A phase IIa trial of molecular radiotherapy with 177-lutetium DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma

Gains, J.; Moroz, Veronica; Aldridge, Matthew; Wan, Simon; Wheatley, Keith; Laidler, Jennifer; Peet, Connie; Bomanji, Jamshed; Gaze, Mark

doi:10.1007/s00259-020-04741-x

Cited by 27 publications

(38 citation statements)

References 42 publications

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“…In this case, a significant extension of survival time of the [28]. Targeting SSTR2 in NB was previously demonstrated clinically using 68 Ga-, 177 Luand 90 Y-labeled DOTA-TATE [16,18,20], although a recent study failed to show a benefit of [ 177 Lu]Lu-DOTA-TATE in NB patients, possibly due to the relatively low administered dose in this study [19]. Middle row c shows a contiguous section that has been stained using immunohistochemistry to demonstrate SSTR2 expression (dark brown) counter-stained with hematoxylin (blue) and its autoradiograph (d).…”

Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 64%

“…In one example, the somatostatin analog octreotate was conjugated with the bifunctional chelator DOTA to generate DOTA-TATE and labeled with either 68 Ga (NETSPOT ® ) for the localization of neuroendocrine tumors (NETs), or 177 Lu (Lutathera ® ) for the treatment of gastroenteropancreatic (GEP) NETs [14][15][16]. A similar approach may be beneficial for the imaging and treatment of SSTR2-positive NB [17][18][19], and [ 68 Ga] Ga-DOTA-TATE for PET imaging of SSTR2-positive neuroblastoma followed by treatment with either 177 Luor 90 Y-labeled DOTA-TATE has shown promising initial results [18,20].…”

Section: Introductionmentioning

confidence: 99%

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Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Dearling

Dam²,

Harris³

et al. 2021

EJNMMI Res

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Background A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. Results PET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). Conclusions Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.

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Section: Early Treatment With [ 67 Cu]cu-sartate Improves Survival Inmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Dearling

Dam²,

Harris³

et al. 2021

EJNMMI Res

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“…publications regarding the safety of 177 Lu-DOTATATE in pediatric patients with high-risk neuroblastoma (HRNBL), another SSTR2positive tumor. [9][10][11] In an initial study, six patients with relapsed HRNBL had 68 Ga-DOTATATE avid disease. 9 These patients received up to three administrations of 177 Lu-DOTATATE at a median interval of 9 weeks and median administration of 7.3 GBq (200 mCi).…”

Section: Discussionmentioning

confidence: 99%

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children

Foster

Sher

Seghers

et al. 2021

Pediatric Blood & Cancer

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Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.

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“…The recently completed LuDO trial was also funded by Cancer Research UK [38]. This was a phase II trial of 177 Lu-DOTATATE in neuroblastoma, based on earlier pilot data [39].…”

Section: Recent and Current Clinical Trialsmentioning

confidence: 99%

“…These three trials, VERITAS [29], LuDO [38] and MINIVAN [43], are of importance in that tumour, normal organ and whole-body dosimetry are integral to them. In the two trials using 131 I-mIBG, treatment aims to achieve a desired wholebody dose: 4 Gy in VERITAS and 2 Gy in MINIVAN.…”

Section: Recent and Current Clinical Trialsmentioning

confidence: 99%

Paediatric Molecular Radiotherapy: Challenges and Opportunities

et al. 2021

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A phase IIa trial of molecular radiotherapy with 177-lutetium DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma

Cited by 27 publications

References 42 publications

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children

Paediatric Molecular Radiotherapy: Challenges and Opportunities

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