure control. Her amlodipine and Terazosin dosage were gradually increased while the procedure was rescheduled. Eventually she underwent Laparotomy exploration and resection of the lesion. Patient tolerated the procedure well and had no major intra or post operative fluctuations in her blood pressure, heart rate or blood glucose. According to the Endocrine Surgery team, the tumor could not be sufficiently removed since it was immovable during surgery and could not be delineated from the spine. The post-operative CT scan showed nodular lesion at aortic bifurcation slightly increased in soft tissue component from prior CT scan. After discussions with surgery and oncology team, patient opted for imaging surveillance for now and will consider genetic counseling and/or radiation therapy if the tumor increases in size. Untreated PPGL carries a high risk of cardiovascular morbidity and mortality, and some may also be malignant with a propensity to cause mass effects and metastasis. Currently, there are scarce evidence-based studies comparing treatment options in biochemically silent PPGL, and there is no consensus for the most appropriate peri-operative management of biochemically silent PPGL. This case adds to the literature on how a combination of calcium channel blocker and alpha blocker can be used to achieve peri-operative blood pressure and heart rate control with no major side effects. It also demonstrates the importance of functional imaging, especially in clinically or radiologically suspected PPGL, even with a normal biochemical work up. We suggest multi-disciplinary evaluation and individualized management to ensure positive outcomes. Presentation: Thursday, June 15, 2023

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours

PurposeWe present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity.MethodsThis study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow.ResultsMedian cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3–99.4), and overall response rate was 21.1% (95% CI: 9.6–37.3).Conclusion[177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing.Trial registrationClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera®) Case.

Lu-177 DOTATATE (Lutathera®) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment. The aim of this work was to study the pharmacokinetics of Lu-177 DOTATATE by a population modeling approach, based on single-photon emission computed tomography (SPECT)/computed tomography (CT) images used as surrogate of plasma concentrations to study the interindividual variability and finally optimize an individual dosage. From a retrospective study, SPECT/CT images were acquired at 4h, 24h, 72h, and 192h postadministration. From these images, volumic activities were calculated in blood and bone marrow. An individual non-compartmental pharmacokinetic analysis was performed, and the mean pharmacokinetic parameters of each tissue were compared together and with reference data. Blood volumic activities were then used to perform a population pharmacokinetic analysis (NONMEM). The pharmacokinetic parameters (non-compartmental analysis) obtained from blood (clearance [CL]=2.65L/h, volume of distribution at steady state [Vss]=309L, elimination half-life [t1/2]=86.3h) and bone marrow (CL=1.68L/h, Vss=233L, t1/2=98.8h) were statistically different from each other and from reference values (CL=4.50L/h, Vss=460L, t1/2=71.0h) published in the literature. SPECT/CT blood images were used as a surrogate of plasma concentrations to develop a population pharmacokinetic model. Weight was identified as covariate on volume of the central compartment, reducing the interindividual variability of all population pharmacokinetic parameters. This study is a proof of concept that obtaining pharmacokinetic parameters with image-based blood concentration is possible. Obtaining observed concentrations from SPECT/CT images, without the need for blood sampling, is a real advantage for the patient and the drug monitoring. Pharmacokinetic modeling could be combined with a deep learning model for automatic contouring and allow precise patient-specific dose adjustment in a non-invasive manner.

Abstract CT194: ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Method: This study was a multicenter phase 1 dose escalation trial [using the Bayesian optimal interval design (BOIN)] of triapine in combination with fixed dose lutetium Lu 177 DOTATATE for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment with an expansion cohort at the recommended phase 2 dose (RP2D). Oral triapine (100mg, 150mg, 200mg) was administered once daily on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. Response and adverse effects were assessed per RECIST and CTCAE 5.0, respectively. Exploratory correlative studies included tumor somatic and germline mutation testing, RNA sequencing, pharmacokinetics, deoxynucleosides and circulating cell free DNA analysis. Primary endpoints were safety and RP2D. Results: Overall, 31 patients were enrolled between 6 sites, 15 in the dose escalation phase and 16 in the dose expansion phase. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. The RP2D of the combination is triapine 150 mg QD (dose level 2) on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Detailed safety and adverse event data will be presented at the meeting. There were 28 patients evaluable for efficacy, of which 6 (21%) achieved a partial response. At 12 months, 6 patients had progressed, while 22 (86%) remained progression free. Median PFS has not been reached. PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Conclusion: The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals, which will be further evaluated in ETCTN 10558, a randomized phase 2 study that is comparing the effectiveness of triapine and Lu-177 DOTATATE to Lu-177 DOTATATE alone. Citation Format: Aman Chauhan, Susanne Arnold, Jill Kolesar, William Carson, Heidi Weiss, Rani Jayswal, Donglin Yan, Riham El Khouli, Aman Khurana, Jan Beumer, Heloisa Soares, Mary Mulcahy, Thorvardur Halfdanarson, Daneng Li, Heather Jacene, Percy Ivy, Elise Kohn, John Wright, Larry Rubinstein, Zeta Chow, Piotr Rychahou, Mark B. Evers, Charles Kunos, Lowell Anthony, Bhavana Konda. ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT194.

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

TPS658 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand break (DSB); targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radiosensitivity. The primary repair mechanism of radiation-induced DSBs is nonhomologous end-joining (NHEJ) pathway, in which the DNA-PK (Deoxyribonucleic acid protein kinase) complex plays a pivotal role. Upregulation of DNA-PK promotes repair of DSBs leading to tumor radio-resistance preclinically and clinically. Thus, DNA-PK is an important molecular target for inhibiting DSB repair and enhancing the cytotoxicity of radiation. Peposertib is a selective inhibitor of DNA-PK that targets tumor cell DNA damage repair and survival by blocking NHEJ. We previously reported strong anti-tumor activity when Peposertib was used as radiation sensitizer in pre-clinical NET models. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of peposertib and Lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with peposertib. Peposertib will be administered orally from D1-21 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating Lu-177 DOTATATE dosimetry in collaboration with NIH IROC and plasma hPG80, a novel blood based diagnostic biomarker. In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954 .

ODP309 Ectopic Cushing's Syndrome: Importance of Methodical Approach to Hide and Seek

Abstract Cushing's syndrome (CS) is associated with high morbidity and fivefold excess mortality. Ectopic ACTH syndrome accounts for 20% of CS cases. It is crucial to identify and localize the source of extrapituitary ACTH secretion because surgical resection of the primary, often malignant, tumor has a high probability of cure with complete remission in 80% of cases. A 72-year-old female was admitted to a community hospital for lateral chest pain after a fall. She endorsed progressive weight gain, new HTN, emotional lability and worsening cognition over the prior 6 months. ACTH and cortisol levels were elevated. MRI brain failed to identify a pituitary lesion. CT chest showed multiple rib fractures and anterior mediastinal mass which was biopsied. While awaiting pathology results, IPS sampling attempted but aborted due to pulmonary edema necessitating ICU care. She was transferred to our institution for planned TSR of suspected pituitary adenoma. Examination showed Cushingoid features. Labs showed hypokalemia, high cortisol and high ACTH. MRI pituitary showed normal sella. MRI spine showed multilevel vertebral compression fractures. CT chest showed interval growth of mediastinal mass. A 1 mg dexamethasone suppression test failed to suppress ACTH and cortisol, confirming ACTH dependent hypercortisolism. A high dose 8 mg dexamethasone test failed to suppress ACTH and cortisol, a 10 mcg DDAVP stimulation test showed a flat response, with ACTH and cortisol levels remaining comparable before and after DDAVP injection. Dynamic testing therefore consistent with ectopic ACTH dependent hypercortisolism. Gallium-68 DOTA-TATE PET Scan demonstrated uptake in mediastinal mass suggestive of somatostatin receptor positive neuroendocrine tumor. Biopsy specimens processed at our institution showed cells positive for epithelial markers Cytokeratin and PAX8. Sample showed neuroendocrine differentiation with positive staining for Chromogranin A, synaptophysin and CD 117. Findings consistent with neuroendocrine thymic neoplasm. The patient was started on oral ketoconazole to control hypercortisolism. Surgical resection of tumor was planned with intent to cure CS. Ultimately, due to proximal myopathy and multiple vertebral fractures her performance status was too poor for safe tumor resection. Unfortunately, she died of complications related to CS while attempting preoperative rehabilitation. This case illustrates the importance of a timely, systematic evaluation for ACTH source in ACTH dependent hypercortisolism. Delay in CS diagnosis and localizing correct ACTH source led to missing the window of fitness for curative surgery. If ACTH is elevated, the most common source is pituitary neoplasia, however ectopic ACTH production must be ruled out. Dynamic testing including high dose dexamethasone suppression test, CRH and DDAVP stimulation tests should be used for preliminary localization of ACTH production. IPS sampling is invasive with greater potential for complications, as in the case of our patient. Therefore, it is only indicated if there are conflicting results from different dynamic tests and imaging studies. Presentation: No date and time listed

Occupational radiation exposure assessment during the management of [68Ga]Ga-DOTA-TOC

BackgroundSince it was first approved in Europe in 2016, the gallium-68 (68Ga) radiopharmaceutical [68Ga]Ga-DOTA-TOC has been widely used for imaging of somatostatin receptor (SSTR) positive tumours using positron emission tomography–computed tomography (PET/CT). Significant patient benefits have been reported, so its use is rapidly increasing. However, few studies have been published regarding occupational doses to nuclear medicine personnel handling this radiopharmaceutical, despite its manual usage at low distances from the skin and the beta-emission decay scheme, which may result in an increased absorbed dose to their hands. In this context, this study aims to analyse the occupational exposure during the administration of [68Ga]Ga-DOTA-TOC for PET/CT imaging. For this purpose, extremity, eye lens and whole-body dosimetry in terms of Hp(0.07), Hp(3) and Hp(10), respectively, was conducted on six workers with both thermoluminescent dosimeters, and personal electronic dosimeters.ResultsThe non-dominant hand is more exposed to radiation than the dominant hand, with the thumb and the index fingertip being the most exposed sites on this hand. Qualitative analysis showed that when no shielding is used during injection, doses increase significantly more in the dominant than in the non-dominant hand, so the use of shielding is strongly recommended. While wrist dosimeters may significantly underestimate doses to the hands, placing a ring dosimeter at the base of the ring or middle finger of the non-dominant hand may give a valuable estimation of maximum doses to the hands if at least a correction factor of 5 is applied. Personal equivalent doses for the eyes did not result in measurable values (i.e., above the lowest detection limit) for almost all workers. The extrapolated annual dose estimations showed that there is compliance with the annual dose limits during management of [68Ga]Ga-DOTA-TOC for diagnostics with PET in the hospital included in this study.ConclusionsImaging with [68Ga]Ga-DOTA-TOC is a safe process for the workers performing the administration of the radiopharmaceutical, including intravenous injection to the patient and the pre- and post-activity control, as it is highly unlikely that annual dose limits will be exceeded if good working practices and shielding are used.

Evaluation of Patient Transmission Factor Following the Administration of 177Lu-DOTATATE.

177Lu-DOTATATE is a radionuclide therapy that is FDA approved for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Treatment facilities are required to determine the maximum radiation dose from such subjects to the maximally exposed member of the public, ensuring that the total effective dose equivalent (TEDE) does not exceed regulatory limits. If the calculated TEDE meets the regulatory limits, the patient is eligible for release and provided instructions with radiation precautions. This study aims to determine a mean transmission factor to the patient to improve accuracy and individualize the estimation of the TEDE.

Practical Considerations for Implementation of 177Lu-DOTATATE Neuroendocrine Tumor Treatment Programs.

The 2018 FDA approval of 177Lu-DOTATATE for the treatment of somatostatin receptor-positive (SSTR) neuroendocrine tumors (NETs) represents a paradigm shifting approach to cancer treatments around the globe. Gastroenteropancreatic (GEP) NETs overexpress the somatostatin subtype receptor 2, which is now exploited for receptor-based imaging and therapy, thus generating significant progress in the diagnosis and treatment of this orphan disease. The recent FDA approval of receptor-based PET radiopharmaceuticals and a new peptide receptor radiopharmaceutical therapy (PRRT), 177Lu-DOTATATE, has dramatically impacted NET patient management. The focus of this paper is to review clinical considerations associated with implementing a 177Lu-DOTATATE program. We review receptor-based NET radiopharmaceuticals, 177Lu-DOTATATE patient selection criteria, administration methods, clinical, regulatory, and radiation safety considerations, technical factors, tissue dosimetry, and reimbursement guidelines.

Treatment Response and Clinical Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors to Lutetium-177-DOTATATE

Introduction: Lutetium-177 (¹⁷⁷Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with ¹⁷⁷Lu-DOTATATE. Materials and Methods: Patients with WD HG NETs treated with ¹⁷⁷Lu-DOTATATE at MSK from 2018 to 2020 were identified. Demographics, response (RECIST 1.1), and progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in the archival tumor. Results: Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22–56). Thirteen patients (68%) completed all four ¹⁷⁷Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7–20.9). Most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), and liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations identified. Conclusion: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with ¹⁷⁷Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.

Lutetium-177 Dotatate-Induced Hemolytic Anemia and Myelodysplastic Syndrome

Lutetium-177 (177Lu) dotatate is a type of peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin for patients with progressive somatostatin receptor-positive gastrointestinal neuroendocrine tumors. While cases of therapy-related myeloid neoplasms (t-MN) have been described as a consequence of 177 Lu dotatate, there are no reports of hemolytic anemia associated with therapy. We present a case of a 68-year-old woman with metastatic low-grade neuroendocrine tumor who presented four weeks after the second dose of 177Lu dotatate with progressive fatigue and dyspnea. Laboratory workup was remarkable for hemolytic anemia. Lutetium-177 dotatate-induced hemolysis was suspected after ruling out other causes. Corticosteroid treatment was initiated with improvement in hemoglobin, and dose-reduced PRRT was planned upon discharge. Six months into the treatment course of 177Lu dotatate, macrocytic anemia was noticed on routine follow-up with normal vitamin B12 and folic acid levels. A bone marrow biopsy was done, revealing myelodysplastic syndrome (MDS) features. Given the temporal relationship between drug introduction and the objective findings, early-onset 177Lu dotatate-induced MDS was diagnosed with a plan for close hematologic follow-up. Myelodysplastic syndrome should be suspected when megaloblastic anemia develops in patients with previous 177Lu dotatate therapy. The latency period between initial treatment and MDS diagnosis reported in the literature ranges between 15 months to seven years. Apart from the unusually early onset of MDS, what is unique about our case is the development of hemolytic anemia after administration of PRRT. The clinical course and the brisk response to steroid therapy, suggest other mechanisms of PRRT toxicity besides DNA breaks, genetic mutations, and myelosuppression by an immune-mediated component that likely plays a role in 177Lu dotatate toxicity. Further investigation and monitoring are needed to identify the frequency of such adverse events and the pathophysiology of their occurrence.

177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial

The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up. Advanced Accelerator Applications, a Novartis company.

Haematotoxicity during peptide receptor radionuclide therapy: Baseline parameters differences and effect on patient's therapy course.

BackgroundMainly severe (CTCAE grade 3–4) haematotoxicity during peptide receptor radionuclide therapy (PRRT) is reported in literature due to major clinical impact, however moderate (CTCAE grade 2) haematotoxicity is common and could affect therapy management. The aim of this study was to evaluate the haematotoxicity course during PRRT and to compare baseline parameters between haematotoxicity grades.MethodsIn this retrospective study, 100 patients with a neuroendocrine tumour treated with PRRT were included. Patients were treated with an aimed number of four cycles with 7.4 GBq [177Lu]Lu-DOTA-TATE administered every 10 weeks. Haematological assessment was performed at baseline and frequently up to 10 weeks after the fourth cycle. The lowest haematological value was graded according to CTCAE v5.0, and patients were classified using the highest observed grade. Differences in baseline parameters, including [68Ga]Ga-DOTA-TATE positive tumour volume, were evaluated between CTCAE grades.ResultsFour cycles were completed by 86/100 of patients, 4/100 patients discontinued due to haematotoxicity, and 10/100 patients due to progressive disease. The treatment course was adjusted due to haematotoxicity in 24/100 patients, including postponed next cycle (n = 17), reduced administered activity (n = 13), and both adjustments (n = 10). The most observed haematotoxicity grade was grade 0–1 in 54/100 patients, grade 2 in 38/100 and grade 3–4 in 8/100. Significant differences in baseline leucocyte, neutrophil and platelet counts were observed between grade 0–1 and grade 2. However, the correlation between baseline and lowest observed values was poor to moderate. No differences between haematotoxicity grades and baseline parameters or somatostatin receptor positive tumour volume was observed.ConclusionsThe incidence of severe haematotoxicity was low with extensive screening and monitoring. The vast majority of patients (96/100) was not restricted in treatment continuation by haematotoxicity; therefore, our selection criteria appeared appropriate for safe PRRT treatment. Baseline parameters showed limited correlation with the degree of decline in haematological values.