A Phase I/II Study of [124I]mIBG PET/CT in Neuroblastoma

• Sponsor: Cancer Research UK (Other)
• Overall Status: Completed
• CT.gov ID: NCT02043899
• Collaborator: (none)
• Enrollment: 36
• Locations: 2
• Arm: 1
• Actual Duration (Months): 80.4
• Patients Per Site: 18
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study aims to show that 3-dimensional PET/CT imaging with a new novel PET tracer (called [124I]mIBG) can detect as many or more sites of neuroblastoma (a type of childhood cancer) compared to the recommended 1-dimensional routine scans (called [123I]mIBG planar scintigraphy).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Neuroblastoma	Drug: [124I]meta-Iodobenzylguanidine	Phase 1/Phase 2

Detailed Description

Neuroblastoma is the most common tumour of childhood after brain tumours. Approximately half of cases are high risk and despite extensive treatments outcome is very poor. More than 60% of high risk patients suffer relapse or further spread of their disease and long-term survival is below 10%. Existing imaging techniques are not sensitive enough to accurately assess the level of risk which is critical in determining the best choice of treatment. This study will compare a new type of imaging against the existing imaging techniques. The new scans use a new tracer called [124I]mIBG which is taken up by the cancer tissue much more than by normal tissues. This tracer can be used with a 3D imaging technique called PET/CT to pinpoint where the disease has spread and quantify the amount of disease. Patients will be those scheduled to have an [123I]mIBG scan for routine care during a planned break in treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Cancer Research UK Phase I/II Study to Compare [124I]Meta-Iodobenzylguanidine (mIBG) Positron Emission Tomography/Computerised Tomography (PET/CT) to [123I]mIBG Imaging in Patients With Metastatic Neuroblastoma
• Actual Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Oct 15, 2020
• Actual Study Completion Date: Oct 15, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm Trial This was a single arm trial, all patients were to undergo the same assessments and interventions.

Drug: [124I]meta-Iodobenzylguanidine; Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.

Outcome Measures

Primary Outcome Measures

1. Comparison of the Number of Lesions Detected as Positive by [123I]mIBG Planar Scintigraphy Which Are Also Considered Positive With [124I]mIBG PET/CT. [[124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan.]

   Analysis of [124I]mIBG PET/CT and [123I]mIBG planar scintigraphy was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective.

Secondary Outcome Measures

1. Comparison of the Number of Lesions Detected as Positive by [123I]mIBG SPECT Which Are Also Considered Positive With [124I]mIBG PET/CT. [[124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan.]

   Analysis of [124I]mIBG PET/CT and [123I]mIBG SPECT/CT was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective.

2. Determining the Causality of Each Adverse Event to [124I]mIBG and Grading Severity According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.02. [Safety data was collected from the date of written informed consent and continued for seven days after administration of [124I]mIBG.]

   Documenting Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs) (Graded According to NCI-CTCAE Version 4.02) and Laboratory Parameters and Determining Their Causality in Relation to [123I]mIBG and [124I]mIBG.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically proven Stage 4 neuroblastoma as defined by the International Neuroblastoma Staging System (INSS).

2. Aged ≥ 1 year at the time that written informed consent is given.

3. Planned to undergo conventional [123I]mIBG planar scintigraphy for routine clinical care of neuroblastoma.

4. Life expectancy of at least 12 weeks.

5. World Health Organisation (WHO) performance status of 0, 1 or 2 for patients aged > 12 years old or Lansky play scale score of ≥ 50% for patients aged ≤ 12 years old.

6. Written (signed and dated) informed consent from patient ≥ 16 years old and/or parent or legal guardian for patients <16 years old and the patient be capable of co-operating with scanning requirements. (N.B. Written or verbal assent as appropriate should be sought from all patients who are under 16 years old).

Exclusion Criteria:

1. Treatment with any medications contra-indicated with mIBG scanning as listed in Appendix 4 of the trial protocol. For example, decongestants containing pseudoephedrine, phenylpropalomine and phenylephrine, sympathomimetics, cocaine, antihypertensives, tricyclic antidepressants. These drugs should be stopped before administration as indicated in this list (usually for four biological half-lives to allow almost complete wash-out but refer to list).

2. Stage 4S neuroblastoma as defined by the INSS.

3. Any anti-cancer treatment planned between the routine [123I]mIBG imaging and the [124I]mIBG PET/CT scan on Day 2. Anti-cancer treatments can be started only after the Off-Study assessment on Day 3 to Day 7, see schedule of assessments in Section 7. N.B. Patients should not be enrolled in the study if their participation will delay their subsequent treatment for neuroblastoma.

4. Female patients who are pregnant or lactating.

5. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.

6. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).

7. Patients with known hypersensitivity to mIBG.

8. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical study.

Clinical Criteria for [124I]mIBG imaging

1. One or more disease foci observed on conventional [123I]mIBG planar scintigraphy. Disease foci will initially be identified by a Nuclear Medicine physician at the investigational site.

2. ≥ 3kg at the time of the [124I]mIBG imaging to agree with the paediatric EANM guidelines.

3. Haematological and biochemical indices within the ranges below:

For patients ≤16 years old, haematological and biochemical indices within the following ranges: Haemoglobin ≥ 7.0 g/dl (N.B transfusions will be allowed); Absolute neutrophil count ≥ 0.2 x 10^{9/L (N.B. G-CSF support will be allowed); Platelet count ≥ 10 x 10}9/L (N.B. transfusions will be allowed); Serum bilirubin ≤ 2.5 x upper limit of normal (ULN); Alanine amino-transferase (ALT), aspartate amino-transferase (AST), and/ or alkaline phosphatase (ALP) ≤ 5 x ULN; and Calculated creatinine clearance using revised Schwartz formula ≥ 60 mL/min/1.73m^2.

For patients >16 years old, haematological and biochemical indices within the following ranges: Haemoglobin ≥ 8.0 g/dl (N.B transfusions will be allowed); Absolute neutrophil count ≥ 0.5 x 10^{9/L (N.B. G-CSF support will be allowed); Platelet count ≥ 50 x 10}9/L (N.B. transfusions will be allowed); Serum bilirubin ≤ 2.5 x upper limit of normal (ULN); Alanine amino-transferase (ALT), aspartate amino-transferase (AST), and/ or alkaline phosphatase (ALP) ≤ 5 x ULN; and Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73m^2.

1. Menarchal female patients must have a negative serum or urine pregnancy test before administration of [124I]mIBG Solution for Injection on Day 1 and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) to be effective from Day 1 and for 7 days afterwards.

2. Male patients with partners of child-bearing potential must agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] from Day 1 and for 7 days afterwards. Male patients with pregnant or lactating partners must agree to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University College London Hospital	London		United Kingdom	NW1 2PG
2	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Cancer Research UK

Investigators

• Principal Investigator: Sue Chua, Dr, Royal Marsden NHS Foundation Trust

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 9, 2021

More Information

Publications

None provided.

• Responsible Party: Cancer Research UK
• ClinicalTrials.gov Identifier: NCT02043899
• Other Study ID Numbers: CRUKD/12/002; 2012-002029-31
• First Posted: Jan 23, 2014
• Last Update Posted: Jun 21, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Cancer Research UK: Neuroblastoma; Positron emission tomography; 124-iodine; Meta-Iodobenzylguanidine
• Additional relevant MeSH terms: Neuroblastoma; 3-Iodobenzylguanidine

Study Results

Participant Flow

Recruitment Details	Trial participants were enrolled at two trial sites between 11 February 2014 and 10 September 2019.

Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
Period Title: Overall Study
STARTED	36
Underwent Routine [123I]mIBG Planar and SPECT/CT Imaging	32
Underwent [124I]mIBG PET/CT Imaging	9
COMPLETED	9
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
Overall Participants	36
Age (Count of Participants)
<=18 years	24 66.7%
Between 18 and 65 years	12 33.3%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	18 50%
Male	18 50%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	36 100%

Outcome Measures

1. Primary Outcome

Title	Comparison of the Number of Lesions Detected as Positive by [123I]mIBG Planar Scintigraphy Which Are Also Considered Positive With [124I]mIBG PET/CT.
Description	Analysis of [124I]mIBG PET/CT and [123I]mIBG planar scintigraphy was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective.
Time Frame	[124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan.

Outcome Measure Data

Analysis Population Description

All patients who received both [123I]mIBG and [124I]mIBG

Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
Measure Participants	9
Number of positive lesions observed using [124I]mIBG PET/CT	714
Number of positive lesions observed using [123I]mIBG planar scintigraphy	405

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Arm Trial
	Comments
	Type of Statistical Test	Other
	Comments	Exact one-sided binomial test of the null hypothesis (p≤90%) using α=0.05 on [124I]mIBG PET/CT SIOPEN consensus scores. If this was accepted and the alternative hypothesis rejected, then trial stopped early for futility. If the null hypothesis was rejected, then a one-sided binomial test of the null hypothesis (p≥97%) was performed (α=0.025). If this was accepted and the alternative hypothesis rejected then the trial stopped early for efficacy.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Overall design has 82% power and an α of 0.03. Total minimum sample size of 100 lesions was calculated based on a single stage A'hern design with p0 = 0.90 and p1 = 0.97. The overall power and α was calculated based on exact binomial probabilities.
	Method	Exact one-sided binomial test
	Comments
Other Statistical Analysis		For the primary endpoint, a sensitivity analysis was also performed on patients with <20 positive lesions on [124I]mIBG PET/CT to test if few patients with large numbers of positive lesions were affecting the results. The results of the sensitivity analysis were consistent with those of the overall analysis. Secondary efficacy analysis, separate exact one-sided binomial test of the null hypothesis (p≥97%), performed (α=0.025) performed for skeletal and soft tissue lesions.

2. Secondary Outcome

Title	Comparison of the Number of Lesions Detected as Positive by [123I]mIBG SPECT Which Are Also Considered Positive With [124I]mIBG PET/CT.
Description	Analysis of [124I]mIBG PET/CT and [123I]mIBG SPECT/CT was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective.
Time Frame	[124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan.

Outcome Measure Data

Analysis Population Description

All patients who received both [123I]mIBG and [124I]mIBG

Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
Measure Participants	9
Number of positive skeletal lesions observed using [124I]mIBG PET/CT	421
Number of positive skeletal lesions observed using [123I]mIBG SPECT/CT	249
Number of positive soft tissue lesions observed using [124I]mIBG PET/CT	132
Number of positive soft tissue lesions observed using [123I]mIBG SPECT/CT	64

3. Secondary Outcome

Title	Determining the Causality of Each Adverse Event to [124I]mIBG and Grading Severity According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.02.
Description	Documenting Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs) (Graded According to NCI-CTCAE Version 4.02) and Laboratory Parameters and Determining Their Causality in Relation to [123I]mIBG and [124I]mIBG.
Time Frame	Safety data was collected from the date of written informed consent and continued for seven days after administration of [124I]mIBG.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
Measure Participants	32
All AEs	25
Pretreatment AEs (occurring before [123I]mIBG administration)	16
Treatment Emergent AEs (occurring following [123I]mIBG administration)	9
SAEs	3
[123I]mIBG Related AEs	0
[124I]mIBG Related AEs	0

Adverse Events

Time Frame	Safety data was collected from the date of written informed consent and continued for seven days after administration of [124I]mIBG.
Arm/Group Title	Single Arm Trial
Arm/Group Description	[124I]meta-Iodobenzylguanidine: Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.
All Cause Mortality
	Single Arm Trial
	Affected / at Risk (%)	# Events
Total	0/32 (0%)
Serious Adverse Events
	Single Arm Trial
	Affected / at Risk (%)	# Events
Total	2/32 (6.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/32 (3.1%)	1
General disorders
Fever	1/32 (3.1%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Single Arm Trial
	Affected / at Risk (%)	# Events
Total	10/32 (31.3%)
Blood and lymphatic system disorders
Anemia	3/32 (9.4%)	3
Ear and labyrinth disorders
Ear Pain	1/32 (3.1%)	1
Gastrointestinal disorders
Abdominal pain	1/32 (3.1%)	1
Constipation	1/32 (3.1%)	1
Diarrhea	1/32 (3.1%)	1
Nausea	4/32 (12.5%)	4
Oral pain	1/32 (3.1%)	1
Vomiting	3/32 (9.4%)	3
General disorders
Fever	2/32 (6.3%)	2
Infections and infestations
Mucosal infection	1/32 (3.1%)	1
Upper respiratory infection	1/32 (3.1%)	1
Metabolism and nutrition disorders
Anorexia	1/32 (3.1%)	1
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	1/32 (3.1%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	1/32 (3.1%)	1

Limitations/Caveats

An exact one-sided binomial test of the null hypothesis: p ≤90% was performed using α=0.05 on the [124I]mIBG PET/CT imaging assessments with SIOPEN consensus scores.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.