Clinical Trial Results:
Phase I Study of Intrathecal Radioimmunotherapy using 131I-omburtamab for Central Nervous System/Leptomeningeal Neoplasms
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Summary
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EudraCT number |
2020-001590-68 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
12 Mar 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Jun 2021
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First version publication date |
10 Jun 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
03-133
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00089245 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Y-mAbs Therapeutics Inc
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Sponsor organisation address |
230 Park Avenue, Suite 3350, New York NY, United States, 10169
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Public contact |
clinical department, Y-mAbs Therapeutics Inc, +45 70261414, info@ymabs.com
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Scientific contact |
clinical department, Y-mAbs Therapeutics Inc, +45 70261414, info@ymabs.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002101-PIP02-18 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Mar 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Jun 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Mar 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the overall survival (OS) at 3 years after the first treatment of dose 131I-omburtamab.
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Protection of trial subjects |
Thyroid protection was ensured by adequate stable iodide saturation (by use of oral potassium iodide and Cytomel). Thyroid protection was initiated one week prior to 131I-omburtamab dosimetry doses and continued until two weeks after each 131I-omburtamab treatment doses.
During the administration of omburtamab, emergency support for anaphylaxis was to be readily available, including at the bedside epinephrine, diphenhydramine, hydrocortisone and/or dexamethasone. Based upon past experience with other radiolabeled monoclonal antibody infusions, symptoms of fever, nausea, vomiting, and headache could occur in the immediate few hours post- injection. It was recommended, if any of those symptoms occured, acetaminophen, hydroxyzine, ondansetron, or Ativan could be given. Patients with myelosuppression could have received support with blood products or GCSF. In addition, if the study doctor feelt it necessary, patients could have banked stem cells reinfused.
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Background therapy |
To alleviate infusion-related AEs, all subjects received premedication, including oral dexamethasone or an intravenous equivalent starting 24 hours prior to 131I-omburtamab infusion twice daily for 6 doses. Furthermore, an anti-pyretic (e.g., oral acetaminophen/paracetamol [15 mg/kg, 650 mg max]), and an antihistamine (e.g., diphenhydramine [1 mg/kg, 50 mg max]) were administered within a few hours before all intracerebroventricular infusions and as needed after infusions. | ||
Evidence for comparator |
None | ||
Actual start date of recruitment |
05 Feb 2004
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
15 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 109
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Worldwide total number of subjects |
109
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
7
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Children (2-11 years) |
99
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Adolescents (12-17 years) |
3
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This was an open-label, non-randomized trial. 107 eligible subjects received treatment. The subjects were consecutively assigned to the currently open dose level cohort. Eligibility required that the subject met all inclusion criteria and did not violate any exclusion criterion | ||||||||||||||||
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Pre-assignment
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Screening details |
Inclusion criteria: 1. Confirmed diagnosis of a malignancy known to be omburtamab reactive. 2. CNS/ leptomeningeal disease. 3. No rapidly progressing or deteriorating neurologic examination. 4. Absolute neutrophil count (ANC) > 1000/ul and a platelet count > 50,000/ul. Exclusion criteria: Obstructive or symptomatic communicating hydrocephalus. | ||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
109 | ||||||||||||||||
Number of subjects completed |
109 | ||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Overall trial | ||||||||||||||||
Arm description |
Single-arm dose escalation part (Part 1) and a cohort expansion part (Part 2). | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
131I-omburtamab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intracerebroventricular use
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Dosage and administration details |
In Part 1, subjects received treatment doses ranging from 10 to 70 mCi administered by intracerebroventricular infusion. In Part 2, dose escalation was closed and all subjects were treated at 50 mCi with dose reductions for children less than 1 and 3 years of age
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
The median age of all SAF subjects was 4.7 years with a range of 0.9 to 15.3 years old. All dose groups were consistent with the age demographic for the neuroblastoma population. The median weight of all SAF subjects was 15.1 kg, ranging from 6.9 to 71.2 kg. The majority of the subjects in the SAF were White (78.9%). The remaining subjects were Black/African American (8.3%), Asian/ Far East/ Indian Subcontinent (2.8%), Unknown (5.5%), and Patient refused to Answer (4.6%). Most of the subjects were Not Hispanic or Latino (72.5%). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Overall trial (full analysis)
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The long-term follow-up and efficacy were primarily concerned with the subgroup of Neuroblastoma patients.
The full analysis set (FAS) included all Neuroblastoma patients enrolled in the trial who began an infusion of the treatment dose of 131I-omburtamab. The FAS included 107 neuroblastoma subjects that had CNS/LM disease. To be included in the FAS, subjects must have had to begin an infusion of the treatment dose of 131I-omburtamab. 2 subjects did not receive the treatment dose of 131I-omburtamab and were excluded from the FAS.
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Subject analysis set title |
Overall trial (safety analysis)
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The analysis of safety data was based on the safety analysis set (SAF), which included all neuroblastoma subjects enrolled in the trial who began an infusion of radiolabeled omburtamab by the enrollment cut-off date (109 subjects).
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End points reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Single-arm dose escalation part (Part 1) and a cohort expansion part (Part 2). | ||
Subject analysis set title |
Overall trial (full analysis)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The long-term follow-up and efficacy were primarily concerned with the subgroup of Neuroblastoma patients.
The full analysis set (FAS) included all Neuroblastoma patients enrolled in the trial who began an infusion of the treatment dose of 131I-omburtamab. The FAS included 107 neuroblastoma subjects that had CNS/LM disease. To be included in the FAS, subjects must have had to begin an infusion of the treatment dose of 131I-omburtamab. 2 subjects did not receive the treatment dose of 131I-omburtamab and were excluded from the FAS.
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Subject analysis set title |
Overall trial (safety analysis)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The analysis of safety data was based on the safety analysis set (SAF), which included all neuroblastoma subjects enrolled in the trial who began an infusion of radiolabeled omburtamab by the enrollment cut-off date (109 subjects).
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End point title |
Evaluate overall survival at 3 years [1] | |||||||||
End point description |
Overall survival, defined as the time from first date of diagnosis of CNS relapse to the date of death. The survival time was calculated from the date of first diagnosis of CNS relapse until the date of death
(event) or until the latest date confirmed alive (censored observation).
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End point type |
Primary
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End point timeframe |
The survival rate at 3 years including its 95% confidence interval.
Additionally, the median OS time was estimated, and 95% confidence intervals were calculated.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This is a single arm study with no comparison groups. |
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Attachments |
Summary of Survival of Subjects in the FAS |
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| No statistical analyses for this end point | ||||||||||
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End point title |
CNS/LM progression-free survival (PFS) at 12 months | |||||||||
End point description |
CNS/LM PFS time was calculated from the date of first dose of omburtamab until the date of CNS/LM progression or death (event) or until the latest date confirmed to be progression-free (censored observation).
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End point type |
Secondary
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End point timeframe |
Central nervous system/leptomeningeal (CNS/LM) progression-free survival (PFS) was estimated using similar methods as overall survival (OS) with events defined by CNS/LM progression or death.
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Attachments |
Summary of CNS/LM Progression-Free Survival |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Evaluate long term safety | |||||||||
End point description |
Full safety and efficacy information collected in neuroblastoma subjects up to the cut-off date of 30 June 2019, with an exception for long-term follow-up data (i.e., survival, 12 March 2020). Long-term follow up data were collected as available.
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End point type |
Secondary
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End point timeframe |
Long term safety was evaluated up to 15 years.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Pharmacokinetics and dosimetry after first dosimetry dose | ||||||||
End point description |
Dosimetry and PK will be summarized with descriptive statistics (n, mean, median, SD, minimum, maximum)
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End point type |
Secondary
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End point timeframe |
After first dosimetry dose
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Attachments |
Summary of pharmacokinetiscs |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the trial
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Safety Analysis set
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Reporting group description |
Summary of treatment emergent adverse events reported for subjects in the safety analysis set | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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23 Feb 2005 |
• “Hyperglycemia or myelosuppression” was added to the toxicities excluded as criteria for removal from study and as criteria not to receive the second injection
• Immunofluorescence of bone marrow was added as a method to confirm 8H9 expression |
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27 Apr 2005 |
Perchloracap was removed from the market, all references to this drug were removed |
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14 Sep 2005 |
• Added to pretreatment: HAMA testing recommended for patients with prior antibody exposure |
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25 Oct 2006 |
• Patients registered to assessment part only – no SAEs will be reported |
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22 Aug 2007 |
• Incorporation of 124I-8H9 instead of 131I-8H9 for dosimetry
• Dose escalation 60-100 mCi/injection as no DLT was seen at 10-50 mCi.
• Decrease in the cognitive function added as a long-term risk |
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10 Dec 2008 |
Language updated to note:
• Patients with non-neuroblastic tumors would be treated at the dose escalating schema and patients with Neuroblastoma would be treated with 50 mCi
• Patients could be treated either in an outpatient setting or admitted to the hospital for treatment |
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25 Feb 2009 |
• Increase the total accrual from 35 patients to 60 patients to reach the 100 mCi maximum dose and to accommodate for neuroblastoma patients, who may continue to be registered at the 50 mCi dose |
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27 Jan 2010 |
• 20 patients added to accrual to accommodate for the additional patients treated on cohorts above 60 mCi and patients with no reserved stem cells that will be treated at 50 mCi
• Patients who did not have stored stem cells available would be treated at a dose of 50 mCi
• Observation period was changed from 4 weeks to 3 weeks
• For safety reasons, doses of 70 mCi and higher were expanded to 6 patients
• Language was clarified so Grade 3 or 4 myelosuppression was not a reason to be removed from study
• Explanation of MTD and DLT was changed since cohort for doses 70 mCi and higher was changed to 6 patients |
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26 Jan 2011 |
• Treatment stopped including dosimetry dose with 124I-8H9. Protocol used 131I-8H9 for the dosimetry dose through Amendment 6, but was changed to 124I-8H9 in Amendment 7. |
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12 Oct 2011 |
• Note that only neurotoxicity would be counted as a DLT
• Clarification that patients treated at 50 mCi will not be counted for DLTs since there were already 3 patients treated on this dose level without experiencing DLT
• A new possible side effect was added: drug extravasation |
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01 Sep 2016 |
• As per IRB Policy the informed consent may be delivered by mail and the consent interview can be conducted by telephone with IRB approval |
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12 Jul 2017 |
• Addition of neurocognitive and QOL assessment measures
• Hama testing and RT-PCR testing removed
• Eligibility updated to include patients diagnosed with an Embryonal tumor do not require immunohistochemical staining of tumor
• Language updated to clarify when patients come off treatment, they will remain on study for life |
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11 Apr 2018 |
• Sponsor name changed to Y-mAbs
• 8H9 name changed to burtomab |
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08 Oct 2019 |
• Compound name was updated to 131I-omburtamab |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
