# Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP

François Sevrin, Hélène Kolesnikov-Gauthier, Olivier Cougnenc, Emilie Bogart, Gudrun Schleiermacher, Frederic Courbon, Marion Gambart, Anne-laure Giraudet, Nadège Corradini, Jean-noël Badel, et al.

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## ► To cite this version:

François Sevrin, Hélène Kolesnikov-Gauthier, Olivier Cougnenc, Emilie Bogart, Gudrun Schleiermacher, et al.. Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP. Pediatric Blood and Cancer, 2023, 70 (11), pp.e30615. 10.1002/pbc.30615. hal-04888144

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DOI: 10.1002/pbc.30615

Pediatric
Blood &
Cancer

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aspho
The American Society of
Pediatric Hematology/Oncology

WILEY

RESEARCH ARTICLE

# Phase II study of ¹³¹I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP

François Sevrin<fnref n="1" />

<figure><img src="image_5.png" /></figure>

Hélène Kolesnikov-Gauthier<fnref n="2" />

Olivier Cougnenc<fnref n="3" />

Emilie Bogart<fnref n="4" />

Gudrun Schleiermacher<fnref n="5" />

<figure><img src="image_6.png" /></figure>

Frederic Courbon<fnref n="6" />

Marion Gambart<fnref n="7" />

Anne-Laure Giraudet<fnref n="8" />

Nadège Corradini<fnref n="9" />

Jean-Noël Badel<fnref n="8" />

Erwann Rault<fnref n="10" />

Aurore Oudoux<fnref n="2" />

Marie Cécile Le Deley<fnref n="4" />

Dominique Valteau-Couanet<fnref n="11" />

Anne-Sophie Defachelles<fnref n="1" />

<figure><img src="image_7.png" /></figure>

Correspondence

François Sevrin and Anne-Sophie Defachelles, Unité d'Oncologie Pédiatrique, Centre Oscar Lambret, 3 rue Frédéric Combemale - BP 307 - 59020 Lille Cedex, France.

Email: f-sevrin@o-lambret.fr and
as-defachelles@o-lambret.fr

Paper previously published as meeting abstract poster:
V325 SIOP19-1277 Phase II Study of 131I-MIBG with Five Days of Topotecan for Patients with Relapsed or Refractory Neuroblastoma (NB): Results of the French Study MIITOP. 51st congress of the International Society of Paediatric Oncology

Abstract

**Purpose:** We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of ¹³¹I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL).

**Methods:** Patients received ¹³¹I-mIBG on day 1, with intravenous topotecan daily on days 1–5. A second activity of ¹³¹I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21–25. Peripheral blood stem cells were infused on day 31.

**Results:** Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2–20). Twenty-one had very high-risk NBL

**Abbreviations:** AE, adverse event; BuMel, busulfan-melphalan; HDC, high-dose chemotherapy; mIBG, metaiodobenzylguanidine; NET, norepinephrine transporter; NBL, neuroblastoma; OR, objective response; ORR, objective response rate; OS, overall survival; PBSC, peripheral blood stem cells; PFS, progression-free survival; PR, partial response; SD, stable disease; VHR, very high risk.

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial-NoDerivs License](http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2023 The Authors. *Pediatric Blood & Cancer* published by Wiley Periodicals LLC.

<footnote n="1">¹Department of Pediatric Oncology, Oscar Lambret Center, Lille, France</footnote>

<footnote n="2">²Department of Nuclear Medicine, Oscar Lambret Center, Lille, France</footnote>

<footnote n="3">³Department of Clinical Pharmacy, Oscar Lambret Center, Lille, France</footnote>

<footnote n="4">⁴Department of Methodology and Biostatistics, Oscar Lambret Center, Lille, France</footnote>

<footnote n="5">⁵SIREDO Integrated Pediatric Oncology Center, Institut Curie, Paris, France</footnote>

<footnote n="6">⁶Service de Médecine Nucléaire, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France</footnote>

<footnote n="7">⁷Hematology and Oncology Unit, Children's Hospital, CHU Toulouse, Toulouse, France</footnote>

<footnote n="8">⁸Department of Nuclear Medicine, Léon Bérard Center, Lyon, France</footnote>

<footnote n="9">⁹Institute of Pediatric Hematology and Oncology, Léon Bérard Center, Lyon, France</footnote>

<footnote n="10">¹⁰Department of Medical Physics, Oscar Lambret Center, Lille, France</footnote>

<footnote n="11">¹¹Department of Childhood and Adolescent Oncology, Gustave-Roussy, Villejuif, France</footnote>
(SIOP), Lyon, France, October 23–26, 2019.
Published in SIOP Abstracts: Pediatr Blood
Cancer. 66:e27989.
https://doi.org/10.1002/pbc.27989

**Funding information**
French National Cancer Institute,
Grant/Award Number: PHRC-K 2006

(VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1–26). Median number of prior lines of treatment was 3 (1–7). Objective response rate was 13% (95% confidence interval [CI]: 4–31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6–32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years).

**Conclusion:** MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

KEYWORDS

¹³¹I-mIBG therapy, neuroblastoma, topotecan

1 | INTRODUCTION

Neuroblastoma (NBL), the most common extracranial solid tumor in children, derives from primitive sympathetic nervous system tissue and typically arises in the adrenal glands or in sympathetic ganglia. Nearly half of patients have metastatic disease at diagnosis and continue to be at high risk for treatment failure.¹,² Outcome of patients with relapsed or refractory high-risk NBL remains poor despite encouraging response rates recently achieved with anti-GD2-mediated chemoimmunotherapy (objective response rate [ORR] ranging from 35% to 53%).³⁻⁷ New strategies are thus needed.

Metaiodobenzylguanidine (mIBG), an analog of adrenergic neuron blockers, is selectively taken up by cells of the sympathetic nervous system and by tumors derived from them, such as NBL and pheochromocytoma, via the norepinephrine transporter (NET).⁸

When labelled with ¹²³I or ¹³¹I, mIBG is used for scintigraphic imaging of NBL. Higher activities of ¹³¹I-mIBG can be used for targeted radionuclide therapy resulting in specific irradiation of the tumor cells in both the primary tumor and metastatic lesions with relative sparing of normal tissues.⁹ ¹³¹I-mIBG has been used as a molecular nuclear therapy of metastatic NBL for three decades, usually with palliative intent.¹⁰⁻²⁰ Clinical trials conducted with high-dose ¹³¹I-mIBG used as monotherapy or in combination with other agents have demonstrated encouraging response rates in refractory or recurrent high-risk NBL, with ORR ranging from 0% to 75%.²¹ Toxicity was mainly myelosuppression, particularly thrombocytopenia.²¹,²² However, the place of ¹³¹I-mIBG in the management of NBL remains unclear.

The cause of suboptimal response has not been well characterized and is likely multifactorial.²³ Strategies to improve response to ¹³¹I-mIBG therapy have consisted of increasing the administered activity and/or number of ¹³¹I-mIBG doses,¹¹,²⁴ combining them with myeloab-

lative chemotherapy and autologous hematopoietic stem cell rescue (ASCR),²⁵ and/or adding radiation sensitizers.²⁶,²⁷

The topoisomerase-1 inhibitor, topotecan, has direct activity against NBL and acts as a radiation sensitizer. In a preclinical trial, combination of topotecan and ¹³¹I-mIBG was more effective than either treatment given alone, giving rise to greater than additive DNA damage, clonogenic cell kill, and tumor growth delay.²⁸ A group in United Kingdom evaluated the feasibility of dosimetry-based high-dose ¹³¹I-mIBG therapy with topotecan as a radiosensitizer in children with metastatic NBL.²⁹ This combination was well tolerated.

We conducted a phase II study (MIITOP) with the primary aim to evaluate the feasibility of this strategy in France and to determine its efficacy in terms of objective response (OR) in children with relapsed/refractory NBL. Secondary aims were to estimate the progression-free survival (PFS) and overall survival (OS) of the patients treated with this regimen, as well as its safety.

2 | MATERIALS AND METHODS

Eligibility criteria included very high-risk neuroblastoma (VHR-NBL) and progressive stage 4 NBL at any time. VHR-NBL were defined as stage 4 NBL at diagnosis or relapse with insufficient response after induction chemotherapy, that is, less than a partial response (PR) of metastases and more than three mIBG spots, but no progressive disease. Patients had to have mIBG uptake in the skeleton or soft tissue by ¹²³I-mIBG scan within 4 weeks of study enrollment, age between 1 and 20 years, Karnosky or Lansky performance status greater than 70%, life expectancy more than 3 months, and adequate organ function. A minimum of 3 × 10⁶ CD34⁺ peripheral blood stem cells (PBSC) per kilogram had to be available at study entry. Leukaphereses could have been performed at any time before study entry or in the study framework
<figure><img src="image_8.png" /><figcaption>**FIGURE 1** Plan of treatment of the MIITOP protocol.</figcaption></figure>

provided that there was no bone marrow involvement at the time of PBSC collection. There was no restriction on the number of prior lines of therapy received before enrollment. This protocol was approved by an independent ethics committee and the appropriate institutional review boards. Informed consent was obtained for all patients. MIITOP consisted of ¹³¹I-mIBG infusions coupled with intravenous topotecan (Figure 1).

Patients received an intravenous infusion of ¹³¹I-mIBG of 444 Mbp/kg on day 1, with a maximum activity of 11,100 Mbp/injection with intravenous topotecan over 5 days at a dose of 0.7 mg/m²/day from day 1 to 5. Prior to mIBG therapy, hydration was started on day 1 (4 hours before ¹³¹I-mIBG infusion) and was continued until 72 hours after the injection of ¹³¹I-mIBG was started. A urinary catheter was introduced for bladder protection from the start of the course to patient discharge. The treatment was administered with thyroid protection with thyroxine, neomercazole, and potassium iodide. Thyroid blockade was performed 2 days before ¹³¹I-mIBG injection and continued until 4 weeks after the last injection of ¹³¹I-mIBG. Patients remained in a radiation-protected isolation room until the dose rate irradiation measured at 1 m was less than 20 mSv/h. In vivo dosimetry, as described by Cougnenc et al., was used to calculate the second dose of ¹³¹I-mIBG to be given on day 21 to deliver a total whole-body dose of 4 Gy, with a second course of topotecan.³⁰ HSCR was performed on day 31 to support the hematological recovery.

MIITOP (NCT00960739) was opened in three French centers.

After study treatment, patients were treated at their reference centers. The choice of treatment was left to the physician's discretion, but it was specified that patients without previous busulfan-melphalan (BuMel) high-dose chemotherapy (HDC) could receive BuMel followed by a second ASCR 6 weeks after the second ¹³¹I-mIBG infusion in the

absence of disease progression. Thereafter, they could receive radiotherapy and maintenance therapy based on retinoic acid ± dinutuximab beta and interleukin 2.

Tumor assessment based on ¹²³I-mIBG scintigraphy, computed tomography (CT) scans, and bone marrow assessment was performed within 4 weeks before study entry, 6 weeks after the last ¹³¹I-mIBG infusion, and then at least at 6 and 12 months after study entry.

The primary endpoint was the OR, that is, complete response (CR), or PR, 6 weeks after the second ¹³¹I-mIBG infusion. Response was evaluated according to the International Neuroblastoma Response Criteria (INRC) recommendations.³¹ Tumor response of metastatic soft tissue and bone sites was evaluated with mIBG scoring, using the Curie score for the main analysis. Following a protocol amendment, the SIOPEN (Society For Paediatric Oncology European Neuroblastoma) score was also calculated for all the mIBG evaluations performed. Sensitivity analyses were done using the SIOPEN score.

Clinical progression that shortly led to death was considered as progression when radiological assessment was not feasible due to patient's condition.

Secondary efficacy endpoints included PFS and OS. PFS was defined as the time interval from the start of treatment to the date of tumor progression, relapse, or death from any cause. Patients alive without progression were censored at the date of last contact. OS was defined as the time interval from the start of treatment until death from any cause. Patients alive were censored at the date of last contact.

Adverse events (AE) were reported up to 6 weeks after the second ¹³¹I-mIBG infusion and graded according to NCI-CTC AE v4.0. Grade 3 or higher AE were classified as severe AE.
The trial was designed using a two-step Green-Dahlberg procedure, with the following hypotheses: $α$ = 5%, 80% power, $P0$ = 15% versus $P1$ = 35%, leading to the recruitment of 30 patients. The study was considered as a success if at least nine ORs were observed at the final analysis. Analysis was performed in the Intention-to-Treat dataset. The ORR 6 weeks after the second $^{131}$I-mIBG infusion was presented with its associated 95% binomial confidence interval. Safety was evaluated by reporting the type and the number of AE classified as related to study treatment. We tabulated the maximal grade by type of AE, classified per System Organ Class and Preferred Term of the medical dictionary MedDRA. OS and PFS curves were estimated using Kaplan-Meier method. Prognostic value of mIBG Curie and SIOPEN scores at baseline on OS and PFS were evaluated using a Cox model after having checked proportional hazard assumption. Statistical analyses were performed with Stata software version 15.

## 3 | RESULTS

### 3.1 | Patient characteristics

Thirty patients were enrolled between November 2008 and June 2015 and were evaluable for efficacy and safety. Median age at study entry was 5.5 years (range: 2–20). Twenty-one patients had VHR-NBL (13 at diagnosis and eight after relapse) and nine patients had progressive metastatic relapsed NBL (Table 1).

Median Curie score at inclusion was 6 (range: 1–26) and median SIOPEN score 7 (range: 0–55). Five patients with metastatic relapsed NBL had a Curie score less than or equal to 2 at inclusion, with progressive disease in four of them. One patient had only metastatic lymph nodes relapse.

Median of prior lines of therapy was 3 (1–7). All patients with VHR-NBL at relapse had previously received HDC, including five BuMel. Seven of the nine patients with progressive metastatic relapsed NBL had previously received BuMel. No patient had previously received anti-GD2 immunotherapy.

### 3.2 | Therapy

All but five patients (17%) received two courses of $^{131}$I-mIBG. Median injected activity of mIBG was 640 MBq/kg (range: 225–1001.7). Median total whole-body absorbed dose by patient was 3.9 Gy (range: 1.85–4.9 Gy). One patient only received a whole-body absorbed dose of 1.85 Gy, because the activity of 444 MBq/kg of $^{131}$I-mIBG could not be reached due to the maximum activity of 11,100 MBq per injection provided by French law. Five patients had only one cycle of treatment: four patients because the dose of 4 Gy was already achieved at cycle 1 and one patient because of complete resolution of mIBG uptake before cycle 2. Among the 25 patients who received two courses, interval between courses was 21 days for 21 patients (range: 14–28), with a variability of this time due to problems with production and delivery of $^{131}$I-mIBG. Twenty-nine patients (97%) had ASCR, with a median

<table><caption>TABLE 1 Patient characteristics at baseline.</caption><thead><tr><th>Characteristics (n = 30)</th><th>n</th><th></th></tr></thead><tbody><tr><td colspan="3"><strong>Patient characteristics at diagnosis</strong></td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Male</td><td>17</td><td>57%</td></tr><tr><td>Female</td><td>13</td><td>43%</td></tr><tr><td>Stage at diagnosis</td><td></td><td></td></tr><tr><td>3</td><td>3</td><td>10%</td></tr><tr><td>4</td><td>26</td><td>87%</td></tr><tr><td>4s</td><td>1</td><td>3%</td></tr><tr><td>MYCN amplification (data missing for 2 patients)</td><td>5</td><td>18%</td></tr><tr><td colspan="3"><strong>Patient and treatment features before the MIITOP protocol</strong></td></tr><tr><td>Age at study entry</td><td></td><td></td></tr><tr><td>0–5 years</td><td>15</td><td>50%</td></tr><tr><td>6–10 years</td><td>8</td><td>27%</td></tr><tr><td>&gt;10 years</td><td>7</td><td>23%</td></tr><tr><td>Disease status at study entry</td><td></td><td></td></tr><tr><td>Very high-risk neuroblastoma</td><td>21</td><td>70%</td></tr><tr><td>at diagnosis</td><td>13</td><td></td></tr><tr><td>at relapse</td><td>8</td><td></td></tr><tr><td>Relapsed neuroblastoma (progressive disease)</td><td>9</td><td>30%</td></tr><tr><td>Median time between diagnosis and study entry (range), years</td><td>2.0</td><td>(0.5–9.4)</td></tr><tr><td>Prior treatment history</td><td></td><td></td></tr><tr><td>Chemotherapy</td><td>30</td><td>100%</td></tr><tr><td>Median of prior lines (range)</td><td>3</td><td>(1–7)</td></tr><tr><td>High-dose chemotherapy</td><td>15</td><td>50%</td></tr><tr><td>Busulfan-melphalan</td><td>12</td><td></td></tr><tr><td>Melphalan</td><td>1</td><td></td></tr><tr><td>Carboplatin-etoposide-melphalan</td><td>2</td><td></td></tr><tr><td>Radiotherapy</td><td>15</td><td>50%</td></tr><tr><td>Surgery</td><td>23</td><td>77%</td></tr><tr><td>Metastases at study entry</td><td></td><td></td></tr><tr><td>Bone</td><td>27</td><td>90%</td></tr><tr><td>Soft tissue including lymph nodes</td><td>14</td><td>47%</td></tr><tr><td>Bone marrow (data missing for 6 patients)</td><td>4</td><td>17%</td></tr><tr><td>mIBG score at baseline</td><td></td><td></td></tr><tr><td>Median Curie score (range)</td><td>6</td><td>(1–26)</td></tr><tr><td>Median SIOPEN score (range)</td><td>7</td><td>(0–55)</td></tr></tbody></table>

Abbreviation: SIOPEN, Society For Paediatric Oncology European Neuroblastoma.
time of 33 days (range: 12–41) from the beginning of treatment. One patient did not have ASCR as she received only one course of ¹³¹I-mIBG (whole-body absorbed dose of 4.2 Gy after the first course of ¹³¹I-mIBG) and had no hematological toxicity.

## 3.3 | Response

In the whole population, ORR after the two courses of ¹³¹I-mIBG/topotecan was 13% (4/30, 95% confidence interval [CI]: 4%–31%) using the Curie and 17% (5/30, 95% CI: 6%–35%) using the SIOPEN score. This proportion was lower than the prespecified minimum efficacy threshold P0 = 15%. The number of OR observed was lower than the minimal number expected (≥9/30) to consider MIITOP as a success.

## 3.4 | Further treatment after MIITOP and before progression

Twenty-two patients had no progressive disease 6 weeks after the last ¹³¹I-mIBG infusion: 17 with VHR-NBL and five with progressive metastatic relapsed NBL. Among the 17 patients with VHR-NBL, one had no further therapy, three received standard chemotherapy, and 13 received HDC (11 BuMel, one thiotepa, and one haploidentical stem cell transplantation). Four of them also had local treatment (two exclusive radiotherapy, two surgery and radiotherapy), and 10 received maintenance therapy based on retinoic acid ± dinutuximab beta and interleukin 2. Among the five patients with progressive metastatic relapsed NBL, one received oral etoposide before progression, the others had no further treatment before progression.

## 3.5 | OS and PFS

Median follow-up was 124 months (range among alive patients: 28–153). According to the Curie score, median PFS was 4.9 months (95% CI: 4.1–10.6); 12-month and 24-month PFS rates were 30% (95% CI: 15%–47%) and 20% (95% CI: 8%–36%), respectively (Figure 2). Estimations were similar using the SIOPEN score. All the 25 events observed were progressions. Twenty-four deaths were observed, all from disease progression. Median OS was 18.5 months (95% CI: 10.2–32.5), 12-month and 24-month OS rates were 63% (95% CI: 44%–78%) and 40% (95% CI: 23%–57%), respectively. Neither of the two scores at baseline was significantly associated to survival.

## 3.6 | Response and PFS according to disease status

ORR using the Curie score was 19% (4/21) for patients with VHR-NBL and 0% (0/9) for patients with progressive metastatic relapsed NBL (Table 2). Table 3 presents PFS endpoints according to disease status at inclusion.

<figure><img src="image_9.png" /><figcaption>**FIGURE 2** Overall survival (OS) and progression-free survival (PFS) curves according to the Curie score.</figcaption></figure>

Among the 16 VHR-NBL patients with no prior exposure to BuMel, 13 had at least stable disease (SD) after MIITOP. Among these 13 patients: one had no further treatment before progression; one subsequently received 12 cycles of topotecan-temozolomide followed by retinoic acid and was still alive without progression after 9 years; and 11 received BuMel. BuMel was administered 6 weeks after the second ¹³¹I-mIBG infusion for 10 patients and 5 months after MIITOP for one patient. Further treatment for these 11 patients included: radiotherapy (four patients) ± retinoic acid (eight patients) or retinoic acid + dinutuximab beta (three patients). Four of them were still alive 10 years after study entry (two in ongoing remission and two in ongoing SD), seven died after progression. Among the five VHR-NBL patients with prior exposure to BuMel, four had at least SD after MIITOP. Among these four patients: one received haploidentical transplantation and was lost to follow-up 44 months after study entry; two received standard chemotherapy, and one received thiotepa-based HDC followed by maintenance therapy. Progression followed by death was observed for these three patients. All remaining VHR-NBL patients who had progressive disease 6 weeks after the second ¹³¹I-mIBG injection died of disease progression. The nine patients with progressive metastatic relapsed NBL at inclusion experienced progression after MIITOP followed by death. Four of the five patients with a Curie score less than or equal to 2 at inclusion died of disease progression, the last one was lost to follow-up 2.4 years after study treatment.

## 3.7 | Safety

The main toxicity of this treatment was hematologic (Figure 3). Grade 4 thrombocytopenia occurred in 18 patients (60%). The median time from the first injection of treatment to grade 4 thrombopenia was 24.5 days (range: 1–36), with a median duration of grade 4 thrombopenia of 13.5 days (range: 1–204). Two patients with progressive bone marrow involvement remained transfusion-dependent until death.
<table><caption>TABLE 2 Overall tumor response using the Curie score after treatment according to disease status at inclusion.</caption><thead><tr><th>Overall tumor response after treatment</th><th>VHR-NBL (n = 21)</th><th>Progressive metastatic relapsed NBL (n = 9)</th><th>Total (n = 30)</th></tr></thead><tbody><tr><td>Complete response</td><td>2</td><td>9.5%</td><td>0%</td><td>2</td><td>7%</td></tr><tr><td>Partial response</td><td>2</td><td>9.5%</td><td>0%</td><td>2</td><td>7%</td></tr><tr><td>Stable disease</td><td>13</td><td>62%</td><td>56%</td><td>18</td><td>60%</td></tr><tr><td>Progressive disease</td><td>3</td><td>14%</td><td>33%</td><td>6</td><td>20%</td></tr><tr><td>Not evaluable</td><td>1</td><td>5%</td><td>11%</td><td>2</td><td>7%</td></tr></tbody></table>

Abbreviation: VHR-NBL, very high-risk neuroblastoma.

<table><caption>TABLE 3 PFS (according to the Curie score) endpoints according to disease status at inclusion.</caption><thead><tr><th>PFS endpoints (n = 30)</th><th>VHR-NBL (n = 21)</th><th>Progressive metastatic relapsed NBL (n = 9)</th><th>VHR-NBL without previous BuMel (n = 16)</th></tr></thead><tbody><tr><td><strong>PFS according to the Curie score</strong></td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>16</td><td>9</td><td>11</td></tr><tr><td>Progression</td><td>16</td><td>9</td><td>11</td></tr><tr><td>Median in months (95% CI)</td><td>9.4 (4.1–18.0)</td><td>4.1 (1.4–8.5)</td><td>9.4 (3.7–NR)</td></tr><tr><td>12-month rate (95% CI)</td><td>38% (18–58)</td><td>11% (0.6–39)</td><td>44% (20–66)</td></tr><tr><td>24-month rate (95% CI)</td><td>29% (12–48)</td><td>0% –</td><td>38% (15–60)</td></tr><tr><td><strong>PFS according to the SIOPEN score</strong></td><td></td><td></td><td></td></tr><tr><td>Number of events</td><td>16</td><td>9</td><td>11</td></tr><tr><td>Progression</td><td>16</td><td>9</td><td>11</td></tr><tr><td>Median in months (95% CI)</td><td>9.4 (4.1–18.0)</td><td>4.1 (1.4–8.5)</td><td>9.4 (3.7–NR)</td></tr><tr><td>12-month rate (95% CI)</td><td>43% (22–62)</td><td>11% (0.6–39)</td><td>50% (25–71)</td></tr><tr><td>24-month rate (95% CI)</td><td>29% (12–48)</td><td>0% –</td><td>38% (15–60)</td></tr></tbody></table>

Abbreviations: BuMel, busulfan-melphalan; CI, confidence interval; NR, not reached; PFS, progression-free survival; SIOPEN, Society For Paediatric Oncology European Neuroblastoma; VHR-NBL, very high-risk neuroblastoma.

Grade 4 neutropenia occurred in 16 patients. The median time from the first injection of treatment to grade 4 neutropenia was 24 days (range: 9–45), with a median duration of 30 days (range: 6–40). There were no cases of failure of neutrophils recover. Febrile aplasia was reported in four patients, and was related to a documented infection in three (two septicemia, one urinary tract infection). No additional grade 3–4 non-hematologic toxicities were observed. Seven patients had nausea, and 11 developed mild vomiting within 48 hours of the $I^{131}$-mIBG infusion. One patient developed asymptomatic hypothyroidism, diagnosed by elevated thyroid-stimulating hormone level 6 weeks after the second infusion. There was no toxicity-related death.

## 4 | DISCUSSION

As patients with relapsed or refractory high-risk NBL have an extremely poor prognostic, there is a pressing need for new strategies that could potentially be incorporated into first-line regimens for these patients with high-risk disease.¹⁶,³² The use of $I^{131}$-mIBG

as a therapeutic agent began as early as 1984. Since then, multiple monotherapy pilot trials have reported ORR ranging between 0% and 66%.¹²,¹⁴,¹⁵,¹⁷–¹⁹,³³,³⁴ In 2007, Matthay et al. reported the results of the largest trial using $I^{131}$-mIBG as monotherapy for patients with progressive, refractory, or relapsed high-risk mIBG-avid NBL.¹⁰ In this phase II trial, 148 patients with cryopreserved stem cells available received 18 mCi/kg (666 MBq/kg) of $I^{131}$-mIBG, whereas additional 16 patients without available cryopreserved stem cells received 12 mCi/kg (444 MBq/kg) of $I^{131}$-mIBG. ORR in this study was 36%. As radiolabeled mIBG uptake parallels NET expression by NBL cells, a promising strategy to improve outcomes with $I^{131}$-mIBG therapy is to enhance the expression of NET by combining other agents with $I^{131}$-mIBG, increasing its uptake and therapeutic effect.²³,³⁵ Included among the ways to increase NET expression are the use of radiosensitizers such as vorinostat, irinotecan, or topotecan.²⁷,³⁶ In 2015, DuBois et al. evaluated the use of fixed doses of vincristine and irinotecan in conjunction with high doses of $I^{131}$-mIBG in patients with refractory NBL. ORR in this trial was 25%.³⁷ More recently, they reported the results of a randomized phase II trial of $I^{131}$-mIBG (18 mCi/kg)
<figure><img src="image_10.png" /><figcaption>**FIGURE 3** Maximal grade per patient and per type of adverse event (AE) related to treatment.</figcaption></figure>

versus ¹³¹I-mIBG/vincristine/irinotecan versus ¹³¹I-mIBG/vorinostat for patients with relapsed or refractory NBL.³⁸ ORR were lower with vincristine/irinotecan (17%) and higher with vorinostat (31%) compared with the results from their previous single-arm trial. However, vorinostat did not improve PFS or OS (median PFS of 6.8 months).

Gaze et al. reported the feasibility of an association of high-dose ¹³¹I-mIBG with topotecan in eight children with metastatic NBL and established that in vivo dosimetry can be used to guide the delivery of a precise total whole-body radiation-absorbed dose of 4 Gy accurately from two ¹³¹I-mIBG treatments.²⁹ There were no data of toxicity.

Based on these results, we conducted the MIITOP study to evaluate the efficacy of tandem infusions of ¹³¹I-mIBG and topotecan in 30 children with relapsed/refractory NBL. OR was achieved in four of them (13%; 95% CI: 4–31) 6 weeks after the two courses of treatment. This ORR is lower than the minimal number expected (≥9/30) to consider MIITOP as a success. This ORR is lower than those reported in previous studies with ¹³¹I-mIBG as single agent or together with radiation-sensitizing agents, while the whole-body absorbed dose by patient was quite the same (median around 4 Gy).¹⁰,²¹,²⁷,³⁹ Possible reasons for the low ORR observed in our study could include a high disease burden at the time of treatment (median pretherapy Curie score: 6) and a high proportion of patients heavily pretreated (median number of previous lines: 3; prior HDC in 50% of cases), even though none of them had received anti-GD2 immunotherapy before enrollment. Twelve-month and 24-month event-free survival (EFS) rates were 27% (95% CI: 13%–43%) and 17% (95% CI: 6%–32%), respectively. These results also confirm the poor outcome of these patients.

However, despite the small number of patients that limits data interpretation, outcome seems different according to disease status with better results for refractory patients. Indeed, ORR was 19% (4/21) for patients with VHR-NBL and 0% (0/9) for patients with progressive metastatic relapsed NBL. These data are consistent with the study of Zhou et al. who evaluated the outcome after ¹³¹I-mIBG therapy

according to disease status and also reported better outcome for refractory NBL.³⁹

Among the 16 patients with VHR-NBL who had not previously received BuMel at study entry, 13 had at least SD after MIITOP; 11 of them subsequently received BuMel (6 weeks after MIITOP for 10 patients and 5 months after MIITOP for one patient). Four of the 10 patients who received BuMel immediately after MIITOP had long-term survival. From data available, none of these 10 patients experienced severe veno-occlusive disease, supporting the feasibility of such a combination in children with NBL.⁴⁰⁻⁴²

Pasqualini et al. evaluated tandem HDC with thiotepa and BuMel in 26 VHR-NBL patients (i.e., stage 4 NBL at diagnosis or relapse, age more than 1 year at diagnosis, less than a PR of metastases, and more than 3 mIBG spots after two lines of conventional chemotherapy in patients <10 years old or no CR of metastases after one line of conventional chemotherapy in patients >10 years old).⁴³ In this study, the 3-year EFS and OS rates after the diagnosis were 37.3% (95% CI: 21.3%–56.7%) and 69.0% (95% CI: 49.7%–83.4%), respectively. In our study, patients were more heavily pretreated and PFS and OS were calculated from the date of enrollment onto MIITOP. Furthermore, the outcome of our 10 patients with VHR-NBL who received BuMel 6 weeks after MIITOP was quite similar to those reported by Pasqualini et al., as four of them had long-term survivals.

Hematologic toxicity was the major toxicity of our study, abrogated by ASCR. Despite myelosuppression, the incidence of grade 3–4 proven infection was low. Patients were only hospitalized twice 8 days for the tandem infusions of ¹³¹I-mIBG and topotecan and were not systematically hospitalized for ASCR, which was done in a day hospital. Finally, four patients (13%) were hospitalized for febrile neutropenia. There was no toxic death and no other acute nonhematologic grade 3/4 toxicity. Furthermore, although our analysis was limited by the small number of patients and their poor outcome, no late toxicity was noticed apart from one patient with asymptomatic hypothyroidism.

It should also be underlined that MIITOP was opened in only three French centers, patients had thus to be referred to one of these centers for study treatment. Therefore, although our study was not strictly speaking monocentric, it took a period of 7 years to enroll all 30 patients. Furthermore, some patients were only referred after numerous lines of chemotherapy. These data underline that access to ¹³¹I-mIBG remains difficult and the need for this therapy to show its effectiveness.

In conclusion, although the efficacy of the combination of ¹³¹I-mIBG and topotecan in VHR-NBL and progressive metastatic relapsed NBL was lower than expected, this therapy was feasible in terms of toxicity. It showed interesting results in patients with VHR-NBL, with four long-term survivals among the 10 patients who received BuMel immediately after MIITOP. The combination of ¹³¹I-mIBG and topotecan is thereby evaluated in the current SIOPEN VHR-NBL protocol VERTAS (NCT03165292). In this trial, patients with first-line refractory metastatic NBL are randomized to receive either tandem HDC comprising thiotepa and BuMel courses, or ¹³¹I-mIBG and BuMel, followed by ASCR.
## ACKNOWLEDGMENTS

We are indebted to: all the patients and their families for their participation in the study; the staff members involved in the trial management and data analysis: Andrew Kramar, Clémence Léguillette, Yvette Vendel, Stéphanie Vasseur, Alicia Probst, Alison Le Bovic, Sophie Marvel, Natacha Merle, Marjane Belmimoun, and Marie Vanseymortier; the data managers from the Northwest Data Center (CTD-CNO), supported by grants from the French National League Against Cancer (LNC) and the French National Cancer Institute (INCA); the French National Cancer Institute (INCA) for the financial support (PHRC-K 2006, grant number: 19-22); and all investigators and their teams who participated in the trial.

## CONFLICT OF INTEREST STATEMENT

We did not receive external funding for this manuscript. We have no financial relationship relevant to this article to disclose. We have no conflicts of interest relevant to this article to disclose.

## DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

## ORCID

François Sevrin https://orcid.org/0009-0005-8824-2729

Gudrun Schleiermacher https://orcid.org/0000-0002-0133-5879

Anne-Sophie Defachelles https://orcid.org/0000-0002-4277-9871

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**How to cite this article:** Sevrin F, Kolesnikov-Gauthier H, Cougnenc O, et al. Phase II study of ¹³¹I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP. *Pediatr Blood Cancer*. 2023;70:e30615.

https://doi.org/10.1002/pbc.30615